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The review aims to review the positioning of meropenem-vaborbactam in clinical practice, taking into consideration the characteristics of other available drugs, namely ceftazidime-avibactam, plazomicin, and colistin. The search terms ���meropenem-vaborbactam��� or RX7009 for the years 2006 until 2021 were used. Coupling of meropenem with the cyclic boronate derivative varobactam enhances considerably the in vitro intrinsic activity of meropenem against isolates producing KPC (Klebsiella pneumoniae-producing carbapenemase). The drug has linear elimination and the ratio of the area under the curve of the free drug to the minimum inhibitory concentration is the main pharmacodynamics variable determining bacterial clearance. Meropenem-vaborbactam is currently approved for the management of complicated urinary tract infections including acute pyelonephritis, complicated intraabdominal infections, and hospital-acquired pneumonia including ventilator-associated pneumonia.

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1 alpha/beta inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR >= 6 ng ml(-1), 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter. The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1 alpha/beta inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor.

Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. Methods In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. Results Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. Conclusions Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.

Digital ischemia has been rarely associated, as a paraneoplastic syndrome, with renal cancer. Since it can severely compromise the patients' quality of life, early recognition is important, in order to optimally address it with currently available treatment options, such as tyrosine inhibitors. Digital ischemia may occur in the general population and it can be the result of other non-cancerous diseases; accordingly, a thorough and aggressive work-up is mandatory, together with appropriate therapeutic steps such as tyrosine kinase inhibitors, vasodilators, and antiaggregants. Herein, we report a 78-year-old male patient with a history of clear-cell renal-cell cancer, who presented in the emergency department with critical ischemia in the upper limbs.

A previous randomized study showed that clarithromycin decreases the risk of death due to ventilator-associated pneumonia and shortens the time until infection resolution. The efficacy of clarithromycin was tested in a larger population with sepsis. Six hundred patients with systemic inflammatory response syndrome due to acute pyelonephritis, acute intra-abdominal infections or primary Gram-negative bacteraemia were enrolled in a double-blind, randomized, multicentre trial. Clarithromycin (1 g) was administered intravenously once daily for 4 days consecutively in 302 patients; another 298 patients were treated with placebo. Mortality was the primary outcome; resolution of infection and hospitalization costs were the secondary outcomes. The groups were well matched for demographics, disease severity, microbiology and appropriateness of the administered antimicrobials. Overall 28 day mortality was 17.1 (51 deaths) in the placebo arm and 18.5 (56 deaths) in the clarithromycin arm (P0.671). Nineteen out of 26 placebo-treated patients with septic shock and multiple organ dysfunctions died (73.1) compared with 15 out of 28 clarithromycin-treated patients (53.6, P0.020). The median time until resolution of infection was 5 days in both arms. In the subgroup with severe sepsis/shock, this was 10 days in the placebo arm and 6 days in the clarithromycin arm (P0.037). The cost of hospitalization was lower after treatment with clarithromycin (P0.044). Serious adverse events were observed in 1.3 and 0.7 of placebo- and clarithromycin-treated patients, respectively (P0.502). Intravenous clarithromycin did not affect overall mortality; however, administration shortened the time to resolution of infection and decreased the hospitalization costs.

Patients with sepsis in the intensive care unit (ICU) are prone to develop Candida infections. Here, we investigated Candida-induced T-helper 17 (Th17) responses during experimental human endotoxemia and in patients with sepsis admitted to the ICU. Peripheral blood mononuclear cells were stimulated with Candida albicans. The Th17 response was significantly lower during endotoxemia, compared with baseline. Patients with gram-negative sepsis had a significantly lower Th17 response as compared to healthy controls. These data demonstrate that the Th17 response is deficient during endotoxin-related systemic inflammation, which likely represents an important risk factor for increased susceptibility to develop Candida infection in patients with sepsis.

Objectives: To identify the role of single nucleotide polymorphisms (SNPs) of the tumor necrosis factor (TNF) gene in the natural course of 2009 influenza A H1N1 virus infection. Methods: Genomic DNA was isolated from 109 patients with an H1N1 infection and from 108 healthy volunteers. SNPs of the TNF gene were assessed after electrophoresis of the digested PCR products by restriction enzymes. Results: The frequency of the -238 A allele was significantly greater among patients than among controls. Viral pneumonia developed in 20 of 96 non-carriers of at least one -238 A allele (20.8%) and in seven of 13 carriers of at least one -238 A allele (53.8%, p = 0.016). Logistic regression analysis showed that the most important factors associated with the development of pneumonia were the presence of an underlying disease (p = 0.021, odds ratio (OR) 3.08) and the carriage of at least one -238 A allele (p = 0.041, OR 3.74). Gene transcripts of the TNF gene were greater among non-carriers of the -238 A allele than among carriers of the -238 A allele. Conclusions: The -238 A SNP allele of the TNF gene imposes on the course of 2009 H1N1 virus infection and is an independent risk factor for pneumonia. (C) 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Objective: To evaluate the long-term efficacy of etanercept for the management of hidradenitis suppurativa. Methods: Analysis was based on the long-term follow-up (weeks 24-144) of 10 patients enrolled in a prospective open-label phase II study; etanercept was initially administered subcutaneously 50 mg once weekly for 12 weeks in 10 patients. Disease recurrence and the need to restart etanercept were recorded. Results: Three patients did not report any disease recurrence. A second course of treatment with etanercept was needed in seven patients. Favourable responses were found in five; two patients failed treatment. Conclusions: The first treatment course achieved long-term disease remission in almost one-third of patients. The remaining needed a second treatment course but even in that case, their disease severity at restart was significantly lower compared with baseline.

