Probing sedimentation non-ideality of particulate systems using analytical centrifugation.

Analytical centrifugation is a versatile technique for the quantitative characterization of colloidal systems including colloidal stability. The recent developments in data acquisition and evaluation allow the accurate determination of particle size, shape anisotropy and particle density. High precision analytical centrifugation is in particular suited for the study of particle interactions and concentration-dependent sedimentation coefficients. We present a holistic approach for the quantitative determination of sedimentation non-ideality via analytical centrifugation for polydisperse, plain and amino-functionalized silica particles spanning over one order of magnitude in particle size between 100 nm and 1200 nm. These systems typically behave as neutral hard spheres as predicted by auxiliary lattice Boltzmann simulations. The extent of electrostatic interactions and their impact on sedimentation non-ideality can be quantified by the repulsion range, which is the ratio of the Debye length and the average interparticle distance. Experimental access to the repulsion range is provided through conductivity measurements. With the experimental repulsion range at hand, we estimate the effect of polydispersity on concentration-dependent sedimentation properties through a combination of lattice Boltzmann and Brownian dynamics simulations. Finally, we determine the concentration-dependent sedimentation properties of charge-stabilized, fluorescently-labeled silica particles with a nominal particle size of 30 nm and reduced interparticle distance, hence an elevated repulsion range. Overall, our results demonstrate how the influence of hard-sphere type and electrostatic interactions can be quantified when probing sedimentation non-ideality of particulate systems using analytical centrifugation even for systems exhibiting moderate sample heterogeneity and complex interactions.

[Chronic chikungunya arthritis]. / Chronische Chikungunya-Arthritis.

This article describes the case of a 48-year-old female traveller returning from Bangladesh who presented with persisting pain and joint swelling due to chikungunya virus infection, which had persisted for months. Typical symptoms are a high fever and musculoskeletal disorders, which can last for months up to years. The chronic inflammatory form is treated similarly to those recommended for other chronic inflammatory joint diseases. Due to the increasing prevalence of the virus and its vectors as well as the unbroken travel activity, an increase in imported cases in Europe and establishment of the pathogen in southern Europe are to be expected.

[Antibiotic stewardship (ABS). Part 1: Basics]. / Antibiotic Stewardship (ABS). Teil 1: Grundlagen.

Against the background of increasing antimicrobial resistance, antibiotic stewardship (ABS) is an important measure to counteract the spread of resistant pathogens and multidrug resistance. For Germany and Austria, a comprehensive S3 guideline is available, which was last updated in 2018. The control of antibiotic or anti-infective use in hospitals should be guided by specialized ABS teams. At the hospital level, ABS also includes a structured ongoing analysis of local antibiotic use and resistance data. Recommendations for locally adapted therapy regimens should be derived and implemented from this data analysis. ABS consists of regular ward rounds ("ABS visits"), during which members of the ABS team review the indication, dosage, route of administration and duration of antimicrobial therapy at the bedside. Here, the key challenge is to save antibiotics without compromising the individual patient. Digitalization and artificial intelligence offer new options for ABS, while the adaption of inpatient concepts to outpatient care is also important.

[Antibiotic stewardship (ABS). Part 2: Application]. / Antibiotic Stewardship (ABS). Teil 2: Anwendung.

Antibiotic stewardship (ABS) is an important measure to counteract the spread of resistant pathogens and multidrug resistance. The most important ABS tools include the implementation of local guidelines, the development of a house-related list of anti-infective agents, regular ABS visits and practice-oriented internal training events. Effective strategies for therapy optimization include indication testing and therapy evaluation, dose optimization as well as determining an appropriate duration of therapy. Oralization of anti-infectives (sequence therapy) should be supported by consistent clinical criteria in in-house guidelines. The incidence of Clostridioides difficile infections (CDI) can be more than halved by restricting the so-called "4C antibiotics". Point-of-care tests help to minimize the use of antibiotics in the outpatient setting. Vaccination reduces the need for antibiotic therapy.

[Treatment of acute and recurrent Clostridium difficile infections : What is new?] / Therapie akuter und rekurrenter Clostridium-difficile-Infektionen : Was gibt es Neues?

