Multidrug-resistant Pseudomonas aeruginosa infection in neutropenic patients successfully treated with a combination of polymyxin B and rifampin.
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Adult↗
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Pseudomonas aeruginosa infection in cystic fibrosis. Bactericidal effect of serum from normal individuals and patients with cystic fibrosis on P. aeruginosa strains from patients with cystic fibrosis or other diseases.
P. aeruginosa strains originating from the respiratory tract of patients with cystic fibrosis (CF) and patients with other diseases (non-CF) were analysed with regard to their sensitivity to the bactericidal activity of human serum. P. aeruginosa strains isolated from CF patients were more sensitive than strains from non-CF patients to the bactericidal activity of normal human serum. The bactericidal activity was heatlabile. As regards the sensitivity to normal human serum, mucoid and non-mucoid variants were not found to differ. Strains originating from chronically infected CF patients with many precipitins against these bacteria did not differ with respect to serum sensitivity from strains originating from intermittently colonized CF patients without P. aeruginosa precipitins. Compared with normal sera, CF sera showed similar or higher bactericidal activity against a panel of P. aeruginosa strains. In this respect, any difference between CF sera with precipitins and CF sera without precipitins against P. aeurginosa was not found. Sera from three CF patients chronically infected with P. aeruginosa, and with many precipitins against these bacteria, showed a selective inability in bactericidal activity against the patients' own P. aeruginosa isolate possibly reflecting the presence of "bactericidal blocking" antibodies.
Adolescent↗
Therapeutic effect of immunization with OEP, protease toxoid and elastase toxoid on corneal ulcers in mice due to Pseudomonas aeruginosa infection.
The effectiveness of immunizing mice with protease toxoid (PT) or elastase toxoid (ET) on the corneal ulcerization due to either protease or elastase were investigated. Consequently, mice immunized with either PT or ET were protected from corneal ulcers experimentally induced by the homologous enzyme, either protease or elastase. Similarly, two kinds of rabbit immune sera, anti-PT and anti-ET, were found to prevent corneal ulcers by the homologous enzyme. Then, the therapeutic effects of vaccination with a single or mixed vaccine consisting of one, two or three components, i.e., PT, ET and/or the common antigen (OEP) of Pseudomonas aeruginosa, were examined on corneal ulcers in mice produced by live cultures of the bacteria. For the same purpose, administration of a single or combined rabbit immune sera against PT, ET and OEP was conducted. As a result, vaccination with the three-component-mixed vaccine or administration with rabbit immune sera combined with anti-PT and anti-ET sera in addition to anti-OEP serum, were found to be the most effective in preventing corneal ulceration as well as in treating corneal ulcers in mice.
Animals↗
Respiratory infections with Pseudomonas aeruginosa in children with cystic fibrosis: early detection by serology and assessment of risk factors.
CONTEXT: Patients with cystic fibrosis (CF) are susceptible to lower respiratory tract infections with Pseudomonas aeruginosa and typically acquire this organism in early childhood. Once P aeruginosa infection is established, eradication may be impossible, and progressive lung disease often aggravates morbidity and mortality risks. The ability to diagnose CF by genetic testing at birth makes it possible to determine the temporal sequence of events that result in P aeruginosa-associated pulmonary infections. OBJECTIVE: To evaluate the longitudinal relationship between the production of an antibody response against P aeruginosa and clinical factors associated with P aeruginosa pulmonary infections in patients with CF diagnosed in early life. DESIGN, SETTING, AND PATIENTS: Serum samples and oropharyngeal cultures (protocol cultures) were obtained at 6-month intervals from April 15, 1985, to April 15, 2000 (or for up to 180 months depending on their enrollment date) from 68 patients at 2 centers in Madison and Milwaukee, Wis, diagnosed through the Wisconsin CF Neonatal Screening Project, a longitudinal cohort study. Additional cultures were obtained at examining physicians' discretion (all cultures). MAIN OUTCOME MEASURES: Time to serum IgG, IgA, and IgM antibody titer of at least 1:256 against P aeruginosa, assessed by enzyme-linked immunosorbent assay using cell lysate, exotoxin A, and elastase as antigens; time to organism isolation from respiratory samples; time to Wisconsin Cystic Fibrosis Radiograph (WCXR) score of 5 or more. RESULTS: The median time to an antibody titer of at least 1:256 was 17.8, 24.2, and 70.9 months for cell lysate, exotoxin A, and elastase, respectively. The rise of anti-cell lysate and anti-exotoxin A titers to 1:256 or more occurred a mean of 11.9 (P<.001) and 5.6 (P =.04) months, respectively, before the isolation of P aeruginosa for all cultures and 18.2 (P<.001) and 11.9 (P =.006) months, respectively, before protocol cultures. There was no significant difference between the rise of anti-cell lysate and anti-exotoxin A titer and a WCXR score of 5 or more (P =.24 and.32, respectively). Treatment with long-term, non-Pseudomonas oral antibiotics and integration of CF infants with older, chronically infected patients were associated with a significantly increased risk of P aeruginosa pulmonary infection. CONCLUSIONS: In CF patients diagnosed through neonatal screening, P aeruginosa pulmonary infections occurred 6 to 12 months before the organism was isolated from respiratory secretions. The longitudinal monitoring of P aeruginosa antibody titers, in concert with WCXR score, should facilitate diagnosis and treatment of P aeruginosa pulmonary infections in young children with CF.
