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PubMed2005

Effects of intratracheal administration of novispirin G10 on a rat model of mucoid Pseudomonas aeruginosa lung infection.

Chronic Pseudomonas aeruginosa lung infection is a major problem for patients with cystic fibrosis (CF). The biofilm mode of growth of the pathogen makes it highly resistant to antibiotic treatment, and this is especially pronounced with mucoid strains. In this study, novispirin G10, a synthetic antimicrobial peptide patterned loosely on sheep myeloid antimicrobial peptide 29, was tested in a rat model of mucoid P. aeruginosa lung infection. P. aeruginosa NH57388A, a mucoid strain isolated from a CF patient, was mixed with the alginate produced by the bacterium itself and adjusted to a concentration of 10(10) CFU/ml. Each rat received 10(9) CFU of bacteria intratracheally in the left lung to establish lung infection. At 0 and 3 h post P. aeruginosa infection, the treated group of rats received novispirin G10 (0.1 mg/ml, 0.1 ml/rat) intratracheally, whereas the control group received vehicle treatment only. The animals were sacrificed on days 3, 5, 7, and 10 after challenge for evaluation of various parameters. On day 5, 50% of the rats in the treated group had cleared the bacteria from the lungs, whereas in the control group, none of the rats cleared the pathogen (P < 0.03). The average bacterial loads remaining in the lungs of treated rats on days 3 and 5 were more than 170- and 330-fold lower than in the control groups (P < 0.0005 and P < 0.0003). In accordance, the macroscopic and microscopic lung pathology was also significantly milder in the treated group compared to the control group (P < 0.0002). Lung cytokine responses in the treated group were significantly lower than in the control group. The results suggest that novispirin G10 might be useful in treating antibiotic-resistant P. aeruginosa lung infections.

Animals↗
PubMedDate not supplied

[Significance of Pseudomonas aeruginosa virulence factors in acute and chronic Pseudomonas aeruginosa infections].

The virulence of Pseudomonas aeruginosa is multifactorial and caused by several extracellular enzymes and other substances. The importance of these virulence factors for the pathogenesis of human P. aeruginosa infections is dependent on the type of infection. For acute, systemic infections in immunocompromised patients, exotoxin A, alkaline protease and elastase are essential virulence factors. In localized infections (e.g., cystic fibrosis) they seem to be of minor importance, since they are neutralized by specific antibodies in immune complexes, and in the case of exotoxin A cleavage by proteinases from polymorphonuclear leukocytes occurs. The rhamnolipid of P. aeruginosa which has been detected in sputa of patients with cystic fibrosis evades the host's immune response and has to be regarded as a potential virulence factor together with the phenazine pigments, also in chronic P. aeruginosa infections.

ADP Ribose Transferases↗
PubMed1987

[Significance of Pseudomonas aeruginosa virulence factors for acute and chronic Pseudomonas aeruginosa infections].

The virulence of Pseudomonas aeruginosa is multifactorial and caused by several extracellular enzymes and other substances. The importance of these virulence factors for the pathogenesis of human P. aeruginosa infections is dependent on the type of infection. For acute, systemic infections in immunocompromised patients, exotoxin A, alkaline protease and elastase are essential virulence factors. In localized infections (e. g., cystic fibrosis) they seem to be of minor importance, since they are neutralized by specific antibodies in immune complexes, and in the case of exotoxin A cleavage by proteinases from polymorphonuclear leukocytes occurs. The rhamnolipid of P. aeruginosa which has been detected in sputa of patients with cystic fibrosis evades the host's immune response and has to be regarded as a potential virulence factor together with the phenazine pigments, also in chronic P. aeruginosa infections.

ADP Ribose Transferases↗
PubMed1989

Evidence for the in vivo degradation of human respiratory mucins during Pseudomonas aeruginosa infection.

