Protective activity of an intravenous immune globulin (human) enriched in antibody against lipopolysaccharide antigens of Pseudomonas aeruginosa.

Human plasmas containing naturally high levels of immunoglobulin G (IgG) to lipopolysaccharide antigens of Pseudomonas aeruginosa immunotypes 1, 2, 4, and 6 were identified by an enzyme-linked immunosorbent assay. The high titered plasmas were collected, pooled, and fractionated. Cohn fraction II IgG was prepared for intravenous infusion. The antibody titers in the hyperimmune intravenous immunoglobulin preparation were approximately fivefold higher against P. aeruginosa immunotypes 1, 2, 4, 5, and 6 and approximately twofold higher against immunotypes 3 and 7 than conventional intravenous immunoglobulin G. When tested for prophylaxis in burned mice, the protective doses 50 percent of Pseudomonas-intravenous immunoglobulin G were approximately fourfold less effective against immunotypes 1, 2, 4, and 7 and International Antigenic Typing System Serotypes (IATS), 8 (= immunotype 6) than conventional intravenous immunoglobulin G. Against immunotype 3 and 5, IATS 13, 15, and 16, both immunoglobulin preparations afforded similar levels of protection. In burned mice challenged with immunotypes 1 and 2 and not treated until 18 hours after infection, Pseudomonas-intravenous immunoglobulin G and tobramycin had synergistic activity in preventing death. Pseudomonas-intravenous immunoglobulin G also afforded significant protection to immunosuppressed mice challenged with immunotype 1. These data suggest that Pseudomonas-intravenous immunoglobulin G may be useful in prevention or treatment of P. aeruginosa infections in man.

Antibody levels in reduced/alkylated intravenous immune globulin.

Antibody titers, found in representative lots of a reduced and alkylated intravenous immune globulin, against a variety of common microorganisms are presented. With the more frequently occurring pathogens the specific antibody level does not vary significantly between lots. Depending upon the type of assay used, antibody titers per se may or may not reflect the therapeutic activity of the preparation against a specific microorganism.

Anti-Pseudomonas aeruginosa activity of an intravenous human IgG preparation in burned mice.

A commercially available human IgG chemically modified for intravenous infusion (IGIV) was tested in burned mice for activity against eight strains of Pseudomonas aeruginosa. An 8.7 to 9.6% full-thickness burn was made with a gas flame on the shaved backs of anesthetized mice. A suspension of P. aeruginosa in 0.5 ml saline was then injected subcutaneously in the burn site. Inocula included seven American Type Culture Collection reference strains representing the seven Fisher-Devlin-Gnabasik immunotypes plus an additional strain of immunotype 1. IGIV immunotherapy did not significantly reduce mortality in burned mice challenged with immunotypes 5 and 6 but was highly protective against immunotypes 1-4 and 7. Groups of mice challenged with these five types and treated with approximately 100 or 400 mg IGIV/kg body weight had cumulative mortality rates at 15 days ranging from 0 to 30%, versus an overall mean 84.3% mortality in human serum-albumin treated controls. IGIV was protective if given up to 12 hours after challenge. These data indicate that IGIV has significant in vivo activity against P. aeruginosa and suggest that IGIV immunotherapy may be of value in the treatment of major thermal trauma in man.

Propionate metabolism in the rat heart by 13C n.m.r. spectroscopy.

High-resolution 13C n.m.r. spectroscopy has been used to examine propionate metabolism in the perfused rat heart. A number of tricarboxylic acid (TCA) cycle intermediates are observable by 13C n.m.r. in hearts perfused with mixtures of pyruvate and propionate. When the enriched 13C-labelled nucleus originates with pyruvate, the resonances of the intermediates appear as multiplets due to formation of multiply-enriched 13C-labelled isotopomers, whereas when the 13C-labelled nucleus originates with propionate, these same intermediates appear as singlets in the 13C spectrum since entry of propionate into the TCA cycle occurs via succinyl-CoA. An analysis of the isotopomer populations in hearts perfused with [3-13C]pyruvate plus unlabelled propionate indicates that about 27% of the total pyruvate pool available to the heart is derived directly from unlabelled propionate. This was substantiated by perfusing a heart for 2 h with [3-13C]propionate as the only available exogenous substrate. Under these conditions, all of the propionate consumed by the heart, as measured by conventional chemical analysis, ultimately entered the oxidative pathway as [2-13C] or [3-13C]pyruvate. This is consistent with entry of propionate into the TCA cycle intermediate pools as succinyl-CoA and concomitant disposal of malate to pyruvate via the malic enzyme. 13C resonances arising from enriched methylmalonate and propionylcarnitine are also detected in hearts perfused with [3-13C] or [1-13C]propionate which suggests that 13C n.m.r. may be useful as a non-invasive probe in vivo of metabolic abnormalities involving the propionate pathway, such as methylmalonic aciduria or propionic acidaemia.