The incidence of clostridium difficile infections (CDI) remains on a high level globally. In Germany, the number of severe or even lethal cases continues to increase. The main risk factor for the development of CDI is exposure to broad spectrum antibiotics, which disturb the physiological microbiome and therefore enable colonization with C. difficile. According to the updated US and European guidelines, orally administered vancomycin is the treatment of choice. Fidaxomicin is as effective as vancomycin but has the advantage of a lower rate of recurrence. Furthermore, recent clinical studies were able to demonstrate that significantly fewer recurrences occurred in patients who additionally received the monoclonal antibody bezlotoxumab. In recent years, several new antibiotics with narrow-spectrum acitivity and low intestinal resorption have been developed for the treatment of CDI, including surotomycin, cadazolid, and ridinilazol. Novel toxoid vaccines are expected to become an efficacious tool in the prevention of CDI; however, pivotal clinical trials have so far not been completed.

[Gastrointestinal infections]. / Gastrointestinale Infektionen.

Infectious diarrhea is one of the most common diseases. This article summarizes the current state of the diagnostics and treatment and includes the most important pathogens, i.e. Norovirus, Rotavirus, Campylobacter, Salmonella, Shigella and pathogenic Escherichia coli. Infections caused by toxin-producing strains of Clostridium difficile are described in more detail due to the increasing importance. Symptomatic therapy is still the most important component of treatment. Empirical antibiotic therapy is reserved for severely ill patients with a high stool frequency, fever, bloody diarrhea, underlying immune deficiency or significant comorbidities. Increasing bacterial resistance (in particular against fluoroquinolones) has to be considered. Motility inhibitors are not recommended for infections due to Shiga toxin-producing E. coli, C. difficile infections (CDI) and severe enterocolitis caused by other pathogens. The macrocyclic antibiotic fidaxomicin can reduce the recurrence rate of CDI. Fecal microbiota transplantation (FMT) currently provides a reserve treatment option for multiple recurrences of CDI and is subject to the Medicines Act (Arzneimittelgesetz, AMG) in Germany.

[Fecal microbiota transplantation]. / Fäkaler Mikrobiomtransfer.

The human intestinal microbiome has important metabolic and immunological functions for the host and is part of the defense against pathogens in the gastrointestinal tract. Antibiotics, probiotics, dietary measures, such as prebiotics, and the relatively newly established method of fecal microbiota transplantation (FMT, also known as fecal microbiome transfer) all influence the intestinal microbiome. The FMT procedure comprises the transmission of fecal microorganisms from a healthy donor into the gastrointestinal tract of a patient. The aim of this intervention is to restore a normal microbiome in patients with diseases associated with dysbiosis. The only indication for FMT is currently multiple recurrence of Clostridium difficile infections. Approximately 85% of affected patients can be successfully treated by FMT compared to only about 30% treated conventionally with vancomycin. Other possible therapeutic applications are chronic inflammatory and functional bowel diseases, insulin resistance and morbid obesity but these have to be evaluated further in clinical trials. Knowledge on the optimal donor, the best dosage and the most appropriate route of administration is still limited. A careful donor selection is necessary. The implementation of FMT in Germany is subject to the Medicines Act (Arzneimittelgesetz, AMG) with a duty of disclosure and personal implementation by the attending physician. By documentation in a central register long-term effects and side effects of FMT have to be evaluated.

[Clinical impact of infections with carbapenem-resistant enterobacteriaceae in liver transplant recipients]. / Klinische Bedeutung von Infektionen durch Carbapenem-resistente Enterobakterien bei Lebertransplantierten.