The comparison of distribution of glycopeptides of sputa from patients suffering from various chronic hypersecretions has already shown an increased acidity with a decreased proportion of neutral glycopeptides in the respiratory secretions of patients suffering from cystic fibrosis, as compared to those of patients with chronic bronchitis. In order to find out whether this decrease is specific to cystic fibrosis mucins or whether it is due to a degradation of mucus by Pseudomonas aeruginosa, which infects most of the sputa from patients with this disease, mucus glycopeptides from patients with different chronic bronchial disorders, infected by Pseudomonas or not, were prepared and fractionated by ion-exchange chromatography. The neutral fraction, which has never been studied in detail, was gel-filtered, and provided two fractions, one containing true mucin glycopeptides and the other containing a mixture of peptides and glycopeptides with a lower molecular mass. In the Pseudomonas-infected samples, the true mucin glycopeptide fraction was greatly diminished as compared to this same fraction in non-Pseudomonas-infected samples; this was not specific to cystic fibrosis secretions. In contrast, the glycopeptide fraction with a lower molecular mass was greatly increased in all the Pseudomonas-infected samples. Polyacrylamide gel electrophoresis of this second fraction showed unique glycopeptide bands between 40-50 kDa in the Pseudomonas-infected samples, regardless of the origin of the samples. These bands were revealed by an antibody directed against whole cystic fibrosis mucin. Infected chronic bronchitis sputa and cystic fibrosis samples without P. aeruginosa did not show these bands. These studies therefore suggest that there are P. aeruginosa-associated changes in mucins which may result from degradation of mucins.

Amino Acids↗
PubMed1977

[Laboratory studies on antibiotic chemotherapy of Pseudomonas aeruginosa infections (author's transl)].

Majority of Pseudomonas aeruginosa strains were inhibited at 25 approximately 50 microng/ml of carbenicillin. There was no difference in MIC'S determined using either MUELLER-HINTON agar or Heart Infusion agar. All strains which showed one plus or more sensitivity in either of mono- or tri-disc test showed MIC of 100 microng/ml or less. In view of the high serum concentrations obtainable with 20 approximately 30 g per day dose of carbenicillin, the disc sensitivity test for this antibiotic should reasonably be interpreted as sensitive when it is one plus or more. The combination of carbenicillin with gentamicin or dibekacin showed marked synergism in vitro against Pseudomonas aeruginosa.

Carbenicillin↗
PubMed1989

Pseudomonas aeruginosa infections associated with use of povidone-iodine in patients receiving continuous ambulatory peritoneal dialysis.

Fifteen episodes of infection due to Pseudomonas aeruginosa, including peritonitis and catheter site infections, occurred in nine patients receiving continuous ambulatory peritoneal dialysis over a 27-month period. Eight episodes were associated with catheter loss. Occurrence of P aeruginosa infection was significantly associated with use of povidone-iodine solution to cleanse the catheter site. There was no association with use of povidone-iodine solution to disinfect tubing connections, use of other skin care products or exposure to other environmental sources of P aeruginosa. Cultures of available povidone-iodine products were negative. Local irritation and alteration in skin flora caused by antiseptic solution or low-level contamination of povidone-iodine solution are potential mechanisms of infection.

Catheters, Indwelling↗
PubMed2005

Activities of Pseudomonas aeruginosa effectors secreted by the Type III secretion system in vitro and during infection.

Pseudomonas aeruginosa utilizes a number of distinct pathways to secrete proteins that play various roles during infection. These include the type II secretion system, which is responsible for the secretion of the majority of exoproducts into the surrounding environment, including toxins and degradative enzymes. In contrast, the type III secretion system mediates the delivery of protein effectors directly into the cytoplasm of the host cell. Using tissue culture assays and a mouse acute-pneumonia model, we have determined the contribution of each of the type III effectors during infection. In strain PAK, ExoS is the major cytotoxin required for colonization and dissemination during infection. ExoT confers protection of tissue culture cells from type III-dependent lysis, while ExoY seemed to have little effect on cytotoxicity. ExoU is over 100-fold more cytotoxic than ExoS. The cytotoxicity of type II secretion was determined following deletion of the genes for the more toxic type III secretion system. The participation of these secretion systems during lifelong colonization of cystic fibrosis (CF) patients is unclear. By comparing clonal strains from the same patient isolated at the initial onset of P. aeruginosa infection and more than a decade later, after chronic colonization has been established, we show that initial strains are more cytotoxic than chronic strains that have evolved to reduce type III secretion. Constitutive expression of genes for the type III secretion system restored ExoS secretion but did not always reestablish cytotoxicity, suggesting that CF strains accumulate a number of mutations to reduce bacterial toxicity to the host.

ADP Ribose Transferases↗
PubMed2000

Impact of siderophore production on Pseudomonas aeruginosa infections in immunosuppressed mice.