Antibody response to a human diploid cell rabies vaccine.

An experimentally killed rabies virus vaccine prepared in a human diploid cell strain (WI-38)-Wyeth rabies vaccine (WRV)-was used by various injection schedules in two separate studies to define more closely in human volunteer subjects an effective vaccination schedule for pre- or postexposure immunization, particularly for donors of rabies-hyperimmune plasma. To permit valid comparisons between our results and those of other workers, antibody levels achieved were expressed in terms of international units (IU) per milliliter of serum. Antibody response of previously nonvaccinated persons were only modest after a single dose of WRV, never reaching a level higher than 0.80 IU/ml over a 56-day testing period. Moreover, antibody was not detected at 0.16 IU/ml before the 14th day, either after a single dose or after two doses given 3 days apart. The best response followed four doses of WRV given within 4 weeks. This schedule resulted in the highest rate of seroconversion to the >/=6 IU/ml antibody level required of potential rabies-immune plasma donors. Giving the first vaccine dose in aluminum hydroxide diluent did not enhance the antibody response. There was a definite suggestion in the various injection schedules that higher and more sustained antibody levels were reached when the interval between the first and second vaccine doses was longest. The greater immunogenicity of WRV as compared with duck embryo vaccine was best demonstrated by the fact that a single booster dose of duck embryo vaccine to previously vaccinated individuals resulted in only a sevenfold antibody rise during the following 56 days, whereas a booster dose of WRV elicited a 69-fold rise. Al(OH)(3) in the first dose of WRV had no effect, but the enhancing effect of a longer interval between vaccine doses was noted once again; 20 of 20 subjects who received three doses of WRV with 4 weeks between doses developed good levels of rabies antibody, and 19 exceeded 6 IU/ml.

Rabies immune globulin of human origin: preparation and dosage determination in non-exposed volunteer subjects.

A clinical study was carried out in volunteer subjects to determine the proper dosage of rabies immune globulin (human) (RIGH) when used in conjunction with rabies vaccine of duck-embryo origin (DEV). Two lots of RIGH were prepared from plasma pools derived from donors with high titres of rabies-neutralizing antibody; both lots had potencies in excess of that accepted for antirabies serum of equine origin. The subjects had never received rabies vaccine but would oridinarily have been given pre-exposure rabies prophylaxis. Serological results obtained during a period of 90 days after the initiation of the study justify the following conclusions: (1) the half-life obtained with RIGH is in agreement with that estimated for homologous passive immune globulin in man; (2) readily detectable levels of rabies antibody were found in all subjects 24 hours after the administration of 40 and 20 international units per kg of RIGH, but not after the administration of 10 international units/kg; and (3) there was an indication that 40 international units/kg may have interfered with optimal active antibody production by the vaccine, and that interference was absent or minimal after doses of 20 intenational units/kg.

[Prevention of gram-negative and gram-positive infections using 3 intravenous immunoglobulin preparations and therapy of experimental polymicrobial burn infection using intravenous Pseudomonas immunoglobulin G and ciprofloxacin in an animal model]. / Prophylaxe gramnegativer und grampositiver Infektionen mit drei intravenösen Immunglobulin-Präparaten und Therapie der experimentellen polymikrobiellen Verbrennungssepsis mit intravenösem Pseudomonas-Immunglobulin G und Ciprofloxacin im Tiermodell.

