Real-World Data Regarding Dalbavancin Use before and during the COVID-19 Pandemic-A Single-Center Retrospective Study.

Dalbavancin is a semisynthetic lipoglycopeptide, which possesses great potential for bactericidal activity similar to antimicrobials with the same mechanism of action, such as vancomycin and teicoplanin. Due to its very prolonged half-life, it can be used in a single or two-dose regimen to treat infections by Gram-positive microorganisms, even resistant ones, such as methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved only for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). The aim of this study was to investigate the clinical and microbiological characteristics of patients to whom dalbavancin was administered at the University Hospital of Heraklion and evaluate its use in regard to the COVID-19 pandemic. In total, 146 patients were included in this retrospective cohort study evaluating the use of dalbavancin from the first time it was used in 2017 until the end of 2022. The median age was 68 years (range: 21-96 years), and 86 (59%) patients were male. The most common indications for dalbavancin use were osteoarticular infections in 43%, followed by ABSSSIs in 37%, and cardiovascular infections in 10%. Dalbavancin was used empirically in one out of three patients, most commonly with the indication of ABSSSIs, and most commonly in the post-COVID-19 era. The most frequently isolated pathogens were coagulase-negative staphylococci in 70%, S. aureus in 27%, Enterococcus spp. in 22%, and Streptococcus spp. in 8%, while one out of three infections were polymicrobial. In 12% of patients, the infection was not cured, but no patients died. For patients with ABSSSIs, endocarditis and vascular infections, and bacteremia, the cure rates were more than 90%, and in osteoarticular infections, the cure rate was 76%. Thus, dalbavancin has great potential for use in complicated and invasive infections that may require prolonged intravenous antimicrobial treatment. However, further studies are required to formally investigate its role in such infections.

Stem Cell Treatments in Preclinical Relevant Stroke Models.

Since stroke has limited treatment options, an active search for new therapeutic approaches is required. Initial excitement of using cell-based therapies to stimulate recovery processes in the ischemic brain turned into a more measured perspective, acknowledging obstacles related to the unfavorable environments associated in part with aging. Given the predominance of stroke in older populations, evaluating the effectiveness of cell therapies in aged brain environments is essential and clinically relevant. Despite a common perception of the aged brain being resistant to regeneration, recent research with neural precursor cells and bone marrow-derived mesenchymal stem cells indicates that cell-based therapy can promote plasticity and remodeling in the aged rat brain. However, significant differences in the aged brain compared to the young brain, such as expedited progression of ischemic injury to brain infarction, decreased rate of endogenous neurogenesis, and delayed onset of neurological recovery, must be noted. The effectiveness of cell-based therapies may further be connected to age-related comorbidities such as diabetes or hyperlipidemia, potentially leading to maladaptive or impaired brain remodeling. These age-related factors need careful consideration in the clinical application of restorative therapies for stroke.

Long Non-Coding RNAs (lncRNAs) in Response and Resistance to Cancer Immunosurveillance and Immunotherapy.

Long non-coding RNAs (lncRNAs) are critical regulatory elements in cellular functions in states of both normalcy and disease, including cancer. LncRNAs can influence not only tumorigenesis but also cancer features such as metastasis, angiogenesis and resistance to chemo-and immune-mediated apoptotic signals. Several lncRNAs have been demonstrated to control directly or indirectly the number, type and activities of distinct immune cell populations of adaptive and innate immunities within and without the tumor microenvironment. The disruption of lncRNA expression in both cancer and immune cells may reflect alterations in tumor responses to cancer immunosurveillance and immunotherapy, thus providing new insights into lncRNA biomarker-based prognostic and therapeutic cancer assessment. Here we present an overview on lncRNAs' functions and underlying molecular mechanisms related to cancer immunity and conventional immunotherapy, with the expectation that any elucidations may lead to a better understanding and management of cancer immune escape and response to current and future immunotherapeutics.

Pulmonary and intestinal microbiota dynamics during Gram-negative pneumonia-derived sepsis.