Pseudomonas aeruginosa produces siderophores, pyoverdin and pyochelin, for high-affinity iron uptake. To investigate their contribution to P. aeruginosa infections, we constructed allelic exchange mutants from strain PAO1 which were deficient in producing one or both of the siderophores. When inoculated into the calf muscles of immunosuppressed mice, pyochelin-deficient and pyoverdin-deficient mutants grew and killed the animals as efficiently as PAO1. In contrast, the pyochelin- and pyoverdin-deficient (double) mutant did not show lethal virulence, although it did infect the muscles. On the other hand, when inoculated intranasally, all mutants grew in the lungs and killed immunosuppressed mice. Compared with PAO1, however, the pyoverdin-deficient mutant and the double mutant grew poorly in the lungs, and the latter was significantly attenuated for virulence. Irrespective of the inoculation route, the pyoverdin-deficient and doubly deficient mutants detected in the blood were significantly less numerous than PAO1. Additionally, in vitro examination demonstrated that the growth of the double mutant was extremely reduced under a free-iron-restricted condition with apotransferrin but that the growth reduction was completely canceled by supplementation with hemoglobin as a heme source. These results suggest that both pyoverdin and pyochelin are required for efficient bacterial growth and full expression of virulence in P. aeruginosa infection, although pyoverdin may be comparatively more important for bacterial growth and dissemination. However, the siderophores were not always required for infection. It is possible that non-siderophore-mediated iron acquisition, such as via heme uptake, might also play an important role in P. aeruginosa infections.

ATP-Binding Cassette Transporters↗
PubMed1974

Virulence and the role of iron in Pseudomonas aeruginosa infection.

The virulence of Pseudomonas aeruginosa can be enhanced by passage in mice or rabbits. Enhanced virulence has some specificity for the host in which the passage is done. Experimental infection in the peritoneal cavity of cannulated rabbits has shown that the injection of iron compounds can lead to a rapid and fatal growth of an otherwise nonlethal dose of bacteria. In vitro the unsaturated iron-binding proteins present in the peritoneal fluid can halve the growth rate of P. aeruginosa. The restricted rate of growth is restored to normal if the iron-binding proteins are saturated with iron. Exactly the same results are achieved with purified transferrin. Both fatal and nonfatal infections with P. aeruginosa cause a sharp fall in the percentage of saturation with Fe of the plasma and peritoneal fluid. In both normal and infected animals the peritoneal fluid is invariably less saturated than the plasma. Specific antiserum not only protects against death but also against the fall in iron saturation of the plasma and peritoneal fluid. In both fatal and nonfatal infections a high proportion of viable bacteria are unphagocytized in the peritoneal cavity.

ABO Blood-Group System↗
PubMed2001

Type III protein secretion is associated with death in lower respiratory and systemic Pseudomonas aeruginosa infections.

The ability of Pseudomonas aeruginosa to secrete specific toxins using the type III-mediated pathway has been reported. To determine the association of this phenotype with human illness, immunoblot analysis was used to detect expression of type III secretory proteins in P. aeruginosa isolates from respiratory tract or blood cultures of 108 consecutive patients. Relative risk of mortality was 6-fold greater with expression of the type III secretory proteins ExoS, ExoT, ExoU, or PcrV. Phenotype was independently correlated with toxicity in cellular and murine models. Prevalence of this phenotype was significantly higher in acutely infected patients than in chronically infected patients with cystic fibrosis. These results suggest that the type III protein secretion system is integral to increased P. aeruginosa virulence. A positive phenotype is a predictor of poor clinical outcome. In the future, such analyses may help distinguish potentially lethal infection from colonization and help determine appropriate therapy for critically ill patients.

Acute Disease↗
PubMed2006

Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis.

