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In this review, we focus on current information on the apheresis procedures for endotoxins removal with Polymyxin B cartridges (PMX). This device has been designed in 2003 in Japan in order to take advantage of the antibiotic effe...
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In this review, we focus on current information on the apheresis procedures for endotoxins removal with Polymyxin B cartridges (PMX). This device has been designed in 2003 in Japan in order to take advantage of the antibiotic effects of Polymyxins on Gram negative bacteria and endotoxins, by-passing the toxicity shown by the intravenous administration. Although its mechanisms of action are nowadays well-known, we felt the need to sum up all the someway scattered information giving an overall sight on the entire process that brings Polymyxins molecules to function as powerful detergents of the endotoxins from the blood flow. Since the first experiences on humans, over one hundred studies have been published about the clinical use of this device. Even if some of them were limited in number of patients and compliance to international standards, they all converged in showing a highly positive impact of PMX on the improvement of clinic condition and outcome. Recently, more significant and large experiences confirmed the benefits of this treatment on hemodynamic, PaO2/FiO2 ratio, APACHE and SOFA scores and outcome at 28 days even on different typologies of sepsis cases, such as in transplanted patients. Summarizing, this relatively new procedure has proven to be a promising tool against Gram negative and endotoxin sepsis, combining clinical and outcome improvements with a fair cost/effectiveness ratio. Given that, there's still need of wider and more structured clinical studies that could steady the use of this device and widen its fields of applications.
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The use of antibiotics has unleashed high bacterial resistance. This outcome triggered the urgent need for effective new antibacterial agents to treat infectious diseases. A promising source for the production of antibiotics and s...
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The use of antibiotics has unleashed high bacterial resistance. This outcome triggered the urgent need for effective new antibacterial agents to treat infectious diseases. A promising source for the production of antibiotics and several other bioactive substances are endophytic fungi. These microorganisms inhabit in and bring benefits to living plant tissues. Thus, the aim of this paper was to know the endophytic fungi associated with Oryctanthus alveolatus (mistletoe) and assess their potential to inhibit pathogenic bacteria. A total of 86 endophytic fungi were isolated from the stems and leaves of O. alveolatus. Of these fungi, 29 were selected for the assessment of antimicrobial activity. The antimicrobial activity of the obtained extracts was evaluated using the agar diffusion method towards two Gram-positive pathogenic bacteria (Staphylococcus aureus and Staphylococcus epidermidis) and two Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli). The extracts were tested at concentrations of 200, 500, 700, 800, 900 and 1000 μg.mL-1. The antimicrobial test showed that two (COA 009 and 014) of the 29 extracts inhibited bacterial growth of at least one of the strains each, from both Gram-positive and Gram-negative bacteria. The extracts with the inhibitory activity were derived from the fungi Curvularia sp. (COA 009) and Diaporthe sp. (COA 014).
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Prostaglandin E2 (PGE2) is an essential immunomodulatory lipid released by cells in response to infection with many bacteria, yet its function in macrophage-mediated bacterial clearance is poorly understood. Yersinia overall inhib...
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Prostaglandin E2 (PGE2) is an essential immunomodulatory lipid released by cells in response to infection with many bacteria, yet its function in macrophage-mediated bacterial clearance is poorly understood. Yersinia overall inhibits the inflammatory circuit, but its effect on PGE2 production is unknown. We hypothesized that one of the Yersinia effector proteins is responsible for the inhibition of PGE2 biosynthesis. We identified that yopB -deficient Y. enterocolitica and Y. pseudotuberculosis deficient in the secretion of virulence proteins via a type 3 secretion system (T3SS) failed to inhibit PGE2 biosynthesis in macrophages. Consistently, COX-2-mediated PGE2 biosynthesis is upregulated in cells treated with heat-killed or T3SS-deficient Y. pseudotuberculosis but diminished in the presence of a MAPK/ERK inhibitor. Mutants expressing catalytically inactive YopJ induce similar levels of PGE2 as heat-killed or Δ yopB Y. pseudotuberculosis , reversed by YopJ complementation. Shotgun proteomics discovered host pathways regulated in a YopJ-mediated manner, including pathways regulating PGE2 synthesis and oxidative phosphorylation. Consequently, this study identified that YopJ-mediated inhibition of MAPK signal transduction serves as a mechanism targeting PGE2, an alternative means of inflammasome inhibition by Yersinia. Finally, we showed that EP4 signaling supports macrophage function in clearing intracellular bacteria. In summary, our unique contribution was to determine a bacterial virulence factor that targets COX-2 transcription, thereby enhancing the intracellular survival of yersiniae. Future studies should investigate whether PGE2 or its stable synthetic derivatives could serve as a potential therapeutic molecule to improve the outcomes of specific bacterial infections. Since other pathogens encode YopJ homologs, this mechanism is expected to be present in other infections. IMPORTANCE PGE2 is a critical immunomodulatory lipid, but its role in bacterial infection and pathogen clearance is poorly understood. We previously demonstrated that PGE2 leads to macrophage polarization toward the M1 phenotype and stimulates inflammasome activation in infected macrophages. Finally, we also discovered that PGE2 improved the clearance of Y. enterocolitica . The fact that Y. enterocolitica hampers PGE2 secretion in a type 3 secretion system (T3SS)-dependent manner and because PGE2 appears to assist macrophage in the clearance of this bacterium indicates that targeting of the eicosanoid pathway by Yersinia might be an adaption used to counteract host defenses. Our study identified a mechanism used by Yersinia that obstructs PGE2 biosynthesis in human macrophages. We showed that Y. pseudotuberculosis interferes with PGE2 biosynthesis by using one of its T3SS effectors, YopJ. Specifically, YopJ targets the host COX-2 enzyme responsible for PGE2 biosynthesis, which happens in a MAPK/ER-dependent manner. Moreover, in a shotgun proteomics study, we also discovered other pathways that catalytically active YopJ targets in the infected macrophages. YopJ was revealed to play a role in limiting host LPS responses, including repression of EGR1 and JUN proteins, which control transcriptional activation of proinflammatory cytokine production such as interleukin-1β. Since YopJ has homologs in other bacterial species, there are likely other pathogens that target and inhibit PGE2 biosynthesis. In summary, our study’s unique contribution was to determine a bacterial virulence factor that targets COX-2 transcription. Future studies should investigate whether PGE2 or its stable synthetic derivatives could serve as a potential therapeutic target.
