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IntroductionPseudomonas aeruginosa is a virulent pathogen. It can exist both in the environment and the human host. Recent work by Turner et al suggests that it is the environment that P. aeruginosa exists that determines the virulence factors that are expressed [1]. P. aeruginosa bloodstream infections (BSI) are predominantly seen in the hospital or healthcareassociated host [2][3][4][5]. This BSI is no longer the rare entity of the original case series in the 1950's, with increasing prevalence over the subsequent decades [6,7]. The associated morbidity and mortality with this infection is considerable [2,[8][9][10]. This has not improved over time [7].The antibiotic treatment options available, in the current age of global antibiotic resistance, has not kept pace. A mortality benefit of combination antibiotic therapy in the setting of P. aeruginosa BSI has not been consistently shown [11][12][13][14][15][16][17]. In the settings of drug resistance or the immunocompromised host, more effective ways to utilise current antibiotic therapy must be considered.It is therefore timely that we further characterise the clinical and molecular epidemiology, virulence genotype and outcome of P. aeruginosa BSI. MethodsBSI episode data was collected retrospectively over a three-year time period from the first of January 2008 to the first of January 2011. This involved seven tertiary care institutions, servicing an urban population of 2.24 million. Extensive epidemiological, clinical, laboratory, treatment and outcome data was collected as per a pre-formulated data collection sheet (Appendix A). For purposes of the study on BSI in the setting of febrile neutropenia, data was collected from a single institution over an extended period of time from the 1 st of January 2006 to the 1 st of April 2014.Ethics approval was obtained from each of the study sites.A P. aeruginosa BSI isolate collection was also collated for study. This involved five public and private laboratories. Isolates were collected from the time period of the first of January 2008 to the first of January 2013. The laboratories service eight tertiary care institutions and one secondary care institution. Permission was obtained from each of the laboratories.ii Results 595 P. aeruginosa BSI episodes were characterised from the study centres. 942 BSI isolates were collated and analysed as part of the BSI isolate collection.A retrospective cohort study of monomicrobial P. aeruginosa BSI described the recent Australian epidemiology of this BSI. The longitudinal mortality of this infection was found to increase with time and at one year was greater than would be expected for the comparative death rate predicted by the median Charlson's co-morbidity index (CCI) of the cohort [18].Detailed description of a retrospective cohort of community acquired (CAI) P. aeruginosa BSI gave new insight into the epidemiology of this group of patients. Multivariate analysis comparing CAI and health-care associated infection cohorts (HCAI) found that CAI is not associated with a shorter len...
IntroductionPseudomonas aeruginosa is a virulent pathogen. It can exist both in the environment and the human host. Recent work by Turner et al suggests that it is the environment that P. aeruginosa exists that determines the virulence factors that are expressed [1]. P. aeruginosa bloodstream infections (BSI) are predominantly seen in the hospital or healthcareassociated host [2][3][4][5]. This BSI is no longer the rare entity of the original case series in the 1950's, with increasing prevalence over the subsequent decades [6,7]. The associated morbidity and mortality with this infection is considerable [2,[8][9][10]. This has not improved over time [7].The antibiotic treatment options available, in the current age of global antibiotic resistance, has not kept pace. A mortality benefit of combination antibiotic therapy in the setting of P. aeruginosa BSI has not been consistently shown [11][12][13][14][15][16][17]. In the settings of drug resistance or the immunocompromised host, more effective ways to utilise current antibiotic therapy must be considered.It is therefore timely that we further characterise the clinical and molecular epidemiology, virulence genotype and outcome of P. aeruginosa BSI. MethodsBSI episode data was collected retrospectively over a three-year time period from the first of January 2008 to the first of January 2011. This involved seven tertiary care institutions, servicing an urban population of 2.24 million. Extensive epidemiological, clinical, laboratory, treatment and outcome data was collected as per a pre-formulated data collection sheet (Appendix A). For purposes of the study on BSI in the setting of febrile neutropenia, data was collected from a single institution over an extended period of time from the 1 st of January 2006 to the 1 st of April 2014.Ethics approval was obtained from each of the study sites.A P. aeruginosa BSI isolate collection was also collated for study. This involved five public and private laboratories. Isolates were collected from the time period of the first of January 2008 to the first of January 2013. The laboratories service eight tertiary care institutions and one secondary care institution. Permission was obtained from each of the laboratories.ii Results 595 P. aeruginosa BSI episodes were characterised from the study centres. 942 BSI isolates were collated and analysed as part of the BSI isolate collection.A retrospective cohort study of monomicrobial P. aeruginosa BSI described the recent Australian epidemiology of this BSI. The longitudinal mortality of this infection was found to increase with time and at one year was greater than would be expected for the comparative death rate predicted by the median Charlson's co-morbidity index (CCI) of the cohort [18].Detailed description of a retrospective cohort of community acquired (CAI) P. aeruginosa BSI gave new insight into the epidemiology of this group of patients. Multivariate analysis comparing CAI and health-care associated infection cohorts (HCAI) found that CAI is not associated with a shorter len...
Endotoxin tolerance develops in the late phase of sepsis to protect cells from an early hyperinflammatory response. Nonetheless, because it induces an immunosuppressive environment, patients with sepsis in its late phase are affected by secondary infections, particularly bacterial pneumonia. Here, we showed that induction of endoplasmic reticulum (ER) stress leads to activation of glycogen synthase kinase 3β (GSK-3β) and X-box-binding protein 1 (XBP-1) in an inositol-requiring enzyme 1α (IRE1α)-mediated manner, which in turn restores the inflammatory response in endotoxin-tolerant macrophages. Animal and in vitro models of endotoxin tolerance were studied along with a model of LPS-induced endotoxin tolerance and a model of cecal ligation and puncture (CLP)-induced endotoxin tolerance. To detect the suppressed inflammatory response during endotoxin tolerance, inflammatory-cytokine expression levels were measured by quantitative real-time PCR and an ELISA. Our research revealed that induction of ER stress alleviated lung injury in a septic host infected with Pseudomonas aeruginosa via the activation of GSK-3β and XBP-1 in an IRE1α-mediated manner. Consequently, in the lungs of the septic host infected with P. aeruginosa, symptoms of pneumonia improved and the infecting bacteria were cleared. Thus, for septic patients, determination of immune status may guide the selection of appropriate immunomodulation, and ER stress can be a novel therapeutic strategy restoring the immune response in patients with endotoxin tolerance.
Infections with Pseudomonas aeruginosa have become a real concern in hospital-acquired infections, especially in critically ill and immunocompromised patients. The major problem leading to high mortality lies in the appearance of drug-resistant strains. Therefore, a vast number of approaches to develop novel anti-infectives is currently pursued. Diverse strategies range from killing (new antibiotics) to disarming (antivirulence) the pathogen. In this review, selected aspects of P. aeruginosa antimicrobial resistance and infection management will be addressed. Many studies have been performed to evaluate the risk factors for resistance and the potential consequences on mortality and attributable mortality. The review also looks at the mechanisms associated with resistance -P. aeruginosa is a pathogen presenting a large genome, and it can develop a large number of factors associated with antibiotic resistance involving almost all classes of antibiotics. Clinical approaches to patients with bacteremia, ventilator-associated pneumonia, urinary tract infections and skin soft tissue infections are discussed. Antibiotic combinations are reviewed as well as an analysis of pharmacokinetic and pharmacodynamic parameters to optimize P. aeruginosa treatment. Limitations of current therapies, the potential for alternative drugs and new therapeutic options are also discussed.
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