RATIONALE: Pseudomonas aeruginosa lung infection in patients with bronchiectasis, a chronic airway disease that is characterized by episodes of exacerbation, is associated with more severe disease and a higher utilization of health-care resources. Inhaled tobramycin solution reduces the number of acute exacerbations in patients with cystic fibrosis (CF)-related bronchiectasis with P aeruginosa infection but remains untested in the treatment of exacerbations in patients with non-CF bronchiectasis. OBJECTIVES: This study tested the effect of adding inhaled tobramycin solution to oral ciprofloxacin (Cip) for the treatment of acute exacerbations of non-CF bronchiectasis in patients with P aeruginosa infection. METHODS: A double-blind, randomized, active comparator, parallel-design study conducted at 17 study centers (5 in the United Kingdom, and 12 in the United States) compared 2 weeks of therapy with Cip with either an inhaled tobramycin solution or placebo in 53 adults with known P aeruginosa infection who were having acute exacerbations of bronchiectasis. MEASUREMENTS: Clinical symptoms, pulmonary function, clinical efficacy, and sputum microbiology were investigated prospectively. MAIN RESULTS: An inhaled solution of Cip with tobramycin, compared to placebo, achieved greater microbiological response but no statistically significant difference in clinical efficacy at days 14 or 21. Clinical and microbiological outcomes at the test of cure (ie, the clinical outcome assessment at day 21) were concordant when an inhaled tobramycin solution was added to therapy with Cip and compared to placebo (p = 0.01). Both subject groups had similar overall adverse event rates, but subjects receiving therapy with an inhaled tobramycin solution reported an increased frequency of wheeze (50%; placebo group, 15%). CONCLUSIONS: The addition of an inhaled tobramycin solution to therapy with oral Cip for the treatment of acute exacerbations of bronchiectasis due to P aeruginosa improved microbiological outcome and was concordant with clinical outcome; the inability to demonstrate an additional clinical benefit may have been due to emergent wheeze resulting from treatment.

Administration, Inhalation↗
PubMed1994

Immunization with Pseudomonas aeruginosa vaccines and adjuvant can modulate the type of inflammatory response subsequent to infection.

Pseudomonas aeruginosa is the predominant pathogen in patients with cystic fibrosis (CF). To study the possibility of preventing lung inflammation and decreasing the progression of the infection by vaccination, we have developed a rat model of chronic P. aeruginosa lung infection. Rats were immunized with P. aeruginosa whole-cell sonicates, O-polysaccharide toxin A conjugate, an alginate-toxin A conjugate, or native alginate. Control animals received sterile saline or incomplete Freund's adjuvant (IFA). The macroscopic (mean score, 2.4 versus 2.7 to 3.2) (P < 0.05) and microscopic (mean score, 2.0 versus 2.1 to 2.8) pathologic abnormalities were less severe in the control rats injected with sterile saline than in the immunized rats and the IFA group. The more severe lung abnormalities observed in immunized rats could be due to the result of immune complex-mediated lung tissue damage. The histopathologic results in the saline control rats were characterized by acute inflammation dominated by numerous polymorphonuclear leukocytes surrounding the alginate beads (microcolonies), as in CF patients. In contrast, the inflammatory response in the IFA group and in the immunized rats had changed from an acute-type inflammation to a chronic-type inflammation dominated by mononuclear leukocytes and scattered granulomas. Cross-reacting antibodies were induced by the two alginate vaccines, and most immunized animals developed a significant (P < 0.001) antibody titer elevation (in enzyme-linked immunosorbent assay) of the immunoglobulin M (IgM), IgG, and IgA classes against the homologous antigens. The bacterial clearance was significantly (P < 0.05) more efficient in most immunized rats than in the control rats given sterile saline. The present study shows that none of the vaccines could completely prevent chronic lung inflammation 4 weeks after challenge. However, the changed pathologic condition in immunized rats to a chronic-type inflammation might be of great benefit in future management of CF patients since the developing lung tissue damage has been shown to be caused by polymorphonuclear leukocyte-released elastase.

Animals↗
PubMedDate not supplied

Current problems in the treatment of infective endocarditis due to Pseudomonas aeruginosa.

Mortality from pseudomonas infective endocarditis remains high despite optimal use of available antibacterial agents. Infection of the tricuspid valve is subacute, but involvement of the mitral or aortic valve precipitates more serious disease. Most valvular infections are due to a single pseudomonad immunotype, but 20% of cases are mixed infections. Antimicrobial susceptibility tests and tests of synergy by beta-lactam and aminoglycoside antibiotics in combination were performed on 30 isolates of Pseudomonas aeruginosa. Azlocillin was the most effective beta-lactam in combination with an aminoglycoside; MKO 787 was least effective. Among the aminoglycosides tested, netilmicin was the most effective. Medical treatment combined with valvulectomy (without valve replacement) is now standard treatment for refractory right-sided endocarditis at this medical center. A high dose of aminoglycoside in combination with a beta-lactam has proved efficacious. For left-sided infection, immediate valve replacement accompanied by a six-week course of the high dose-combined drug regimen is recommended. Newer beta-lactam antibiotics, such as piperacillin, may be limited in usefulness due to beta-lactamase inactivation.