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BackgroundDrug-resistance genes found in human bacterial pathogens are increasingly recognized in saprophytic Gram-negative bacteria (GNB) from environmental sources. The clinical implication of such environmental GNBs is unknown.
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ABSTRACT Kingella kingae is a leading cause of bone and joint infections and other invasive diseases in young children. A key K. kingae virulence determinant is a secreted exopolysaccharide that mediates resistance to serum comple...
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ABSTRACT Kingella kingae is a leading cause of bone and joint infections and other invasive diseases in young children. A key K. kingae virulence determinant is a secreted exopolysaccharide that mediates resistance to serum complement and neutrophils and is required for full pathogenicity. The K. kingae exopolysaccharide is a galactofuranose homopolymer called galactan and is encoded by the pamABC genes in the pamABCDE locus. In this study, we sought to define the mechanism by which galactan is tethered on the bacterial surface, a prerequisite for mediating evasion of host immune mechanisms. We found that the pamD and pamE genes encode glycosyltransferases and are required for synthesis of an atypical lipopolysaccharide (LPS) O-antigen. The LPS O-antigen in turn is required for anchoring of galactan, a novel mechanism for association of an exopolysaccharide with the bacterial surface.
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The emergence of new human pathogens and increasing antimicrobial resistance in well-established pathogens are critical public health concerns. Unfortunately, the pipeline of new antimicrobial candidates remains remarkably lean fo...
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The emergence of new human pathogens and increasing antimicrobial resistance in well-established pathogens are critical public health concerns. Unfortunately, the pipeline of new antimicrobial candidates remains remarkably lean for molecules active against increasingly problematic Gram-negative bacterial pathogens, such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although a number of new anti-Gram-negative antibacterial agents are likely to be introduced soon for clinical use, they will not represent a quantum leap in our ability to effectively treat these human pathogens of great concern. New classes of antimicrobials with novel mechanisms of action and new approaches to increasing the effectiveness of traditional antimicrobials are urgently needed. Renewed research and development efforts must become a priority, lest we fall further behind in our therapeutic initiatives.
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Sepsis and septic shock remain serious consequences of infections, with reported mortality rates in excess of 40 percent. Timely antibiotic therapy in cases of sepsis and septic shock is recognized as an important determinant of o...
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Sepsis and septic shock remain serious consequences of infections, with reported mortality rates in excess of 40 percent. Timely antibiotic therapy in cases of sepsis and septic shock is recognized as an important determinant of outcome. However, the administration of ineffective empirical treatment (IET) (an initial antibiotic regimen that is not active against the identified pathogen[s] based on in vitro susceptibility testing results) is associated with excess mortality compared to effective empirical treatment (EET). We examined all hospitalized patients at Barnes-Jewish Hospital with a sterile site (blood or pleural, abdominal, cerebrospinal, synovial, and pericardial fluid) culture positive for Gram-negative (GN) bacteria combined with a primary or secondary ICD-9-CM code for severe sepsis (995.92) or septic shock (785.52) between January 2010 and October 2015. Variables significantly associated with early-onset (<48 h of hospitalization) IET of GN sterile site sepsis and septic shock included age, recent hospitalization, and prior intravenous antibiotics. Late-onset IET was associated with increasing numbers of hospitalization days before infection onset and prior intravenous antibiotic administration. For patients with early-onset infection, we found no difference in rates of survival between patients receiving IET and EET. However, patients in the late-onset infection group receiving IET had a statistically lower rate of survival than those receiving EET. These data suggest that risk factors and outcomes for IET can vary based on the time of onset of infection. Our results also highlight the importance of prior intravenous antibiotic exposure as a risk factor for IET in infections by GN bacteria regardless of the time of onset of infection.
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Colistin is an old drug, and its use has recently resurged because of increasing antibiotic resistance in gram-negative bacteria such as Acinetobacter baumannii. Although the colistin resistance rates in gram-negative bacteria are...
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Colistin is an old drug, and its use has recently resurged because of increasing antibiotic resistance in gram-negative bacteria such as Acinetobacter baumannii. Although the colistin resistance rates in gram-negative bacteria are currently not high, many colistin-resistant isolates are being identified and the possibility of horizontal transmission of colistin resistance has increased because of the plasmid-borne colistin resistance gene mcr-1 (mobilized colistin resistance). In this review, we have discussed colistin resistance in A. baumannii. In addition, we have reviewed an abnormal phenomenon called colistin dependence in A. baumannii.
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