ADP Ribose Transferases↗
[Pseudomonas aeruginosa infection].
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Humans↗
Efficacy of a monoclonal antibody directed against tumor necrosis factor in protecting neutropenic rats from lethal infection with Pseudomonas aeruginosa.
A monoclonal antibody directed against murine tumor necrosis factor-alpha (TNF) was studied in a neutropenic rat model to determine its efficacy in protecting animals from lethal infection with Pseudomonas aeruginosa. Anti-TNF monoclonal antibody at a dose of 20 mg/kg given intravenously at 0 and 120 h resulted in a 53% survival rate (8/15) compared with no survival in control animals (0/15) (P less than .005). The combination of anti-TNF monoclonal antibody and oral ciprofloxacin at a suboptimal dose of 2.5 mg/kg/day resulted in a 100% survival rate in neutropenic animals (16/16), while ciprofloxacin alone produced only a 67% survival rate (10/15) during the 7-day period of neutropenia (P less than .05). Thus anti-TNF monoclonal antibody alone or in addition to antimicrobial agents improved survival in neutropenic animals after infection with P. aeruginosa.
Agranulocytosis↗
Adoptive transfer of resistance to Pseudomonas aeruginosa infection by splenocytes and bone marrow cells from BALB/c mice immunized by Pseudomonas aeruginosa lectin preparations.
BALB/c mice immunized by intraperitoneal injection of purified Pseudomonas aeruginosa lectin preparations are fully protected against a lethal dose of the live bacteria. Intraperitoneal inoculation of splenocytes or bone marrow cells obtained from actively immunized mice into naive syngeneic mice was shown to significantly increase their resistance to P. aeruginosa infection. A similar transfer of splenocytes or bone marrow cells from untreated control mice did not provide protection against a lethal Pseudomonas challenge. Administration of immunocompetent cells from immunized animals to naive mice by the i.v. route was less efficient than the i.p. inoculation, probably due to different homing of the cells. Only the i.p. injection concentrated the immune cells to the site of infection.
Animals↗
Immunology of Pseudomonas aeruginosa infection in cystic fibrosis.
Adherence of P. aeruginosa to the lining of the respiratory tract is probably mediated by interaction of pili or alginate with lactosyl and sialosyl residues on the respiratory cells. The toxins produced by P. aeruginosa (for example, elastase and alkaline protease) may play a key role during the initial persistent colonization as they interfere with important defense mechanisms. Neutralizing antibodies are eventually produced, and a poor prognosis is correlated to a pronounced antibody response. The bacteria are protected against the host's defense mechanisms by production of alginate which encapsulates microcolonies of P. aeruginosa in the lungs. During the chronic infection, toxins of P. aeruginosa probably play little if any direct pathogenic role, however, immune complexes seem to be a major trigger of chronic inflammation in the lungs. Proteolytic enzymes and oxygen radicals released from the abundance of neutrophils in the lungs are probably responsible for most of the tissue damage. The individual course of the chronic infection may be explained by regulatory mechanisms, such as cleavage of immune complexes by neutrophil elastase, and by the balance between the different IgG subclass-specific antibody responses.
Bacterial Adhesion↗
Pseudomonas bloodstream infections associated with a heparin/saline flush--Missouri, New York, Texas, and Michigan, 2004-2005.
On January 26, 2005, CDC was notified of four cases of Pseudomonas fluorescens bloodstream infection among patients at an oncology clinic in Missouri. All patients had received a heparin/saline flush to prevent clotting of indwelling, central venous catheters. The flushes were preloaded in syringes by IV Flush and distributed by Pinnacle Medical Supply (Rowlett, Texas). On January 31, a nationwide alert against use of all heparin or saline flushes preloaded in syringes by IV Flush was issued by the Food and Drug Administration; the company recalled these products. As of February 15, state and local health departments and CDC had identified a total of 36 Pseudomonas species infections in patients in four states who were administered the heparin/saline flushes from multiple lots. This report describes the ongoing investigation and provides recommendations for investigation and management of potential cases.
Adolescent↗
Immunogenic efficacy of differently produced recombinant vaccines candidates against Pseudomonas aeruginosa infections.
Three different variants of the recombinant hybrid outer membrane protein OprF (aa 190-342)-OprI (aa 21-83) could be obtained in high yield after expression in Escherichia coli. The hybrid protein was modified N terminally, either with a minimal histidine tag or with a homologous sequence of OprF. Both recombinant proteins were purified by nickel chelate affinity chromatography under native and denaturing conditions, and this produced three suitable candidates for a vaccination trial, protein His-F-I, which was purified in its native as well as in its refolded form; and the native purified N terminally extended protein, ex-F-I. In mice, significantly higher antibody titers and survival rates after challenge with Pseudomonas aeruginosa were observed following immunization with protein His-F-I, purified under native conditions.
Amino Acid Sequence↗
Role of IL-12 and IFN-gamma in Pseudomonas aeruginosa corneal infection.
PURPOSE: In Pseudomonas aeruginosa ocular infection, T-helper cell 1-responsive mouse strains are susceptible (the cornea perforates), and neutralization of IFN-gamma before infection has been shown to delay the onset of perforation. IFN-gamma is the predominant cytokine induced by IL-12, and positive regulation of IL-12 by IFN-gamma, if unchecked, leads to excessive cytokine production and toxicity. Despite its potential importance, the role of IL-12 in ocular infection with P. aeruginosa remains unexplored and was the purpose of this study. METHODS: IL-12 knockout mice, histopathology, RT/PCR and ELISA analyses, immunocytochemistry, and quantitation of viable bacteria in cornea were used to examine the role of IL-12 in IFN-gamma production and the susceptibility phenotype. RESULTS: To directly test the effect of IL-12 on IFN-gamma production, IL-12 knockout and wild-type C57BL/6 mice were used. Both groups of mice were susceptible to infection, with corneal perforation seen at 5 to 7 days after infection. RT-PCR and ELISA analyses confirmed that IL-12 message and protein levels were elevated after infection only in the wild-type mouse cornea. Other differences between the two groups were detected. Knockout versus wild-type mice showed a significant decrease in IFN-gamma mRNA levels in the cornea and cervical lymph nodes and decreased TNF-alpha protein levels in cornea. Corneas of knockout mice also had a significant increase in bacterial load at 5 days after infection when compared with wild-type mice. CONCLUSIONS: These data provide evidence that IL-12 is important in IFN-gamma production and in the absence of the cytokine, both IFN-gamma and TNF-alpha levels in cornea are significantly decreased, resulting in unchecked bacterial growth and perforation.
Animals↗
Cefsulodin treatment for serious Pseudomonas aeruginosa infections.
Cefsulodin, a narrow-spectrum cephalosporin with excellent antipseudomonal activity was used to treat 48 patients with 51 Pseudomonas aeruginosa infections. These included osteomyelitis, infected prostheses, post-operative and post-traumatic superficial wounds, decubitus and stasis ulcers, lower respiratory tract infections and infections of the urinary tract. Many of the patients were compromised by underlying debilitating conditions such as severe trauma, diabetes mellitus, vascular impairment, and abuse of alcohol and drugs. In cases of polymicrobial infections, a concomitant non-antipseudomonal antibiotic was sometimes administered. Cefsulodin was administered intravenously to 47 patients and by intramuscular injections to one individual. The dosage ranged from 0.5 to 2.0 g every six hr and duration of therapy was from 4 to 70 days. A satisfactory clinical response was observed in 88% of the patients. P. aeruginosa was eradicated from 76% of the infection sites. Failures, which included relapse within one year, were generally associated with prior severe trauma or vascular impairment in cases of osteomyelitis. Reinfections and superinfections developed in 12 individuals. Adverse reactions reported for two patients were nausea and vomiting. A third patient had transient increases in alkaline phosphatase and SGOT. These data indicate that cefsulodin is an effective and safe antibiotic in various types of P. aeruginosa infections.
