Fecal Microbiota Transplant in Patients With Recurrent Clostridium Difficile Infection.

BACKGROUND: The clinical effectiveness of fecal microbiota transplant (FMT) for the treatment of recurrent Clostridium difficile infections (rCDI) has been demonstrated in randomized controlled trials. To assess the current status of FMT in Germany with respect to active centers, local standards, clinical effectiveness and safety, the MicroTrans Registry (NCT02681068) was established. METHODS: In a long-term retrospective multicenter observational study by the German Clinical Microbiome Study Group (GCMSG), primary and secondary cure on day 30 and 90, as well as occurrence of treatment-related adverse events were assessed. In addition to patient demographic data, we provide an overview of the FMT procedures and techniques used at different centers. RESULTS: Overall, 133 eligible patients from 33 centers were included, of which 64.7% were female (n = 86). The mean age was 75 years (interquartile range: 59.5-81.5). Administration via the duodenal route (n = 59; 44.4%) was the most frequently applied option, followed by colonic (n = 55; 41.1%), capsule (n = 13; 9.8%), and gastric administration (n = 4; 3.0%). Primary cure on day 30 and 90 was achieved in 84.2% (n = 101/120) and 78.3% (n = 72/92) of patients, respectively. Including re-treatment, secondary response was achieved in 87.5% (d 30; n = 105/120) and 85.9% (d 90; n = 79/92), respectively. Treatment- elated adverse events were documented in 16 patients (12.0%). CONCLUSION: FMT is a safe and effective treatment option for rCDI. However, FMT is currently available only in few centers in Germany, and treatment options vary from one center to another.

Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota.

Reduced anticancer efficacy of cyclophosphamide and platinum salts has been reported in animals treated with anti-Gram-positive antibiotics. These effects were related to translocation of Gram-positive bacteria during mucositis with subsequent induction of cytotoxic oxygen reactive species and tumor invasion by pathogenic Th17 cells. To assess these hypotheses in a clinical setting, we identified patients receiving cyclophosphamide for chronic lymphocytic leukemia (CLL) and cisplatin for relapsed lymphoma. Data originated from the CLL8 trial (NCT00281918) and the Cologne Cohort of Neutropenic Patients (NCT01821456). Relevant antibiotics were defined as compounds with primary activity against Gram-positive bacteria. We evaluated their impact on response, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier methodology and Cox proportional hazards regression analysis. Among 800 available CLL patients, those receiving anti-Gram-positive antibiotics (n = 45/800) achieved a significantly lower overall response rate (OR 74.3% vs. 90.2%, p = 0.007). Patients with anti-Gram-positive antibiotics progressed significantly earlier, had a reduced OS (median PFS 14.1 vs. 44.1 mo, p < 0.001; median OS 56.1 vs. 91.7 mo, p < 0.001) and multivariate analysis showed that administration of anti-Gram-positive antibiotic treatment was independently associated with reduced PFS (Hazard ratio (HR) 2.090, p = 0.001) and OS (HR 2.966, p < 0.001). Of 122 patients with relapsed lymphoma, those treated with anti-Gram-positive antibiotics (n = 21/122) achieved a significantly lower OR rate (70.3% vs. 42.9%, p = 0.016). Patients with anti-Gram-positive antibiotics progressed significantly earlier than others (median PFS 2.3 vs. 11.5 mo, p = 0.001). As for multivariate analysis, the use of anti-Gram-positive antibiotics was independently associated with reduced PFS (HR 2.237, p = 0.012) and OS (HR 7.831, p < 0.001). Our data supports a potential negative impact of anti-Gram-positive antibiotics on the anticancer activity of cyclophosphamide and cisplatin in a clinical setting.

Bone and joint infections by Mucorales, Scedosporium, Fusarium and even rarer fungi.

Mucorales, Scedosporium and Fusarium species are rarely considered as cause for bone and joint infections. However, these moulds are emerging as important fungal pathogens in immunocompromised and immunocompetent patients. Typical pre-disposing host conditions are immunosuppression and diabetes. Most common causative pathogens are Mucorales followed by Scedosporium and Fusarium. Acremonium and Phialemonium species are rare but some case reports exist. MRI is the gold standard imaging technique. Tissue specimens obtained as aspirates, imaging guided biopsy or open surgery need mycological and histopathological work-up for genus and species identification. Multimodal treatment strategies combine surgical debridement, drainage of joints or abscesses, removal of infected prosthetic joints and systemic antifungals. The treatment of mucormycosis is polyene based and may be combined with either posaconazole or - in rare cases - caspofungin. As Scedosporium species are intrinsically resistant to polyenes and azoles show absence of in vitro activity, voriconazole plus synergistic treatment regimens become the therapeutic standard. In fusariosis, fungal susceptibility is virtually impossible to predict, so that combination treatment of voriconazole and lipid-based amphotericin B should be the first-line strategy while susceptibility results are pending. In the absence of randomized controlled trials, infections due to the above moulds should be registered, e.g. in the registries of the European Confederation of Medical Mycology (ECMM).

Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology.

Invasive fungal infections cause substantial morbidity and mortality in immunocompromised patients, particularly in those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. Difficulties in diagnosing invasive fungal infections and subsequent delays in treatment initiation lead to unfavourable outcomes and emphasise the importance of prophylaxis. Since the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology in 2009, results of 14 additional clinical studies have been published comprising 2,899 patients and initiating this update. Key recommendations for adult patients are as follows: Posaconazole remains the drug of choice during remission-induction chemotherapy in acute myeloid leukaemia, myelodysplastic syndrome and allogeneic haematopoietic stem cell transplantation with graft versus host disease (AI). In the pre-engraftment period of allogeneic transplantation, several antifungals are appropriate and can be recommended with equal strength: voriconazole (BI), micafungin (BI), fluconazole (BI) and posaconazole (BII). There is poor evidence regarding antifungal prophylaxis in the post-engraftment period of allogeneic haematopoietic stem cell transplantation if no steroids for treatment of graft versus host disease are required. Aerosolised liposomal amphotericin B inhalation in conjunction with fluconazole can be used in patients with prolonged neutropenia (BII).

Our 2014 approach to candidaemia.

Candidaemia remains a relevant challenge in everyday patient care on intensive care units and general wards. Delays to adequate treatment increase mortality rates and institutional standard operating procedures facilitate optimal treatment. A positive blood culture requires immediate treatment. Echinocandins are the first-line drugs of choice. Indwelling catheters have to be removed if feasible. Daily blood cultures until persistently negative exclude ongoing fungaemia. In case of Candida parapsilosis antifungal therapy should be switched to intravenous fluconazole. After 10 days of intravenous either echinocandin or fluconazole treatment, step-down to oral application of fluconazole simplifies antifungal therapy. Depending on organ involvement and clinical presentation of the patient antifungal treatment should be continued for at least 14 days after the last positive blood culture. We present our institutional management algorithm for candidaemia which is based on current guidelines and recommendations to improve patient outcome.

Our 2014 approach to mucormycosis.

Mucormycosis, previously termed as zygomycosis, is caused by fungi belonging to the order Mucorales and is a very severe disease in immunocompromised patients with an often unfavourable outcome. Given the high morbidity and mortality of mucormycosis, establishing a timely diagnosis followed by immediate treatment is of major importance. As randomised clinical trials are lacking, we present our current diagnostic and treatment pathways for mucormycosis in the immunocompromised host. Due to the difficulty to distinguish mucormycosis from other filamentous fungi, mucormycosis always has to be considered as differential diagnosis in predisposed patients. Diagnostic procedures comprise imaging, microscopy, culture and histopathology and need to be rigorously used. In patients with a high suspicion of mucormycosis, e.g. reversed halo sign on computed tomography scanning, our approach combines liposomal amphotericin B (LAmB) with surgical debridement. In light of the rapid deterioration and poor prognosis of these patients, we prefer a daily dose of LAmB of at least 5 mg kg(-1) despite nephrotoxicity. In patients with stable disease we switch to posaconazole 200 mg four times per day. In case of progression antifungal combination is an option.

Clostridium difficile infection in patients with acute myelogenous leukemia and in patients undergoing allogeneic stem cell transplantation: epidemiology and risk factor analysis.

Patients receiving treatment for acute myelogenous leukemia (AML) and recipients of allogeneic stem cell transplantation (aSCT) are at high risk of contracting Clostridium difficile infection (CDI), the most frequently observed nosocomial diarrhea and enterocolitis. Data were retrieved from the prospective Cologne Cohort of Neutropenic Patients. Patients hospitalized for aSCT as well as patients receiving treatment for AML were included in the analysis. Risk factor analysis for the occurrence of CDI was performed by backward-stepwise logistic regression (P < .1). During the period from January 2007 to August 2010, 310 hospitalizations of 152 patients with AML and 229 hospitalizations of 223 patients undergoing aSCT were eligible for analysis. Incidence rates for CDI per 10,000 patient days were 17.9 for AML patients and 27.4 for aSCT recipients. Among AML and aSCT patients, median time from initiation of chemotherapy to CDI was 10 days (range, -8 to 101 days) and 17 days (range, 6 to 79), respectively. Logistic regression identified carbapenem exposure to be associated with development of CDI in AML patients (odds ratio [OR], 2.2) and aSCT recipients (OR, 1.4). In both groups, previous exposure to carbapenems was significantly associated with development of CDI. A follow-up study, assessing the effect of an antibiotic stewardship intervention to decrease the administration of carbapenems in hematological high-risk patients, is warranted.

