Treatment Of Bacterial Sepsis Research Articles

Acute lipopolysaccharide (LPS)-induced cell membrane hyperpolarization is independent of voltage gated and calcium activated potassium channels

The gram-negative toxin lipopolysaccharides (LPS) are known to trigger inflammatory cytokines in mammals, which can result in pathological responses. Upon treatment of bacterial sepsis with antibiotics, the lysing bacteria can present a surge in LPS, inducing a cytokine storm. However, LPS can also have direct cellular effects, including transient rapid hyperpolarizing of the membrane potential, blocking glutamate receptors and even promoting release of glutamate. The detailed mechanism of action for these immediate responses is still unresolved. In addressing the membrane hyperpolarization, voltage gated K+ channel blockers 4-aminopyridine (4-AP, 3 mM), quinidine hydrochloride monohydrate (0.1 mM) and tetraethylammonium (TEA, 20 mM) were examined along with RNAi knockdowns of potential calcium activated K+ channels. The immediate responses of LPS were not blocked. Even in the presence of glutamate, the membrane still hyperpolarizes with LPS. When the driving gradient for the ionotropic glutamate receptors is enhanced during hyperpolarization, spontaneous quantal responses are dampened in amplitude. Thus, glutamate receptors are blocked, and the mechanism of hyperpolarization remains unresolved. The larval Drosophila glutamatergic neuromuscular junction is used as a model synaptic preparation to address the direct rapid actions by LPS.

Antibiotic Sensitivity pattern of Bacterial Isolates of Neonatal Septicemia in Peshawar, Pakistan.

Septicemia plays an important role in neonatal morbidity and mortality, especially in developing countries. To investigate the bacterial pathogens causing neonatal sepsis and their antibiotic susceptibility profile. A total of 2,685 neonates aged 0-28 days were included in the study. Blood from each neonate was cultured and isolates were identified using standard biochemical tests. Antibiotic sensitivity pattern was analyzed using modified Kirby-Bauer disc diffusion method. Blood culture positivity was observed in 1,534 (57.1%) samples. Most of the cases (1089 counts - 71%) were of early onset sepsis while 445 (29%) were of late onset sepsis. The incidence of sepsis was higher in males 856 (55.8%) than females 678 (44.2%) with a 1:2 ratio. Similarly, 58.3% of septicemic patients were neonates with low birth weights. Twelve hundred and six (78.6%) isolates were gram negative while 328 (23.4%) were gram positive bacteria. E. coli was the dominant pathogen seen in 811 (52.8%) followed by Staphylococcus aureus 300 (19.5%), Pseudomonas 199 (13%), Klebsiella 102 (6.7%), Proteus 87 (5.7%), Staphylococcus epidermidis 28(1.8%) and Salmonella in 7 (0.5%) samples. All bacterial isolates showed high sensitivity to Imipenem, Enoxacin, Ofloxacin and Ciprofloxacin while low sensitivity was observed for other antibiotics (n = 16). The Proteus species showed high level of multiple resistances to all antibiotics (5.9%). Imipenem, Enoxacin, Ofloxacin and Ciprofloxacin can be used as an effective antibiotic regimen for treatment of bacterial sepsis in neonates.

Usefulness of presepsin (sCD14 subtype) measurements as a new marker for the diagnosis and prediction of disease severity of sepsis in the Korean population

PurposePresepsin has recently emerged as a new useful sepsis marker, and our study is focused on the usefulness of presepsin as earlier detection and monitoring biomarker for sepsis comparing with other conventional biomarkers. Materials and methodsWe compared the mean values of presepsin, procalcitonin, interleukin 6, and high-sensitivity C-reactive protein levels between infection group and noninfection group of study subjects and assessed whether the values decreased during treatment. Furthemore, we evaluated the diagnostic accuracy of presepsin in sepsis and compared the mean level of presepsin to the Acute Physiology and Chronic Health Evaluation III score and mortality rate on the 30th day. ResultsMean presepsin levels were significantly different between infection group and noninfection group (1403.47 pg/mL vs 239.00 pg/mL). During treatment, mean levels of presepsin decreased significantly, and in the receiver operating characteristic curve analysis, the area under curve value of presepsin was significantly higher than that of other biomarkers. The presepsin levels did not correlate significantly with Acute Physiology and Chronic Health Evaluation III scores and mortality rates on the 30th day. ConclusionsPresepsin showed significantly higher values in infection group than in noninfection group. The diagnostic accuracy of presepsin was higher than other conventional biomarkers. For early diagnosis and treatment of bacterial sepsis, presepsin could be a more useful marker than the other markers.

Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2.

Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis.