Adult↗
Iron deficiency in cystic fibrosis: relationship to lung disease severity and chronic Pseudomonas aeruginosa infection.
BACKGROUND: Iron deficiency (ID) is common in patients with cystic fibrosis (CF) and may be related to GI factors and chronic inflammation. Pseudomonas aeruginosa (PA) infection is predominantly responsible for chronic lung suppuration in patients with CF, but its survival is critically dependent on the availability of extracellular iron, which it obtains via highly efficient mechanisms. OBJECTIVE: To determine whether ID in CF patients is directly related to the severity of suppurative lung disease. DESIGN: We determined the iron status of 30 randomly selected adult CF patients (13 women) and assessed the relationship to lung disease severity and GI factors by determining their daily sputum volume, FEV(1) percent predicted, C-reactive protein (CRP) level, erythrocyte sedimentation rate, and degree of pancreatic supplementation. Additionally, we measured the sputum concentrations of iron and ferritin in a randomly selected subgroup of 13 of the 30 subjects. SETTING: Adult CF Service in a tertiary-care center. RESULTS: Seventy-four percent of subjects experienced ID (ie, serum iron levels < or = 12 micromol/L and/or transferrin saturation levels < or = 16%). There was no relationship found with the degree of pancreatic supplementation. The daily sputum volume was strongly associated with low serum iron levels, transferrin saturation, ferritin/CRP ratio, and FEV(1) percent predicted (p < 0.05). Serum iron levels and transferrin saturation were negatively related to CRP (r = -0.8 and r = -0.7, respectively; p < 0.01) and erythrocyte sedimentation rate (r = -0.5 and r = -0.4, respectively; p < 0.05). FEV(1) percent predicted was positively related to serum iron level (r = 0.5; p < 0.01), transferrin saturation (r = 0.4; p < 0.05), and ferritin/CRP ratio (r = 0.7; p < 0.05). Sputum iron concentration (median, 63 micromol/L; range, 17 to 134 micromol/L) and ferritin concentration (median, 5,038 microg/L; range, 894 to 6,982 microg/L) exceeded plasma levels and negatively correlated with FEV(1) percent predicted (r = -0.6 and r = -0.5, respectively; p < or = 0.05). CONCLUSION: In our CF patients, ID was directly related to the increased severity of suppurative lung disease but not to the degree of pancreatic insufficiency. Iron loss into the airway may contribute to ID and may facilitate PA infection.
Adult↗
Effect of carbenicillin, gentamicin and vaccines on rats experimentally burned and infected with Pseudomonas aeruginosa.
Carbenicillin and gentamicin were tested on rats experimentally burned and infected by a selected strain of Pseudomonas aeruginosa. Carbenicillin injection was found to be the best treatment as it decreased pus formation and enhanced healing. Gentamicin was less effective than carbenicillin. The use of hydrophilic base ointment containing antibiotics is contraindicated, as it probably provides a favourable environment for Pseudomonas aeruginosa growth. The administration of supernatant vaccines and cell vaccines alone and in conjunction with the antibiotics did not modify the course of infection and healing.
Animals↗
[Monotherapy of systematic Pseudomonas aeruginosa infections with ceftazidime. The causes of therapeutic failures].
