Serial Quantitation of Endotoxemia and Bacteremia During Therapy for Gram-Negative Bacterial Sepsis

Shenep, Jerry L.; Flynn, Patricia M.; Barrett, Frederick F.; Stidham, Gregory L.; Westenkirchner, David F.

doi:10.1093/infdis/157.3.565

Cited by 170 publications

(93 citation statements)

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“…Although the acute bacterial infusion model has been extensively tested and described in a variety of nonhuman primates (17-20, 38, 39), to our knowledge there have been no attempts to determine whether bacteria were bound to E or free in the plasma. In addition, although there is an extensive literature describing human clinical conditions associated with bacteremias, these reports have not revealed whether the bacteria in the bloodstream were free in the plasma or bound to E (33,34,50). Our results demonstrate immune adherence of bacteria to E in the nonhuman primate infusion model.…”

Section: Immune Adherencecontrasting

confidence: 53%

Targeting of Pseudomonas aeruginosa in the Bloodstream with Bispecific Monoclonal Antibodies

Lindorfer

Nardin

Foley³

et al. 2001

The Journal of Immunology

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We examined the ability of a bispecific mAb reagent, consisting of a mAb specific for the primate erythrocyte complement receptor cross-linked with an anti-bacterial mAb, to target bacteria in the bloodstream in an acute infusion model in monkeys. In vitro studies demonstrated a variable level of complement-mediated binding (immune adherence) of Pseudomonas aeruginosa (strain PAO1) to primate E in serum. In vivo experiments in animals depleted of complement revealed that binding of bacteria to E was <1% before administration of the bispecific reagent, but within 5 min of its infusion, >99% of the bacteria bound to E. In complement-replete monkeys, a variable fraction of infused bacteria bound to E. This finding may have significant implications in the interpretation of animal models and in the understanding of bacteremias in humans. Treatment of these complement-replete monkeys with the bispecific reagent led to >99% binding of bacteria to E. Twenty-four-hour survival studies were conducted; several clinical parameters, including the degree of lung damage, cytokine levels, and liver enzymes in the circulation, indicate that the bispecific mAb reagent provides a degree of protection against the bacterial challenge.

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Section: Immune Adherencecontrasting

confidence: 53%

Targeting of Pseudomonas aeruginosa in the Bloodstream with Bispecific Monoclonal Antibodies

Lindorfer

Nardin

Foley³

et al. 2001

The Journal of Immunology

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“…h Total excluding studies with ND 108 (44) 137 (56) 59 (60) 40 (40) Total all studies 142 (49) 144 (51) 66 (62) 41 (38) a The following bacteria causing bacteremia (with numbers of Limulus amebocyte lysate-positive patients and the total numbers of patients) from 17 studies (2,9,10,11,17,22,23,34,37,39,41,52,54,57,58,59,61) are not included in this analysis: N. meningitides (six of six), Salmonella species (seven of nine), Enterobacter species (13 of 33), and Haemophilus influenzae (eight of nine). ND, no data.…”

Section: (55)mentioning

confidence: 99%

Diagnosis of Endotoxemia with Gram-Negative Bacteremia Is Bacterial Species Dependent: a Meta-Analysis of Clinical Studies

Hurley

2009

J Clin Microbiol

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Endotoxemia is undetectable for up to 60% of cases of bacteremia caused by gram-negative (GN) species, a discordance attributed to the limitations of the Limulus assay for endotoxemia. The lipid A structure of the endotoxin molecule is critical for the sensing of GN bacteria by the host immune system although not so for sensing by the Limulus assay. The lipid A structure of commensal Enterobacteriaceae is hexa-acyl, whereas non-Enterobacteriaceae have a broader range of structures. By using a previously published classification of lipid A structures (R. . This finding is consistent across all the unrestricted studies, even including studies with seemingly contrary results for endotoxemia diagnosis among cases of bacteremia caused by GN bacteria overall. Surprisingly, with bacteremia caused by commensal Enterobacteriaceae, the diagnosis of endotoxemia appears to be unrelated to the Limulus assay sensitivity. Across these 45 studies, the association of endotoxemia with GN bacteremia is variable but consistent for different types of GN bacteremia.There are key structural differences between the lipid A components of the endotoxin molecule (lipopolysaccharide) of different gram-negative (GN) bacteria. Members of the Enterobacteriaceae characteristically have a lipid A structure with a hexa-acyl structure, whereas other lipid A structures are present for non-Enterobacteriaceae (45). These differences in lipid A structure are now known to be critically important for the recognition of GN bacteremia by the host immune system (45) by the MD-2-Toll-like receptor 4 receptor but not for sensing by the clotting proteins of the blood cells of the Limulus polyphemus horseshoe crab, from which the Limulus amebocyte lysate assay is derived (56). If the recognition of hexaacyl lipid A by the host immune system has a role in the pathogenesis of bacteremia, it might be expected that the proportion with detectable endotoxemia among patients with GN bacteremia might depend on the lipid A structure of the isolate.Attempts to define the concordance between GN bacteremia and endotoxemia in patients with sepsis have been elusive. Indeed, two of those studies (15, 54), with over a hundred patients each, concluded that there is no concordance. The purpose of this review is to attempt to reconcile the disparate findings from studies of clinically detected sepsis by examining the proportion with endotoxemia detected by using the Limulus assay for patients with different types of GN bacteremia for which the lipid A structures are known. Of particular interest is the proportion with endotoxemia among cases of bacteremia caused by commensal Enterobacteriaceae versus non-Enterobacteriaceae. The statistical techniques of meta-analysis are used to derive study-specific and summary estimates of these proportions expressed as an OR and more so to obtain estimates of the consistency in these ORs across the panel of studies (24). MATERIALS AND METHODS Data sources.A comprehensive search of the literature from 1966 to April 2009 was performed by using...

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“…The hemodynamic and pathologic consequences of septic shock caused by gram-negative bacilli are principally triggered by bacterial endotoxin or lipopolysaccharide (LPS). Circulating levels of endotoxin accompany active gram-negative bacteremia and may be transiently elevated after the initiation of antimicrobial therapy, presumably from the lysis of bacteria (5). Circulating endotoxin initiates a cascade of potentially harmful biologic effects.…”

Section: Introductionmentioning

confidence: 99%

“…This MAb is of the IgG, isotype and was given intravenously at adose of2.5 mg/kg at time 0 and 120 h. The antibody has previously been shown to possess serotype-specific opsonophagocytic activity and to protect rodents from lethal challenge with P. aeruginosa 12.4.4 (20). To determine ifMAb 11.14.1 possessed antiendotoxin activity, SDS-PAGE of P. aeruginosa LPS immunotypes [1][2][3][4][5][6][7] and Western blots were performed as previously described (20). Limulus lysate reactivity by the turbidometric method (Associates of Cape Cod, Woods Hole, MA) was used to compare endotoxin activity of P. aeruginosa 12.4.4 LPS before and after the addition of MAb 11.14.1.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of antilipopolysaccharide and anti-tumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis.

Opal

Cross²,

Sadoff³

et al. 1991

J. Clin. Invest.

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Monoclonal antibodies (MAb) directed against bacterial lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF) provide partial protection in experimental models of septic shock. To determine if additional benefit accrues from a combination of anti-TNF and anti-LPS MAb in the treatment of septic shock, a neutropenic rat model was developed to study active infection with Pseudomonas aeruginosa 12.4A. Animals were treated intravenously with an irrelevant MAb (group 1); anti-TNF MAb (group 2); MAb directed against P. aeruginosa 12.4.4 LPS (group 3); or a combination of anti-TNF and anti-LPS MAb (group 4). None of the control animals in group 1 survived the 7-d period of neutropenia (0/16). In contrast, the survival rate was 44% in group 2 (P < 0.02); 37% in group 3 (P < 0.05); and 75% in group 4 (P < 0.0002). The combination of monoclonal antibodies provided greater protection than either MAb given alone (P < 0.05). Serum TNF levels during infection were significantly greater in groups 1 and 3 (20.1±3.3 U. mean±SE) than in groups 2 and 4 (0.9±0.8 U, P < 0.0001). These results indicate that a combination of monoclonal antibodies to LPS and TNF have additive benefit in experimental Pseudomonas aeruginosa sepsis. This immunotherapeutic approach may be of potential utility in the management ofserious, gram-negative bacterial infection in neutropenic patients. (J.

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Serial Quantitation of Endotoxemia and Bacteremia During Therapy for Gram-Negative Bacterial Sepsis

Cited by 170 publications

References 0 publications

Targeting of Pseudomonas aeruginosa in the Bloodstream with Bispecific Monoclonal Antibodies

Targeting of Pseudomonas aeruginosa in the Bloodstream with Bispecific Monoclonal Antibodies

Diagnosis of Endotoxemia with Gram-Negative Bacteremia Is Bacterial Species Dependent: a Meta-Analysis of Clinical Studies

Efficacy of antilipopolysaccharide and anti-tumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis.

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