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Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa.

BACKGROUND: Non-cystic fibrosis (CF) patients with bronchiectasis usually develop chronic bronchial infection with Pseudomonas aeruginosa (PA) that is related to worsening lung function and increased morbidity and mortality. OBJECTIVE: To determine whether direct aerosol delivery of tobramycin to the lower airways may control infection and produce only low systemic toxicity. METHODS: A double-blind, placebo-controlled crossover trial involving 30 patients was conducted to determine the clinical effectiveness and safety of 6-month tobramycin inhalation therapy. Patients received 300 mg of aerosolized tobramycin or placebo twice daily in 2 cycles, each for 6 months, with a one-month washout period. The number of exacerbations, number of hospital admissions, number of hospital admission days, antibiotic use, pulmonary function, quality of life, tobramycin toxicity, density of PA in sputum, emergence of bacterial resistance, and emergence of other opportunistic bacteria were recorded. RESULTS: The number of admissions and days of admission (mean +/- SD) during the tobramycin period (0.15 +/- 0.37 and 2.05 +/- 5.03) were lower than those during the placebo period (0.75 +/-1.16 and 12.65 +/- 21.8) (p < 0.047). A decrease in PA density in sputum was associated with tobramycin administration in the analysis of the first 6-month cycle (p = 0.038). No significant differences were observed in the number of exacerbations, antibiotic use, pulmonary function, and quality of life. The emergence of bacterial resistance and other bacteria did not differ between the 2 periods of study. Inhaled tobramycin was associated with bronchospasm in 3 patients, but not with detectable ototoxicity or nephrotoxicity. CONCLUSIONS: Aerosol administration of high-dose tobramycin in non-CF bronchiectatic patients for endobronchial infection with PA appears to be safe and decreases the risk of hospitalization and PA density in sputum. Nevertheless, pulmonary function and quality of life are not improved, and the risk of bronchospasm is appreciable.

Administration, Inhalation↗

[Development of a latex agglutination method for the diagnosis of Pseudomonas aeruginosa infection].

The present investigation has revealed the possibility of using different kinds of monodispersed polystyrene latex, produced in the USSR, as carriers in the process of the preparation of antibody diagnosticums intended for the detection of water-soluble slime antigens of Pseudomonas aeruginosa strains belonging to the most widespread serological types. The optimum conditions for the preparation of latex reagents and for making the latex-agglutination test have been experimentally established. The new diagnosticums+ have been shown to be highly species- and type-specific, which permits making judgment on the presence or absence of slime antigens of P. aeruginosa strains belonging to definite serovars in the clinical material under study. The preparations thus obtained have been found to retain their sensitivity for 16 months (the term of observation).

Antibodies, Bacterial↗

Experimental studies of the pathogenesis of Pseudomonas aeruginosa infection: evidence for the in-vivo production of a lethal toxin.

Evidence is presented that a lethal toxin is produced by P. aeruginosa growing in the burned skin of experimental mice. After injection of approximately 100 P. aeruginosa cells into the burned skin there was a rapid proliferation of organisms at the site of inoculation. When the organisms in the burned skin tissue reached a critical concentration, there was generalised toxaemia with subsequent mortality; the process was not reversible at this stage, even by reducing substantially the numbers of infecting organisms. However, when the reduction was accompanied by administration of rabbit serum prepared against filter-sterilised extracts of infected burned tissues, approximately 40% of the animals survived for at least 96 h. The data suggests that the antiserum afforded protection by inactivating a toxin produced by the organisms growing in the infected burned tissues rather than by further reducing the numbers of infecting organisms.

Animals↗

Type-specific indirect hemagglutinating antibody in patients with Pseudomonas aeruginosa Infection.

Lipopolysaccharide antigens were extracted from heated cell extracts of several serotypes of Pseudonomas aeruginosa. Indirect hemagglutination with the extracts indicated specific reactivity with sera from rabbits immunized with homologous serotypes of P. aeruginosa. Sera from healthy adults and patients infected with P. aeruginosa were studied subsequently and shown to possess antibodies against P. aeurginosa. In patients infected with P. aeruginosa type E, indirect hemagglutination antibody against type E was resistant to 2-mercaptoethanol (2-ME) and classified as immunoglobulin G. In patients infected with any other type of P. aeruginosa and in healthy adults, it was sensitive to 2-ME and classified as immunoglobulin M. The antibody in the seven patients infected with P. aeruginosa was titrated during the course of infection with lipopolysaccharide antigen prepared from the infecting strain. As a result, all patients either possessed 2-ME-resistant antibody or showed antibody rise to homotypic antigen during the infection. However, no patient showed 2-ME-resistant antibody against hetero-typic lipopolysaccharide antigens. In hospitalized patients, the incidence of anti body against type E, G, and I Pseudomonas strains was greater than that against type A. In particular, 2-ME-resistant antibody to all four serotypes was detected at a higher rate in hospitalized patients than in healthy adults.

Antibodies, Bacterial↗

Combined use of topical cyclosporin A and silver sulphadiazine on allografts infected with Pseudomonas in burned rats.