Infections with carbapenem-resistant Enterobacteriaceae (CRE) are an emerging cause of morbidity and mortality among liver transplant recipients (LTR) worldwide, particularly Klebsiella pneumoniae carbapenemase (KPC)-producing organisms. Approximately 3 - 13 % of solid organ transplant recipients in CRE-endemic areas develop CRE infections, and the infection site correlates with the transplanted organ. The cumulative 30-day mortality rate of LTR infected with carbapenem-resistant K. pneumoniae is 36 %, and the 180-day mortality rate is 58 %. Awareness of the high vulnerability of LTR to fatal bacterial infection leads to the more frequent use of ultrabroad-spectrum empirical antibiotic therapy, which further contributes to the selection of extreme drug resistance. Moreover, it comprises a relevant risk of failure to initiate adequate empirical treatment due to the fact that culture-based techniques used to identify CRE imply a 48- to 72-hour delay from blood culture collection until administration of the targeted therapy. This vicious circle is difficult to avoid and leads to increased clinical intricacy and narrowed antimicrobial therapeutic options. Because available options are extremely limited, infection prevention measures have gained outstanding importance, particularly in the phase after liver transplant requiring intense immunosuppression early on. Improving clinical outcomes is a major challenge and involves a multi-targeted approach combining strictly applied hygiene measures, active surveillance tests, the use of modern, time-saving methods of molecular biology, and enforced antibiotic stewardship. This article reviews the current literature regarding the incidence and outcome of CRE infections in LTR, and it summarises current preventive and therapeutic recommendations to minimise the threat by CRE in real-life clinical transplant settings.

Colonization of liver transplant recipients with KPC-producing Klebsiella pneumoniae is associated with high infection rates and excess mortality: a case-control analysis.

PURPOSE: From mid-2010 to early 2013 there was a large single-center (Leipzig University Hospital, Germany) outbreak of Klebsiella pneumoniae carbapenemase (KPC) type 2 producing K. pneumoniae (KPC-2-KP) involving a total of 103 patients. The aim of this study was to compare KPC-positive liver transplant recipients (LTR) and KPC-negative controls to determine both the relative risk of infection following colonization with KPC-2-KP and the case fatality rate associated with KPC-2-KP. METHODS: The study cohort of this retrospective observational study comprised nine patients who had undergone orthotopic liver transplantation (LTx) (median age of 52 years, range 28-73 years) with confirmed evidence of colonization with KPC-2-KP. The data from these nine LTR were matched to 18 LTR (1:2) in whom carbapenem-resistant pathogens were not present and compared for clinical outcomes. RESULTS: Of these nine cases, eight (89 %) progressed to infection due to KPC-2-KP, and five (56 %) were confirmed to have bloodstream infection with KPC-2-KP. Matched-pair analysis of KPC-positive LTR and KPC-negative controls revealed a substantially increased relative risk of 7.0 (95 % confidence interval 1.8-27.1) for fatal infection with KPC-2-producing K. pneumoniae after transplantation with a mortality rate of 78 % (vs. 11 %, p = 0.001). CONCLUSIONS: Colonization with KPC-2-KP in LTR leads to high infection rates and excess mortality. Therefore, frequent screening for carbapenem-resistant bacteria in patients on LTx waiting lists appears to be mandatory in an outbreak setting. Patients with evidence of persistent colonization with KPC-producing pathogens should be evaluated with extreme caution for LTx.

Invasive cardiac aspergillosis after orthotopic liver transplantation.

Invasive aspergillus infection occurs in 5 - 42 % of liver-transplanted recipients and is a dangerous complication, associated with high mortality if untreated. However, the early diagnosis of invasive aspergillosis can be elusive, as clinical signs are unspecific and the pathogenic agent is difficult to demonstrate. We here report about a 58-year-old man with acute liver failure caused by newly diagnosed chronic hepatitis B infection who underwent liver transplantation. The postoperative course was uneventful, and the patient was discharged after 30 days. After 105 days the patient was readmitted because of fever, recurrent chest and abdominal pain. Computed tomography revealed a cardiac lesion; other diagnostic steps including bone-marrow and endomycordial biopsy, virological and microbiological investigations gave no clear findings. To exclude a malignant process, thoracotomy with mass and simultaneous lower left lobe resection were performed. Histopathological findings revealed an invasive perimyocardial aspergillosis. Immediate intravenous therapy with voriconazole and caspofungin was initiated and monitoring of the mass was performed with transesophageal echocardiography and Cardio-MRI. Due to slightly increase of the lesion, medication was switched to posaconazole and caspofungin. Under this dual fungal treatment the lesion regressed and the patient could be discharged after two months in good clinical condition. Frequent Cardio-MRI scan after discharge showed further mass-regression. Therefore antifungal treatment was switched to oral posaconazole mono-therapy. After one year, complete reduction of the mass was achieved and antifungal therapy was discontinued. Recent diagnostic imaging follow-up showed no pathological finding.