Aspergillosis of bones and joints - a review from 2002 until today.

Poor clinical outcome and complicated neurological complications illustrate the severity of bone and joint infections with Aspergillus species. Host predisposing conditions are immunosuppression, intravenous drug use, a variety of chronic underlying diseases and prior surgical interventions. Nosocomial infections may originate from contaminated air ventilation systems or water pipes. Most common causative pathogen is Aspergillus fumigatus, followed by Aspergillus flavus and Aspergillus nidulans. A. niger, A. tubingensis and A. terreus are rare but stress the need of targeted and adapted antimycotic therapy. Diagnosis has to be pursued by means of MRI imaging techniques and tissue specimens. Multimodal treatment strategy is based on a combination of surgical debridement of necrotic bone and cartilage and systemically active antifungal treatment. Voriconazole combines satisfactory systemic antifungal effect, high oral bioavailability and good bone penetration. Development of fungicidal cement spacers still continues and in vitro data show promising results of bioactive cements. Purpose of this review of literature published between 2002 and 2013 was to provide up-to-date information on pathogenesis, diagnostic approach and treatment recommendations. Properly established treatment guidelines and prophylaxis for patients at risk are required as the high mortality rate continues to pose a future challenge.

Fungal endocarditis.

PURPOSE OF REVIEW: Fungal endocarditis remains a rare disease occurring mostly in patients with predisposing host conditions. Regarding its poor prognosis because of severe complications, there is an urgent need for properly established treatment guidelines and prophylaxis for patients at risk. In this review we provide up-to-date information on treatment recommendations, and discuss recent case reports on fungal endocarditis and challenges in prophylaxis and treatment. RECENT FINDINGS: Over the last year, an increase in cases caused by non-albicans species of Candida and other fungi like Fusarium solani, Lodderomyces elongisporus and Exophiala dermatitidis was reported. They were treated individually in case-by-case approaches, lacking randomized controlled trials and, mostly, treatment recommendations. SUMMARY: The scarcity of fungal endocarditis demands a high index of suspicion and knowledge of the group of at-risk patients. Diagnosis aggressively pursued by echocardiography and multiple blood cultures or surgical specimens has the potential to improve outcome. Candida endocarditis should be treated immediately, including surgical treatment in combination with liposomal amphotericin B or caspofungin with optional addition of flucytosine. Aspergillus endocarditis requires rapid surgery and voriconazole.

Correlation of EPS content in activated sludge at different sludge retention times with membrane fouling phenomena.

In this study, activated sludge characteristics were studied with regard to membrane fouling in membrane bioreactors (MBRs) for two pilot plants and one full-scale plant treating municipal wastewater. For the full-scale MBR, concentrations of extracellular polymeric substances (EPS) bound to sludge flocs were shown to have seasonal variations from as low as 17mgg(-1) dry matter (DM) in summer up to 51mg(gDM)(-1) in winter, which correlated with an increased occurrence of filamentous bacteria in the colder season. Therefore, it was investigated at pilot-scale MBRs with different sludge retention times (SRTs) whether different EPS contents and corresponding sludge properties influence membrane fouling. Activated sludge from the pilot MBR with low SRT (23d) was found to have worse filterability, settleability and dewaterability. Photometric analysis of EPS extracts as well as LC-OCD measurements showed that it contained significantly higher concentrations of floc-bound EPS than sludge at higher SRT (40d) The formation of fouling layers on the membranes, characterised by SEM-EDX as well as photometric analysis of EPS extracts, was more distinct at lower SRT where concentrations of deposited EPS were 40-fold higher for proteins and 5-fold higher for carbohydrates compared with the membrane at higher SRT. Floc-bound EPS and metals were suggested to play a role in the fouling process at the full-scale MBR and this was confirmed by the pilot-scale study. However, despite the different sludge properties, the permeability of membranes was found to be similar.