Background: To investigate whether angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) are implicated in the hypoxemic resuscitation from hemorrhagic shock. Methods: Twenty rabbits were subjected to hemorrhagic shock after blood exsanguination; resuscitation was performed by infusion of the shed blood in ten rabbits under normoxemic conditions (NormoxRes) and in 10 under hypoxemic conditions (HypoxRes); four rabbits were subjected to sham operation. Serum was drawn at serial time intervals: serum was applied for stimulation of U937 monocytes. Results: Serum concentrations of Ang2 were higher in the NormoxRes group compared to the HypoxRes group at 90 min (p: 0.049) and at 120 min (p: 0.028). Serum concentrations of VEGF did not differ between groups. Concentrations of VEGF in the supernatants of U937 stimulated with sera of all groups were below detection limit The wet to dry. lung ratio of the HypoxRes group was significantly lower than the NormoxRes group (p < 0.0001). Conclusions: Hypoxemic resuscitation from hemorrhagic shock is a process accompanied by reduced serum levels of Ang2. These findings add significantly to our understanding of that experimental treatment strategy of resuscitation. (C) 2009 Elsevier Ltd. All rights reserved.

In an attempt to define the most important driver responsible for recurrence of cystitis in women, 18 1 records were retrospectively analysed among 1010 consecutive references in a tertiary centre for lower urinary tract infections (UTIs). All 181 women had more than three episodes of cystitis per year; 129 were under continuous prophylaxis and 52 were under postcoital prophylaxis. Analysis revealed that the most important factor affecting successful outcome of chemoprophylaxis was the compliance of patients (odds ratio 0.074; P < 0.0001). Among women treated for > 6 months, the most effective regimen was nitrofurantoin, with a success rate of 96.8% compared with 82.8% for trimethoprim/sulphamethoxazole and 72.3% for norfloxacin (P = 0.046 between agents). Failure of chemoprophylaxis was observed in 51 women in total; in 26 of them resistance to the administered agent had developed. Results of this retrospective study revealed that the most important driver leading to failure of prophylaxis for recurrent lower UTIs was the lack of compliance of women with their medication. Nitrofurantoin was the most potent among the administered agents. (c) 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Introduction Our aim was to define early changes of lymphocytes and of NK cells in severe sepsis and to correlate them with serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1). Methods Blood was sampled from 49 patients with proven highly suspected infection by Gram-negative pathogens, within 12 hours of the advent of severe sepsis, and was also sampled from six healthy volunteers. White blood cells were targeted with monoclonal antibodies and were analyzed by flow cytometry. The concentrations of sTREM-1 were estimated by ELISA. Results The presence of CD3/CD4 cells was significantly lower ( P < 0.0001) and that of NK cells significantly higher among patients with sepsis compared with controls ( P = 0.011). The proportions ( median +/- standard error) of ANNEXIN-V/CD4/ CD3-positive cells, of ANNEXIN-V/CD8/CD3-positive cells and of ANNEXIN-V/CD14-positive cells of the patient population were 7.41 +/- 2.26%, 7.69 +/- 3.42% and 1.96 +/- 4.22%, respectively. Patients with NK cells > 20% survived longer compared with those patients with NK cells 180 pg/ml survived longer compared with those patients with sTREM-1 concentrations 20%. The survival benefit resulting from elevated NK cells might be connected to elevated serum levels of sTREM-1.

Objectives Triggering receptor expressed on myeloid cells (TREM-1) is a promoter of cytokine production triggered by microbial components. To investigate the significance of its soluble counterpart, sTREM-1, for the pathogenesis of peptic ulcer disease, sTREM-1 was compared with the proinflammatory mediators and the pathology score of gastritis. Methods Forty patients with dyspepsia were enrolled: 20 with peptic ulcer and 20 controls without any macroscopic abnormalities. All patients were examined by endoscopy; gastric juice was aspirated and biopsy specimens were collected from the antrum and corpus of the stomach. sTREM-1 was estimated by at hand-made enzyme immunoassay. Interleukin-8 was estimated by enzyme-linked immunosorbent assay and lipid peroxidation, indexed by malondialdehyde, by the thiobarbituric assay, after passage through a high-performance liquid chromatography system. Results The median (+/- SE) of sTREM-1 of controls and patients with ulcer was 3.91 +/- 0.57 and 44.27 +/- 241.55 R U, respectively (P=0.006). The median (+/- SE) of interleukin-8 of controls and patients with ulcer was 1802.97 +/- 122.10 and 2030.66 +/- 64.44 pg/ml, respectively (P = 0.023). sTREM-1 was positively correlated with the density of neutrophil and mononuclear infiltration scores and the total Sydney score (P=0.029, 0.043 and 0.041, respectively). sTREM-1 was positively correlated with interleukin-8 (P=0.042). Conclusions sTREM-1 might be an independent factor involving with the peptic ulcerative inflammatory process that is positively correlated with histopathological abnormalities of gastritis.