[Clostridium difficile infection (CDI) in the course of time - an issue only for the internist?]. / Clostridium-difficile-Infektionen (CDI) im Wandel der Zeit - ein Thema nur für den Internisten?

BACKGROUND: Toxigenic strains of Clostridium (C.) difficile are the most prevalent pathogens of antibiotic associated intestinal disease and nosocomial diarrhoea. During the last 10 years, incidences of C. difficile infection (CDI) have increased worldwide. MATERIALS AND METHODS: With clinical and microbiological original data for 2002-2012 from the University Hospitals Leipzig and Halle (Saale), Germany, the authors illustrate the current situation regarding CDI in the states of Saxony and Saxony-Anhalt and exemplify the latest developments in terms of incidence, prevalence of resistance, diagnosis and treatment strategies regarding CDI with an emphasis on surgical options. RESULTS: Following the general trend, at the University Hospitals of Leipzig and Halle (Saale) there was also an increase in incidence of CDI, especially of severe clinical courses. In primary and secondary care facilities, prevention of CDI is based on hygiene management and restricted usage of antibiotics, preferably as "Antibiotic Stewardship" programmes. In 2012, the new macrocyclic antibiotic Fidaxomicin was approved in the European Union for the treatment of CDI. The therapeutic armamentarium, previously based on metronidazole or vancomycin, has now been enriched by a substance that presumably will reduce the rate of recurrence of CDI. Moreover, early data from case series and controlled trials suggest that the re-establishment of eubiosis in the colon of patients with recurrent CDI by stool transplantation from healthy donors is an alternative to antibiotics. Standard surgical intervention for refractory CDI is subtotal colectomy with terminal ileostomy. In patients with adequate life expectancy and without organ dysfunction, a colon-saving surgical technique should be considered. CONCLUSION: Taking antibiotics for most remains the main risk factor for suffering from symptomatic CDI. With the introduction of Fidaxomicin there is hope for an improvement in the conservative treatment of CDI. Stool transplants from healthy donors are now considered to be better than giving antibiotics for severe CDI, but this treatment has not found broad acceptance yet. In cases with a lack of early treatment success, the surgeon must be consulted. Here, the evidence for preferably colon-saving surgical procedures is so far unfortunately low.

[Pitfalls in Diagnosis and Therapy for CMV Colitis in a 30-Year-Old HIV-Positive Patient]. / Tücken der Diagnosestellung und Therapie einer CMV-Kolitis bei einem 30-jährigen HIV-positiven Patienten.

We report on a 30-year-old patient who presented with bloody diarrhoea. After initially, assuming a previously not diagnosed ulcerative colitis, an immunosuppressive therapy was initiated, a week later an HIV infection stage C2 according to the CDC classification, complicated by CMV viraemia, was diagnosed. In this case report the course of treatment with highly active antiretroviral therapy (HAART), ganciclovir and prednisolone is reported and discussed on the basis of histological, immunohistochemical and microbiological findings. The case illustrates the difficulty to distinguish between ulcerative colitis, immune reconstitution syndrome, CMV colitis and HIV-associated diarrhoea.

[Immunosuppressive treatment as a risk factor for the occurrence of clostridium difficile infection (CDI)]. / Immunsuppressive Behandlung als Risikofaktor für das Auftreten einer Clostridium-difficile-Infektion (CDI).