Adolescent↗
PubMed2001

Effect of Lactobacillus casei and yogurt administration on prevention of Pseudomonas aeruginosa infection in young mice.

Pseudomonas aeruginosa is an opportunistic pathogen that rarely causes pulmonary disease in normal hosts but one that is an important cause of acute pneumonia in immunocompromised patients, including neonates, and of chronic pneumonia in patients with cystic fibrosis. The aim of this work was to study the effect of oral administration of Lactobacillus casei and yogurt on prevention of P. aeruginosa lung infection in young mice (3 weeks old). This study demonstrates that oral administration of L. casei or yogurt to young mice enhanced lung clearance of P. aeruginosa and phagocytic activity of alveolar macrophages through a dose-dependent effect. There were, however, no significant differences in white blood cell (WBC) differential counts. Furthermore, it was observed that previous administration of L. casei or yogurt induced a significant increase in IgA and IgM levels in bronchoalveolar lavages (BALs) after a P. aeruginosa infection, although there was no relationship with the serum values.

Administration, Oral↗
PubMed2006

HIV-related bronchopulmonary infection by Pseudomonas aeruginosa in the HAART era: radiological findings.

PURPOSE: To evaluate whether highly active antiretroviral therapy (HAART) modifies radiographic appearances of Pseudomonas aeruginosa bronchopulmonary infection in HIV-infected patients. P. aeruginosa is increasingly reported as a respiratory pathogen in HIV+ patients with very low levels of CD4 lymphocytes. Few studies have analyzed the radiological presentation of bronchopulmonary disease that occurs in HAART-treated patients. MATERIAL AND METHODS: We retrospectively reviewed the chest radiographs of 46 HIV-infected patients with bronchopulmonary diseases in which P. aeruginosa was the sole respiratory pathogen that was isolated. All cases were community-acquired infection. Twenty-four of the patients were on HAART treatment, and 22 were not. Chest radiographs were assessed for the presence and distribution of parenchymal consolidation, reticular or reticulonodular infiltrates, bronchial wall thickening, ground-glass opacities, cavitation, pleural effusion, and adenopathies. Statistical analysis was done using Epi-Info version 6 (CDC, Atlanta, GA, USA). RESULTS: Normal chest radiographs were observed in 11 patients. Eight of these 11 (73%) were receiving HAART, and 3/11 (27%) were not. The most common radiographic abnormality was bronchopneumonia, present in 24 of 46 patients (52%): in 10 of 24 (42%) patients with HAART and 14 of 22 (64%) without. Cavitation was seen in 1 of 24 (4%) patients with HAART and in 5 of 22 (23%) without HAART. CONCLUSION: Cavitation was more frequent in patients that were not receiving HAART, and normal chest radiographs were more frequently seen in patients on HAART.

Adult↗
PubMed1976

Epidemiology of Pseudomonas aeruginosa infections: determination by pyocin typing.

The epidemiology of hospital infections due to Pseudomonas aeruginosa was investigated by pyocin typing. The typing method, which determined the pyocin activity of clinical isolates of P. aeruginosa on 27 indicator strains, was 43.7% reproducible, but elimination of 9 indicator strains doubled the reproducibility and yielded more readable pyocin inhibition zones. Seventy-eight of 1,084 isolates (7.2%) were untypable. In the second part of the study, P. aeruginosa was isolated from 110 patients (5.4% of all admissions) in a 3-month period and typed with the revised method. Twenty pyocin types were identified, 10 of which were obtained from five or more patients. P. aeruginosa was isolated from 45 of 353 environmental samples, including water fountains, ice machines, bar soaps, and germicide solutions for toilet brushes. Twenty percent of the environmental samples were untypable but, among typable strains, the five most common environmental strains were the same as the strains most frequently isolated from patients. The organism was frequently isolated from noses (39%), throats (39%), and stools (29%) of patients with P. aeruginosa infections or colonizations in urine, sputum, surgical wounds, or skin lesions. Six of eight patients had P. aeruginosa in their tracheostomy wounds. Autoinfections by strains already acquired on carrier sites may be significant.

Bacteriocins↗