Monoclonal antibodies and the treatment of gram-negative bacteremia and shock

Article Abstract:

Bacteremia, in which a bacterial infection is carried through the body in the blood, is serious indeed, but the advent of modern antibiotics has improved its treatment greatly. However, in the case of bacteremia with gram-negative organisms, the condition remains very serious. Between 100,000 and 300,000 cases of gram-negative bacteremia occur in the US each year, usually associated with diabetes, some cancers, or serious burns. As many as 100,000 people die as a result. Many of the effects of gram-negative bacteremia result from endotoxins, large complex carbohydrate molecules that exert a variety of toxic effects on the infected organism. These endotoxins share a common feature of their molecular structure called lipid A, which is believed to be responsible for many of endotoxin's deleterious effects. It has long been appreciated that antibodies to the portion of the endotoxin containing the lipid A may block some of the toxic effects, but it has not been until the advent of monoclonal antibody technology that antibodies could be made in sufficient quantities and with sufficient purity to be of clinical importance. In the February 14, 1991 issue of The New England Journal of Medicine, researchers report the use of HA-1A, a monoclonal antibody against endotoxins, in the treatment of bacteremia. They found that the antibody was of no value in patients with bacteremia resulting from other organisms, but that the rate of death was significantly lower among patients with gram-negative bacteremia treated with HA-1A. Serious questions might be raised, however, about the ethics of treating half the patients with placebo only. Half the patients could have been treated with an alternate form of antibody; the scientific validity could have been retained, and lives might have been saved. Furthermore, it is clear that the death rate for gram-negative bacteremia remains unacceptably high, even with antibody treatment. Since the half-life of HA-1A within the body is just over half a day, it might be wise to use repeated injections rather than a single dose, as was done in the reported study. (Consumer Summary produced by Reliance Medical Information, Inc.)

Health aspects, Complications and side effects, Monoclonal antibodies, editorial

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Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial

Article Abstract:

Septicemia, in which bacteria have spread from an infection and are being carried through the body in the blood, is a major cause of illness and death, particularly among hospitalized patients. About 400,000 cases occur in the US each year and the incidence is on the rise. About 30 percent of these cases involve gram-negative bacteria; the mortality for gram-negative bacteremia ranges from 20 to 60 percent, depending on the characteristics of the patients involved. A significant portion of the physiological damage that results from gram-negative septicemia stems from the poisonous effects of endotoxins. Endotoxins are a class of lipopolysaccharide compounds, and the different endotoxin molecules share a common feature, called lipid A, which is believed to be directly responsible for the toxic effects. It is possible to obtain antibodies to the region of endotoxin containing the lipid A by inoculating human volunteers, but there are numerous drawbacks to this approach. Now, however, a line of hybrid human cells has been developed which secretes a monoclonal antibody directed against the endotoxins. This antibody, dubbed HA-1A, has been tested in a controlled study of 543 patients with bacterial sepsis. Among the 343 patients whose septicemia was found not to involve gram-negative bacteria, intravenous administration of the antibody provided no benefit, as might be expected. However, among the patients with gram-negative bacteremia, there were 32 deaths among 105 patients injected with HA-1A, in contrast to 45 deaths among the 92 patients treated only with placebo. When only the patients who entered bacteremic shock were considered, 18 of 54 antibody recipients died, compared with 27 of 47 recipients of placebo. The study demonstrated that the human monoclonal antibody HA-1A is effective in the treatment of sepsis with gram-negative bacteria. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein

Article Abstract:

Tumor necrosis factor receptor:Fc (TNFR:Fc) does not appear to reduce mortality rates in patients in septic shock and may in fact increase mortality. This compound is created by fusing part of TNFR with the Fc portion of immunoglobulin G. It was given in various dosages to 141 patients allocated to receive a low, moderate or high dose or a placebo. At 28 days, mortality rates were 30% in the placebo group, 30% in the low-dose group, 48% in the moderate-dose group and 53% in the high-dose group.

Drug therapy

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