International journal of antimicrobial agents
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Severe sepsis and septic shock are lethal complications of infection, characterised by dysregulated inflammatory and immune responses. Our understanding of the pathogenesis of sepsis has improved markedly in recent years, but unfortunately has not been translated into efficient treatment strategies. Epigenetic mechanisms such as covalent modification of histones by acetylation are master regulators of gene expression under physiological and pathological conditions, and strongly impact on inflammatory and host defence responses. ⋯ Strikingly, proof-of-principle studies demonstrated that HDACi protect from lethal toxic shock and septic shock. Overall, our observations argue for a close monitoring of the immunological and infection status of patients treated with HDACi, especially immunocompromised cancer patients. They also support the concept of pharmacological inhibitors of HDACs as promising drugs to treat inflammatory diseases, including sepsis.
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The failure of the PROWESS-SHOCK study of recombinant human activated protein C (drotrecogin alfa) has generated much scepticism about the future of immunomodulatory interventions in sepsis. This review presents a summary of the few remaining promising strategies for immunointervention. ⋯ This approach comprises: septic shock and multiple organ dysfunction syndrome arising in the field of ventilator-associated pneumonia as an indication for intravenous clarithromycin; abdominal severe sepsis/shock for PMX-B haemoperfusion; sepsis and acute coagulopathy for rTM; and early septic shock for IgMA. However, specific diagnostic tools should be developed to make this personalised approach more robust.
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Int. J. Antimicrob. Agents · Jun 2013
Can population pharmacokinetic modelling guide vancomycin dosing during continuous renal replacement therapy in critically ill patients?
Treatment of resistant bacteria such as meticillin-resistant Staphylococcus aureus (MRSA) relies on achieving adequate antibiotic concentrations at the site of infection. Strategies to attain such targets in septic critically ill patients receiving renal replacement therapy (RRT) are uncommon but could be useful for increasing the likelihood of therapeutic dosing. The aim of this study was to conduct a population pharmacokinetic (PK) analysis in septic patients undergoing continuous RRT and to determine which parameters were associated with inadequate vancomycin concentrations. ⋯ When covariates were tested, none were found to adequately explain changing vancomycin CL or Vd in the population PK model. In particular, the lack of correlation between CL and RRT settings was likely due to the multiple confounders known to influence antibiotic prescription in this setting. These data provide a cautionary tale of the challenges of describing pharmacokinetics in critically ill patients receiving RRT and highlights the need for a detailed, prospective, multicentre study to better inform dosing practice.
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Int. J. Antimicrob. Agents · Jun 2013
Management of candidaemia and invasive candidiasis in critically ill patients.
Critically ill patients in the intensive care unit (ICU) are at increased risk of encountering bloodstream infections (BSIs) with Candida spp., associated with an elevated crude mortality rate. This supports the significance of early detection of infection and identification of the most effective management approach. A review of the various antifungal treatments and an evaluation of the diverse management approaches for invasive candidiasis in critically ill patients is necessary for guiding evidence-based decision-making. ⋯ This paper summarises the most recent literature as well as the guidelines issued by the Infectious Diseases Society of America. The objective is to identify the best diagnosis and management approaches for serious Candida infections in critically ill patients. In addition, this article addresses an important aspect associated with managing candidaemia in critically ill patients pertaining to the decision for intravenous catheter removal.
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Int. J. Antimicrob. Agents · Jun 2013
ReviewControversies in the management of the critically ill: the role of probiotics.
Probiotics are commercially available, viable, non-pathogenic micro-organisms that, when ingested in sufficient quantities, exert a health benefit to the host derived through modification of the gut flora, local release of antimicrobial factors, maintenance of integrity of the gut barrier, competition for epithelial adherence, prevention of bacterial translocation, and modulation of the local immune response. In critically ill patients, probiotics appear to lead to decreased susceptibility to antibiotic-associated diarrhoea, Clostridium difficile infections, ventilator-associated pneumonia, necrotising enterocolitis, acute severe pancreatitis, sepsis and multiple organ dysfunction syndrome as well as a shortened duration of infections. ⋯ The most commonly reported adverse events include bacteraemia, fungaemia and sepsis. At present, based on the available evidence and although helpful and relatively safe for certain disease conditions, routine use of probiotics in the critically ill is not recommended.