BACKGROUND: Toxigenic Clostridium difficile strains are known as the most common infectious cause of antibiotic-associated intestinal disease and nosocomial diarrhoea. The increased incidence of hypervirulent strains gives rise to worldwide concern. In particular, courses with multiple recurrences are observed in the presence of immunosuppression. METHODS: In this retrospective controlled observational study we aimed to determine immunosuppression as an independent risk factor for symptomatic CDI and to identify characteristics and differences of immunocompromised patients with respect to disease severity, disease progression, intestinal manifestations, recurrence rates and other factors. We compared symptoms and clinical features of 55 immunosuppressed patients with confirmed CDI with those of 50 patients without immunosuppressive medication (mean age 59.3 years ±â€Š16.2 vs. 69.2 years ±â€Š15.0) who were treated at the Departments of Internal Medicine I and IV of the University Hospital Halle (Saale), Germany, between 2006 and 2009. Multivariate analysis using binary logistic regression was performed for a control group of 105 patients without CDI. In this group, there were 62 patients without evidence of immunosuppression and 43 immunosuppressed patients (mean age 66.9 years ±â€Š12.4 vs. 56.0 years ±â€Š13.7). RESULTS: The clinical courses of the two groups differed considerably. Immunosuppressed patients were significantly more frequently colonised with Clostridium difficile without clinically detectable manifestation or only mild clinical symptoms not requiring therapy (22 vs. 2 %, p = 0.003), while there were similar numbers of moderate (46 vs. 52 %, p = 0.503) but less severe CDI cases (27 vs. 40 %, p = 0.167). Relapses were observed more frequently in the group of immunosuppressed patients (15 vs. 6 %, p = 0.153). Multivariate analysis using logistic regression identified immunosuppression as an independent risk factor for CDI (OR = 2.75), in addition to prior antibiotic therapy (OR = 10.15) and PPI intake (OR = 2.93). CONCLUSION: We conclude that immunosuppression has to be regarded as an independent risk factor for CDI. Immunosuppressive treatment increases the risk of colonisation and infection with Clostridium difficile and leads to a higher relapse rate in patients with CDI.

[Drug therapy of infectious diarrhea: part 1: acute diarrhea]. / Medikamentöse Therapie der infektiösen Diarrhö: Teil 1: akute Diarrhö

BACKGROUND: Diarrhea is one of the most commonly occurring diseases. AIM: This article gives a review of the current state of the treatment of acute infectious diarrhea (part 1) and chronic infectious diarrhea (part 2) as well as of the most important pathogens. MATERIAL AND METHODS: Following a presentation of the general principles of the therapy of diarrhea, the targeted antimicrobial therapy of the most important bacterial gastrointestinal infections is described. This includes salmonellosis, shigellosis and Campylobacter infections, infections with pathogenic Escherichia coli strains, yersiniosis and cholera. Due to the increasing incidence and changes in the severity of the disease and important new aspects in the treatment of diarrhea caused by toxigenic Clostridium difficile strains, these disease entities will be described in detail. RESULTS: Symptomatic therapy is still the most important aspect of the treatment of infectious diarrhea. For severely ill patients with a high frequency of stools (> 8/day), immunodeficiency, advanced age or significant comorbidities, empirical antibiotic therapy should be considered. Increasing resistance, in particular against fluoroquinolones must also be taken into consideration. Due to the risk of excessive pathogen proliferation and concomitant intestinal toxin production with protracted or multiple complications during the disease, therapy with motility inhibitors is not recommended. With respect to the treatment of Clostridium difficile infections a promising novel aspect arose in 2012. The macrocyclic antibiotic fidaxomycin can reduce the rate of recurrent disease with the same effectiveness as vancomycin. Furthermore, evidence for the benefits of allogenic stool transplantation is increasing. CONCLUSION: The treatment of acute diarrhea is still primarily supportive. The benefits of general empirical antibiotic therapy for acute diarrhea are not evidence-based.

[Drug therapy of infectious diarrhea. Part 2: Chronic diarrhea]. / Medikamentöse Therapie der infektiösen Diarrhö. Teil 2: Chronische Diarrhö.

Diarrheal diseases are among the most common diseases worldwide. In this review the current treatment recommendations for acute (Part 1) and chronic (Part 2) infectious diarrhea are summarized and typical enteropathogens are discussed. The second part of the article describes chronic diarrhea, its related pathogens and treatment. In contrast to acute diarrhea which is mainly caused by viral and typical bacterial pathogens, chronic diarrhea has mainly non-infectious origins. Protozoal pathogens, such as Giardia lamblia and Entamoeba histolytica in particular are found and more rarely bacterial pathogens, such as Tropheryma whipplei. Opportunistic pathogens cause diarrhea in immunocompromised patients, such as in HIV patients. In these patients cytomegalovirus (CMV) colitis or infections with Cryptosporidium spp., Cyclospora cayetanensis, Isospora belli or microsporidia have to be considered. Besides targeted specific antimicrobial therapy, anti-retroviral drugs improving the underlying immunosuppression and thus the reconstitution of the adaptive immune response remain a cornerstone of the treatment in HIV-positive patients.