Bactericidal/permeability-increasing protein in host defense and its efficacy in the treatment of bacterial sepsis

The 55-kD bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived polypeptide belonging to a family of lipid and endotoxin binding proteins. BPI is composed of two functionally distinct structural domains: a potently antibacterial and antiendotoxin ∼ 20-kD aminoterminal half, and an opsonic carboxy-terminal portion. In multiple animal models, a recombinant amino-terminal fragment of BPI (rBPI21) is nontoxic and protects against gram-negative bacteria and endotoxin. In humans, rBPI21 is also nontoxic and nonimmunogenic and has undergone phase II/III clinical trials with apparent therapeutic benefit.

Activity of the De Novo Engineered Antimicrobial Peptide WLBU2 against Pseudomonas aeruginosa in Human Serum and Whole Blood: Implications for Systemic Applications

Cationic amphipathic peptides have been extensively investigated as a potential source of new antimicrobials that can complement current antibiotic regimens in the face of emerging drug-resistant bacteria. However, the suppression of antimicrobial activity under certain biologically relevant conditions (e.g., serum and physiological salt concentrations) has hampered efforts to develop safe and effective antimicrobial peptides for clinical use. We have analyzed the activity and selectivity of the human peptide LL37 and the de novo engineered antimicrobial peptide WLBU2 in several biologically relevant conditions. The host-derived synthetic peptide LL37 displayed high activity against Pseudomonas aeruginosa but demonstrated staphylococcus-specific sensitivity to NaCl concentrations varying from 50 to 300 mM. Moreover, LL37 potency was variably suppressed in the presence of 1 to 6 mM Mg(2+) and Ca(2+) ions. In contrast, WLBU2 maintained its activity in NaCl and physiologic serum concentrations of Mg(2+) and Ca(2+). WLBU2 is able to kill P. aeruginosa (10(6) CFU/ml) in human serum, with a minimum bactericidal concentration of <9 microM. Conversely, LL37 is inactive in the presence of human serum. Bacterial killing kinetic assays in serum revealed that WLBU2 achieved complete bacterial killing in 20 min. Consistent with these results was the ability of WLBU2 (15 to 20 microM) to eradicate bacteria from ex vivo samples of whole blood. The selectivity of WLBU2 was further demonstrated by its ability to specifically eliminate P. aeruginosa in coculture with human monocytes or skin fibroblasts without detectable adverse effects to the host cells. Finally, WLBU2 displayed potent efficacy against P. aeruginosa in an intraperitoneal infection model using female Swiss Webster mice. These results establish a potential application of WLBU2 in the treatment of bacterial sepsis.

Bactericidal/permeability-increasing protein in host defense and its efficacy in the treatment of bacterial sepsis

Bactericidal/permeability-increasing protein in host defense and its efficacy in the treatment of bacterial sepsis

Meta-analysis of clinical studies of the efficacy of granulocyte transfusions in the treatment of bacterial sepsis.

Meta-analysis was used to explain disagreements across controlled clinical studies of the efficacy of granulocyte transfusions (GTX) in the treatment of bacterial sepsis. Studies published in English in 1970-1994 were retrieved. Seven studies of adults and five of neonates were eligible for analysis. Summary relative odds (RR) of survival in treated patients versus controls were computed for patient subsets defined on the basis of microbiologic proof of infection, recovery of bone marrow function, method of procurement of granulocytes for transfusion, dose of granulocytes transfused, assessment of leukocyte compatibility, and survival rate of controls. The random-effects method was used for all analyses. Differences between the reviewed studies in the dose of granulocytes transfused and the survival rate of controls were primarily responsible for the disagreements across the reports. Adults (RR = 4.2) and neonates (RR = 18.0) receiving adequate doses of granulocytes and adults transfused in centers with a low survival rate of controls (RR = 8.9) experienced a significant (P < .05) benefit from GTX. GTX of adequate dose may be indicated in the 1990s for the treatment of sepsis in neonates, and perhaps also adults admitted to centers with an unusually high mortality rate of untransfused controls. More research is needed to reassess the proper role of GTX, in the light of modern transfusion medicine technology and the presently available options for the treatment of sepsis.

Meta‐analysis of clinical studies of the efficacy of granulocyte transfusions in the treatment of bacterial sepsis

Meta‐analysis of clinical studies of the efficacy of granulocyte transfusions in the treatment of bacterial sepsis

Diagnosis and Treatment of Postoperative Bacterial Sepsis

Early diagnosis and treatment of bacterial sepsis is essential if septicemia is to be successfully overcome. Too often, treatment is delayed for want of overt signs of sepsis, while more subtle early changes have gone unrecognized. A pragmatic approach to diagnosis and treatment of bacterial sepsis following operative procedures is described. The emphasis is on infection by gram-negative organisms.