Ceftazidime, a new cephalosporin, is characterized by very good in-vitro action against P. aeruginosa. Nonetheless, clinical and (or) microbiological failure occurred in four patients with severe P. aeruginosa infections being treated with ceftazidime. Main cause infections being treated with ceftazidime. Main cause of the discrepancy between in-vitro and in-vivo results during treatment of three patients was a rapid drop in bacterial sensitivity. Superinfection with resistant microorganisms was excluded by the identity of the isolated bacteria in the different epidemiological markers before and during treatment. This rise in resistance was also demonstrated in-vitro by culturing clinically isolated material in ceftazidime-containing media: a 16-fold decrease in sensitivity was demonstrated within three subcultures. Increased beta-lactamase activity of the resistant strains makes it likely that enzymatic inactivation was part of the resistance mechanism. Good inducibility of beta-lactamases and absent resistance transfer argue for chromosomal localisation of the resistance. Because of the development of resistance, severe infections caused by P. aeruginosa should not be treated by ceftazidime alone. In order early to discover the development of resistance, microbiological samples should be taken periodically and examined for their sensitivity.
Ceftazidime↗
DNA vaccines against chronic lung infections by Pseudomonas aeruginosa.
Vaccines containing outer membrane protein F (OprF) of Pseudomonas aeruginosa are effective in reducing lesion severity in a mouse pulmonary chronic infection model. One OprF-based vaccine, called F/I, contains carboxy oprF sequences fused to oprI in an expression vector. When delivered three times biolistically by gene gun, the F/I vaccine induces protection that is antibody-mediated in outbred mice. To demonstrate the role of F/I-induced antibody-mediated immunity, B-cell-deficient [B(-)] and B-cell-intact [B(+)] mice were immunized with F/I, challenged with Pseudomonas, and examined for lesion severity. As expected, F/I-immunized B(+) mice had fewer and less severe lesions than vector-immunized B(+) mice. However, surprisingly, F/I- and vector-immunized B(-) mice were equally protected to levels similar to F/I-immunized B(+) mice. Examination of immune cell populations and cytokine levels indicated a relative increase in the quantity of CD3+ T-lymphocytes in vector- or F/I-immunized and challenged B(-) mice compared to B(+) mice. These data indicate the protective role played by cell-mediated immunity in B(-) mice, which supports our hypothesis that cell-mediated immunity can play an important role in protection against P. aeruginosa.
Animals↗
Oral ciprofloxacin compared with conventional intravenous treatment for Pseudomonas aeruginosa infection in adults with cystic fibrosis.
40 adult patients with cystic fibrosis (CF) were admitted to hospital with acute exacerbations of infection associated with isolation of Pseudomonas aeruginosa from sputum. The patients were randomly allocated (20 per group) to receive intravenous azlocillin 5 g and gentamicin 80 mg, or oral ciprofloxacin 500 mg. Both treatments were given three times a day for 10 days. The patients were assessed on days 1 and 10, and at 6 weeks. There was a significant improvement in lung function between days 1 and 10 in both groups (p less than 0.001). Significant improvement was maintained at 6 weeks after ciprofloxacin but not in the intravenous group. Improvement after ciprofloxacin was superior at day 10. Sputum weight decreased in both groups (p less than 0.001). Patient-recorded symptoms also improved in both groups. There was no serious toxicity or side-effects. Drug resistant organisms were isolated no more frequently after ciprofloxacin than after intravenous therapy. 17 of the ciprofloxacin-treated patients said they preferred oral treatment to intravenous therapy. Oral ciprofloxacin is a useful short-term treatment for patients with CF who are infected with Ps aeruginosa.
Acute Disease↗
Pseudomonas aeruginosa infections in the intensive care unit.
Pseudomonas aeruginosa is a common and highly lethal agent of nosocomial infection, especially among intensive care unit patients. It is widespread in the environment and commonly recovered from water in nature and in hospital settings. P. aeruginosa is endowed with a formidable array of virulence factors that facilitate attachment to host cells, tissue invasion, and systemic disease. It is intrinsically resistant to many commonly employed antibiotics due to a complex variety of mechanisms briefly reviewed here. Resistance to fluoroquinolones appears to be increasing particularly rapidly. Recent advances in the understanding of the molecular biology of this organism have shed considerable light on its ability to form biofilms, which facilitate adherence, especially in cystic fibrosis patients, and confer resistance to clearance by host immune mechanisms and antimicrobial killing. Treatment studies have demonstrated a significant risk of emergence of resistance during therapy with a variety of agents. Several studies suggest that two drugs are better than one for therapy of serious infections, although dual therapy does not always prevent emergence of resistant strains. The sequencing of the genome will lead to new understanding of pathogenesis and may identify new drug targets.
Journal Article↗