In this study, we investigated the effects of a combination of topical Cyclosporin A (CyA) and silver sulphadiazine on infected and normal skin allografts in burned and unburned rats. Buffalo (Buf) allografts on unburned Lewis (Lew) recipients survived 16.8 +/- 0.9 days after a 10-day course of topical CyA and silver sulphadiazine, as compared to 7.4 +/- 1.1 days for untreated allografts and 18.6 +/- 0.9 days for those receiving CyA only for 10 days. Allografts infected with Pseudomonas aeruginosa and placed on burned recipients survived significantly longer (13.7 +/- 1.1 days) when treated with silver sulphadiazine and topical CyA for 7 days compared to a similar group of animals treated with silver sulphadiazine alone (8.4 +/- 1.0 days). The mortality rate for burned, infected and allografted animals receiving no medication or topical CyA was 50 per cent compared with zero in animals treated with silver sulphadiazine only or combined silver sulphadiazine and topical CyA.

Administration, Topical↗

Immunization of burned patients against Pseudomonas aeruginosa infection at Safdarjang Hospital, New Delhi.

Patients (746) aged one to 60 years admitted to Safdarjang Hospital with full skin-thickness burns over 5%-70% of their body surface were randomly allocated to a group in a controlled clinical trial in which polyvalent pseudomonas vaccine (PEV-01), antipseudomonas human immunoglobulin, pseudomonas vaccine and immunoglobulin, or no immunologic prophylaxis was administered. The mortality rate for 297 patients immunized with PEV-01 was reduced fourfold in adults and more than twofold in children as compared with that for the 263 patients who received no immunoprophylaxis. Children particularly benefited from prophylaxis with immunoglobulin; the mortality rate for children who received PEV-01 was more than twofold less than that for a control group of unimmunized children. In both children and adults, immunoprophylaxis with PEV-01 plus immunoglobulin was less effective in reducing mortality than was PEV-01 or immunoglobulin administered alone. Antibodies measured by passive hemagglutination and by passive protection tests failed to correlate with one another, but all three immunologic regimens enhanced the bactericidal capacity of whole blood against Pseudomonas aeruginosa. Klebsiella pneumoniae emerged as the dominant gram-negative bacterial species causing bacteremia in patients receiving immunoprophylaxis against P. aeruginosa.

Adolescent↗

A mathematical model of partial-thickness burn-wound infection by Pseudomonas aeruginosa: quorum sensing and the build-up to invasion.

Pseudomonas aeruginosa remains a significant pathogen in burn-wound infection, its pathogenicity being associated with the production of a cocktail of virulence determinants which is regulated by a population-density-dependent mechanism termed quorum sensing. Quorum sensing is effected through the production and binding of signalling molecules. Here we present a mathematical model for the early stages of the infection process by P. aeruginosa in burn wounds which accounts for the quorum sensing system and for the diffusion of signalling molecules in the burn-wound environment. The results of the model and the effects of important parameters are discussed in detail. For example, the effect of the degradation rate of signalling molecules and its significance for anti-signalling therapies is discussed.

4-Butyrolactone↗

Role of alveolar macrophages in the neutrophil-dependent defense system against Pseudomonas aeruginosa infection in the lower respiratory tract. Amplifying effect of muramyl dipeptide analog.

Alveolar macrophages are thought to be important in immune or inflammatory reactions. We investigated the role of alveolar macrophages in defense against Pseudomonas aeruginosa infection in the lower respiratory tract. Intratracheal inoculation of formalin-inactivated P. aeruginosa (1 x 10(8)-1 x 10(10) organisms) into normal rats resulted in increase in the number of neutrophils in the bronchoalveolar lavage (BAL) fluid obtained 24 h later. The phagocytic activity of neutrophils for P. aeruginosa was higher than that of alveolar macrophages. These findings indicate that neutrophils are essential for phagocytosis of P. aeruginosa in the lower respiratory tract. On incubation with P. aeruginosa, alveolar macrophages released neutrophil chemotactic factor (NCF) dose-dependently. MDP-Lys(L18), a muramyl dipeptide analog, stimulated alveolar macrophages to phagocytize P. aeruginosa and stimulate the release of NCF from alveolar macrophages in vitro and enhanced the neutrophil response to inoculated P. aeruginosa in vivo. These results indicate that alveolar macrophages are important in initiating the neutrophil-dependent defense system against P. aeruginosa by releasing NCF and that MDP-Lys(L18) can amplify the defense system.

Acetylmuramyl-Alanyl-Isoglutamine↗

Regulation and function of CCSP during pulmonary Pseudomonas aeruginosa infection in vivo.

Clara cell secretory protein (CCSP) is a 16-kDa homodimeric polypeptide secreted by respiratory epithelial cells in the conducting airways of the lung. To assess the role of CCSP in bacterial inflammation and to discern whether CCSP expression is influenced by bacterial infection, CCSP-deficient [(-/-)] gene-targeted mice and wild-type mice were given Pseudomonas aeruginosa intratracheally. Infiltration by polymorphonuclear cells was significantly increased in the lungs of CCSP(-/-) mice 6 and 24 h after the administration of the bacteria. The number of viable bacteria isolated from the lungs in CCSP(-/-) mice was decreased compared with that in wild-type mice. Concentrations of the proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha were modestly increased after 6 and 24 h, respectively, in CCSP(-/-) mice. The concentration of CCSP protein in lung homogenates decreased for 1-5 days after infection and recovered by 14 days after infection. Likewise, CCSP mRNA and immunostaining for CCSP markedly decreased in respiratory epithelial cells after infection. CCSP deficiency was associated with enhanced pulmonary inflammation and improved killing of bacteria after acute pulmonary infection with P. aeruginosa. The finding that Pseudomonas infection inhibited CCSP expression provides further support for the concept that CCSP plays a role in the modulation of pulmonary inflammation during infection and recovery.

Animals↗