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Study of pathogenesis and intracellular survival of B. pseudomallei is advancing and may lead to better methods of therapy and vaccine production. New antimicrobial agents and immunomodulators are being studied to shorten the duration of treatment in the acute and maintenance phases, reduce the high mortality rate in septicemic melioidosis, and prevent relapses.

Platelet-activating factor (PAF) is a potent endogenous proinflammatory mediator implicated in the pathogenesis of septic shock. A double-blind randomized placebo-controlled trial of an intravenous PAF receptor antagonist (lexipafant) was conducted with 131 adult Thai patients with suspected severe sepsis (66 of whom had positive blood cultures). Detailed serial clinical, biochemical, and cytokine measurements were performed. Lexipafant treatment was well tolerated. The 28-day mortality in the lexipafant group (61.4%) was similar to that in the placebo group (62.6%). There was also no evidence that lexipafant affected clinical or biochemical measures of disease severity or the profile of sequentially measured plasma cytokine levels. PAF may not have an important role in the pathogenesis of severe sepsis.Despite significant advances in antimicrobial treatment and intensive care support, sepsis remains a difficult medical management problem with mortality rates between 30 and 50% (5, 11). Proinflammatory cytokines and platelet-activating factor (PAF) are generated in large amounts during the septic response (1). PAF, an ether-linked phospholipid, is one of the most hypotensive and inflammatory agents yet discovered (1, 2, 3, 7). The effects of PAF are mediated through specific PAF receptors. PAF is produced by a broad range of cell types, including monocytes, macrophages, eosinophils, and platelets as well as vascular, kidney glomerular, and gastrointestinal endothelial cells. A wide variety of mediators stimulate these cells to produce PAF; many of these mediators are secreted during the cytokine cascade associated with septic shock. These include tumor necrosis factor (TNF), thrombin, leukotrienes, and bradykinin. PAF has several biological actions characteristic of a proinflammatory agent. When administered systemically to animals, it produces many of the features of septic shock. In experimental septic shock, blocking either the proinflammatory cytokines TNF and interleukin 1 (IL-1) or lipid mediators such as PAF decreases the severity of the disease (12, 13). In one study, the PAF antagonist BN 52021 was shown to be a safe and promising treatment of patients with severe gram-negative sepsis (6).Lexipafant (BB-882; British Biotechnology Ltd., Watlington, Oxford, United Kingdom) is another newly developed PAF antagonist. Lexipafant was shown to be a potent antagonist of PAF in in vitro studies involving the inhibition of [ 3 H]PAF receptor binding and in a PAF receptor binding assay conducted on human platelet membranes. In the latter system, lexipafant bound to the receptor seven times more avidly than native PAF (unpublished data). We report here results of a randomized placebo-controlled study to evaluate the clinical safety and efficacy of lexipafant as an adjunct to the treatment of severe sepsis. Lexipafant has been shown to be well tolerated when given intravenously to volunteers, to patients with pancreatitis, and to patients with sepsis (unpublished data). MATERIALS AND METHODSStudy design and patient ...

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Background. Inappropriate empiric antimicrobials could be a major cause of unfavorable mortality rates in co-morbid patients. This study aimed to assess the prevalence and impact of first-dose and 24-hour inappropriate antimicrobials on mortality rates of bacteremic septic patients. Methods. A retrospective cohort study was employed. Case record forms of patients diagnosed as sepsis, severe sepsis, or septic shock with positive hemoculture during 2009 were retrieved from the medical wards, Siriraj Hospital. Demographic data, antimicrobial use, types of bacteria isolated from blood and susceptibilities, patients' comorbidities, 28-day and overall mortality rates were collected and analyzed. Results. There were 229 cases, mean age (SD) of 63.5 (17.2) years and mean (SD) APACHE II score of 24.7 (6.8). The prevalence of first-dose and 24-hour inappropriate antimicrobials was 29.7% and 25.3%, respectively. The 28-day and overall mortality rates between first-dose inappropriate and appropriate antimicrobial were 67.6% versus 60.2% (P = 0.301) and 75.0% versus 68.3% (P = 0.345), consequently. Patients with septic shock and inappropriate first-dose antimicrobials significantly had higher 28-day mortality rate (61.6% versus 41.9%; P = 0.017). Conclusion. Higher mortality rates in bacteremic septic patients were substantially associated with inappropriate first-dose antimicrobials and 3-hour delayed antimicrobial administration after sepsis diagnosis.