Three immunoglobulin preparations for intravenous infusion were compared in vivo to determine their relative protective capacity against several gram-negative and gram-positive pathogens. Polyglobin N is a conventional IgG concentrate. Psomaglobin N is identical in formulation to Polyglobin N but is prepared from the plasma of donors who have naturally high levels of antibody to lipopolysaccharide antigens of Pseudomonas aeruginosa. IgGMA is a conventional IgG concentrate containing 12% IgG and 16% IgA. In a murine model of burn wound sepsis the three IgG preparations were similarly protective against three or ten strains of P. aeruginosa. Psomaglobin N and Polyglobin N were significantly (p less than or equal to 0.015) more protective than IgG-MA against six of ten and three of ten strains of P. aeruginosa, respectively. In a murine model of Streptococcus pneumoniae type 3 pneumonia, the three Ig preparations were similarly protective. IgG-MA was significantly more protective (p less than or equal to 0.025) than Psomaglobin N and Polyglobin N against Salmonella typhimurium in murine peritonitis. However, the mean protective dose (PD50) of the two later preparations was less than or equal to 20 mg/kg body weight. In models of peritonitis both Psomaglobin N and Polyglobin N were more protective than IgGMA (p less than or equal to 0.004) against Haemophilus influenzae b, Klebsiella pneumoniae, Serratia marcescens 06:H3 and group B Streptococcus types 1b and 1c. Psomaglobin N and ciprofloxacin were employed to treat established polymicrobial murine burn wound sepsis resulting from contamination of the burn site with mixtures of P. aeruginosa and Staphylococcus aureus. Psomaglobin N or albumin was given once 16 h after challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoglobulin G: potentiation of tobramycin and azlocillin in the treatment of Pseudomonas aeruginosa sepsis in neutropenic mice and neutralization of exotoxin A in vivo.

Mice with cyclophosphamide-induced neutropenia were challenged with four immunotypes of Pseudomonas aeruginosa by contamination of a small dorsal surface wound. The infections were lethal; 100% of control animals (n = 80) treated only with albumin died. Administration of an immunoglobulin G intravenous preparation (IGIV) and/or therapy with tobramycin or azlocillin was begun 16 hr after challenge. Mortality among mice (n = 120) treated only with an antibiotic was 75.0%, while that among mice (n = 80) treated only with IGIV was 78.8%. Combination therapy with IGIV and an antibiotic (n = 120) resulted in mortality of 38.3%. The protection afforded by IGIV may have resulted in part from neutralization of exotoxin A, as mice treated with IGIV before challenge with exotoxin A were subject to lower mortality and had lower levels of serum aspartate and alanine aminotransferases than controls.

[Prevention of gram-negative and gram-positive infections with 3 intravenous immunoglobulin preparations and therapy of experimental polymicrobial burn infection with intravenous Pseudomonas immunoglobulin G and ciprofloxacin in an animal model]. / Prophylaxe gramnegativer und grampositiver Infektionen mit drei intravenösen Immunglobulin-Präparaten und Therapie der experimentellen polymikrobiellen Verbrennungssepsis mit intravenösem Pseudomonas-Immunglobulin G und Ciprofloxacin im Tiermodell.

Three immunoglobulin preparations for intravenous infusion were compared in vivo to determine their relative protective capacity against several gram-negative and gram-positive pathogens. Polyglobin N is a conventional IgG concentrate. Psomaglobin N is identical in formulation to Polyglobin N but is prepared from the plasma of donors who have naturally high levels of antibody to lipopolysaccharide antigens of Pseudomonas aeruginosa. IgGMA is a conventional IgG concentrate containing 12% IgG and 16% IgA. In a murine model of burn wound sepsis the three IgG preparations were similarly protective against three or ten strains of P. aeruginosa. Psomaglobin N and Polyglobin N were significantly (p less than or equal to 0.015) more protective than IgGMA against six of ten and three of ten strains of P. aeruginosa, respectively. In a murine model of Streptococcus pneumoniae type 3 pneumonia, the three Ig preparations were similarly protective. IgGMA was significantly more protective (p less than or equal to 0.025) than Psomaglobin N and Polyglobin N against Salmonella typhimurium in murine peritonitis. However, the mean protective dose (PD50) of the two later preparations was less than or equal to 20 mg/kg body weight. In models of peritonitis both Psomaglobin N and Polyglobin N were more protective than IgGMA (p less than or equal to 0.004) against Haemophilus influenzae b, Klebsiella pneumoniae, Serratia marcescens 06:H3 and group B Streptococcus types 1b and 1c. Psomaglobin N and ciprofloxacin were employed to treat established polymicrobial murine burn wound sepsis resulting from contamination of the burn site with mixtures of P. aeruginosa and Staphylococcus aureus.(ABSTRACT TRUNCATED AT 250 WORDS)