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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Int. J. Antimicrob. Agents · Jun 2013
ReviewAntimicrobial resistance: action to combat the rising microbial challenges.
Antimicrobial therapy transformed medical practice from a merely diagnosis-focused approach 80 years ago to a treatment-focused approach, saving millions of lives in the years to follow. Today, numerous medical advances made possible by effective antibiotics are being threatened by the relentlessly rising rates of bacteria resistant to all currently available antibiotics. This phenomenon is a consequence of antibiotic misuse, which exerts undue selective pressure on micro-organisms, combined with defective infection control practices that accelerate their spread. ⋯ It should include actions aiming at optimising antibiotic use, strengthening surveillance and infection control, and improving healthcare worker and public education with regard to antibiotics. Research efforts to bring new effective antibiotics to patients need to be fostered in order to negate the consequences of the current lack of antimicrobial therapy options. A holistic view of AMR as well as intersectoral collaboration between human and veterinary medicine is required to best address the problem.
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Int. J. Antimicrob. Agents · Jun 2013
ReviewIntraventricular and intrathecal colistin as the last therapeutic resort for the treatment of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii ventriculitis and meningitis: a literature review.
Acinetobacter baumannii ventriculitis/meningitis due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has become a clinical entity of considerable importance in recent years. A review of the available literature regarding intraventricular (IVT) or intrathecal (ITH) administration of colistin in MDR and XDR A. baumannii ventriculitis/meningitis was conducted and a total of 83 episodes in 81 patients were identified (71 cases in adults and 10 in children and neonates). Colistin was administered via the IVT and ITH route in 52 and 22 cases, respectively, whilst in 7 cases the exact route was not identified. ⋯ The median duration of treatment of IVT/ITH polymyxin E was 18.5 days, whilst the median time to achieve sterilisation of cerebrospinal fluid was 4 days. The rate of successful outcome was 89%, and toxicity related to treatment mainly manifested as reversible chemical ventriculitis/meningitis was reported in nine cases (11%). Nowadays, IVT and ITH colistin represents the last resort treatment of MDR and XDR A. baumannii ventriculitis/meningitis, offering a unique, rather safe and successful mode of therapy.
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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.