BACKGROUND: The gut microbiome plays a protective role in the host defense against pneumonia. The composition of the lung microbiota has been shown to be predictive of clinical outcome in critically ill patients. However, the dynamics of the lung and gut microbiota composition over time during severe pneumonia remains ill defined. We used a mouse model of pneumonia-derived sepsis caused by Klebsiella pneumoniae in order to follow the pathogen burden as well as the composition of the lung, tongue and fecal microbiota from local infection towards systemic spread. RESULTS: Already at 6 h post-inoculation with K. pneumoniae, marked changes in the lung microbiota were seen. The alpha diversity of the lung microbiota did not change throughout the infection, whereas the beta diversity did. A shift between the prominent lung microbiota members of Streptococcus and Klebsiella was seen from 12 h onwards and was most pronounced at 18 h post-inoculation (PI) which was also reflected in the release of pro-inflammatory cytokines indicating severe pulmonary inflammation. Around 18 h PI, K. pneumoniae bacteremia was observed together with a systemic inflammatory response. The composition of the tongue microbiota was not affected during infection, even at 18-30 h PI when K. pneumoniae had become the dominant bacterium in the lung. Moreover, we observed differences in the gut microbiota during pulmonary infection. The gut microbiota contributed to the lung microbiota at 12 h PI, however, this decreased at a later stage of the infection. CONCLUSIONS: At 18 h PI, K. pneumoniae was the dominant member in the lung microbiota. The lung microbiota profiles were significantly explained by the lung K. pneumoniae bacterial counts and Klebsiella and Streptococcus were correlating with the measured cytokine levels in the lung and/or blood. The oral microbiota in mice, however, was not influenced by the severity of murine pneumonia, whereas the gut microbiota was affected. This study is of significance for future studies investigating the role of the lung microbiota during pneumonia and sepsis.

Effect of antibiotic gut microbiota disruption on LPS-induced acute lung inflammation.

BACKGROUND: An increasing body of evidence is indicating that the gut microbiota modulates pulmonary inflammatory responses. This so-called gut-lung axis might be of importance in a whole spectrum of inflammatory pulmonary diseases such as acute respiratory distress syndrome, chronic obstructive pulmonary disease and pneumonia. Here, we investigate the effect of antibiotic disruption of gut microbiota on immune responses in the lung after a intranasal challenge with lipopolysaccharide (LPS). METHODS/RESULTS: C57Bl/6 mice were treated for two weeks with broad-spectrum antibiotics supplemented to their drinking water. Afterwards, mice and untreated control mice were inoculated intranasally with LPS. Mice were sacrificed 2 and 6 hours post-challenge, after which bronchoalveolar lavage fluid (BALF) and lung tissues were taken. Gut microbiota analysis showed that antibiotic-treated mice had a pronounced reduction in numbers and diversity of bacteria. A modest, but time consistent, significant increase of interleukin (IL)-6 release was seen in BALF of antibiotic treated mice. Release of tumor necrosis factor alpha (TNFα), however, was not statistically different between groups. CONCLUSION: Antibiotic induced microbiota disruption is associated with alterations in host responses during LPS-induced lung inflammation. Further studies are required to determine the clinical relevance of the gut-lung axis in pulmonary infection and inflammation.

Vendor effects on murine gut microbiota and its influence on lipopolysaccharide-induced lung inflammation and Gram-negative pneumonia.

BACKGROUND: The microbiome has emerged as an important player in the pathophysiology of a whole spectrum of diseases that affect the critically ill. We hypothesized that differences in microbiota composition across vendors can influence murine models of pulmonary lipopolysaccharide (LPS) inflammation and Gram-negative pneumonia. METHODS: A multi-vendor approach was used with genetically similar mice derived from three different vendors (Janvier, Envigo, Charles River). This model was employed to study the effect on the host response to a pulmonary LPS challenge (1 µg Klebsiella pneumoniae LPS, intranasal), as well as experimental K. pneumoniae infection (ATCC43816, 1 × 104 CFU, intranasal). RESULTS: Gut microbiota analysis revealed profound intervendor differences in bacterial composition as shown by beta diversity and at various taxonomic levels. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 release in lung and bronchoalveolar lavage fluid (BALF) were determined 6 and 24 h after intranasal treatment with LPS. No differences were found between the groups, with the exception for Envigo, showing a higher level of TNFα in lung and BALF at 6 h compared to Janvier and Charles River. In another set of experiments, mice from different vendors were subjected to a clinically relevant model of Gram-negative pneumonia (K. pneumoniae). At 12 and 36 h post-infection, no intervendor differences were found in bacterial dissemination, or TNFα and IL-6 levels in the lungs. In line, markers for organ failure did not differ between groups. CONCLUSIONS: Although there was a marked variation in the gut microbiota composition of mice from different vendors, the hypothesized impact on our models of pulmonary inflammation and severe pneumonia was limited. This is of significance for experimental settings, showing that differences in gut microbiota do not have to lead to differences in outcome.

The emerging role of the microbiota in the ICU.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .