Treatment of Gram-Negative Bacteremia and Septic Shock with HA-1A Human Monoclonal Antibody against Endotoxin

Abstract

HA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia.

Gram-negative bacteria induce proinflammatory cytokine production by monocytes in the absence of lipopolysaccharide (LPS)

“…LPS complexed to CD14 and LPS binding protein signals through Toll-like receptors (TLR) to activate NFkB and induce production of proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-a ), IL-1 and IL-6 [5,6]. Novel therapeutic interventions in Gram-negative septicaemia have been directed at modulating the effects of LPS [7] but with limited success [8±11]. The reason why LPS antagonists have not been effective is presently unknown.…”

Use of Immunoglobulins in Prevention and Treatment of Infection in Critically III Patients: Review and Critique

“…Protection appeared to be specific for gram-negative bacteria because the MoAb to E. coli J5 failed to protect against the pneumococcus, a gram-positive organism that lacks endotoxin. The results of ELISAs and binding inhibition experiments led to the conclusion that the MoAb specifically recognized lipid A [54].…”

“…Indeed, a total of 101 serious complications (e.g., disseminated intravascular coagulation, adult respiratory distress syndrome, acute hepatic failure, and acute renal failure) [54] were noted at entry in the 95 placebo recipients (mean, 1.06 per patient); 85 such complications were noted in the 105 HA-IA recipients (mean, 0.81 per patient) (P = .07 by comparison of Poisson distributions). The 16 additional serious complications in the placebo group might partially account for the higher mortality (13 more deaths) in this group.…”

“…It bound to a large range of gram-negative bacteria and also to gram-positive bacteria, fungi, and lipids unrelated to lipid A, including cardiolipin and lipoproteins (use of such controls has not been previously reported [30,54]). This broad binding pattern suggested nonspecific interactions with hydrophobic constituents and may bring into question the specificity ofHA-IA for lipid A (D. Heumann and J-D Baumgartner, unpublished data).…”

“…Ziegler and colleagues [54] administered HA-lA (or albumin as a control preparation) to patients with a presumptive diagnosis of gram-negative sepsis. The patients were randomized to receive a single dose of HA-lA (100 mg intravenously) or a similar volume of human albumin.…”