[Antibiotic treatment of enterococcal infections in gastroenterology with daptomycin - first experiences from the EU-CORE registry study (European Cubicin® Outcomes Registry and Experience)]. / Antibiotische Therapie von Enterokokken-Infektionen in der Gastroenterologie mit Daptomycin - erste Erfahrungen aus der Registerstudie EU-CORE (European Cubicin® Outcomes Registry and Experience).

Enterococci are a frequent cause of nosocomial infections in gastroenterology. The increase of Enterococcus faecium infections with development of resistance to gentamicin and vancomycin as well as possible linezolid resistance require alternative antibiotic therapies. Study data show that daptomycin, a highly bactericidal antibiotic is effective in enterococcal infections. However, in Germany daptomycin is so far only approved for the treatment of complicated skin and soft tissue infections, bacteremia and infective endocarditis caused by Staphylococcus aureus. In the Department of Internal Medicine I, University Hospital Halle (Saale) from May 2 009 to April 2 010 all gastroenterological patients with evidence of invasive enterococcal infection received intravenous daptomycin treatment at inclusion in the European Cubicin® Outcomes Registry and Experience (EU-CORE). Gastroenterological diseases treated were necrotising pancreatitis, infected pancreatic pseudocysts, abscesses, obstructive cholangitis and sepsis. The clinical outcome was retrospectively detected by protocol-defined criteria. A total of 13 patients (8 male, 5 female, median age 59 years) with microbiologically assured enterococcal infections (10 × E. faecium, including 1 × VRE, 6 × E. faecalis, including double infections) were treated with intravenous daptomycin (6 mg per kg body weight). In the presence of polymicrobial infections (10 of 13 patients), an additional anti-infective therapy was initiated according to sensitivity testing. Concomitantly a direct focus approach with stenting, puncture or drainage was performed. The clinical cure rate was 92 % (12 of 13 patients). One patient died from a non-surgically uncontrollable malignancy (Klatskin tumour Bismuth IIIb). There were no adverse events. These results allow us to conclude that antibiotic therapy with daptomycin in invasive or bacteraemic enterococcal infections leads to high cure rates (up to 90 % and more) when concomitant and adequate focus relief is performed. Larger clinical studies to obtain an extended drug approval are desirable.

[Unexplained fever and B-symptoms in a young male Black African]. / Unklares Fieber und B-Symptome bei einem jungen Schwarzafrikaner.

An immunocompetent Nigerian developed a fulminant hemophagocytic lymphohistiocytosis due to Epstein-Barr virus reactivation. The patient initially presented with fever, hepatosplenomegaly and pancytopenia. The clinical status of our patient deteriorated quickly despite treatment with corticoids. Escalation of immunosuppressive treatment was not possible. He died of lung, liver and circulatory failure in our intensive care unit.Hemophagocytic lymphohistiocytosis is a rare disease characterized by inflammation due to prolonged and excessive activation of antigen-presenting cells. High plasma ferritin levels and phagocytosis of hematopoetic cells in bone marrow, spleen and liver lead to the diagnosis. Hemophagocytic lymphohistiocytosis should therefore be included in the differential diagnosis in patients with persistent fever, hepatosplenomegaly and cytopenia.

[Septic shock in a renal transplanted patient after consumption of uncooked pork meat]. / Septischer Schock bei einem nierentransplantierten Patienten nach Genuss von rohem Schweinefleisch.

Salmonellosis caused by Salmonella enteritidis is an acute and in most cases zoonotic disease, but chronic human carriers are also known. Mostly, affected persons recover without treatment, but severe complications occur occasionally. For the first time we report a case of probably food-borne invasive Salmonella enteritidis infection with septic shock in a patient with Tacrolimus treatment, 13 years after renal transplantation, probably acquired by uncooked ground pork meat.