Johansen, H K; Espersen, F; Pedersen, S S;
We have compared a chronic lung infection with Pseudomonas aeruginosa embedded in alginate beads in normal and athymic rats with an acute infection with free live P. aeruginosa bacteria. The following parameters were observed and described: mortality, macroscopic and microscopic pathologic changes...
Pewzner-Jung, Yael; Tavakoli Tabazavareh, Shaghayegh; Grassmé, Heike; Becker, Katrin Anne; Japtok, Lukasz; Steinmann, Jörg; Joseph, Tammar; Lang, Stephan; Tuemmler, Burkhard; Schuchman, Edward H; Lentsch, Alex B; Kleuser, Burkhard; Edwards, Michael J; Futerman, Anthony H; Gulbins, Erich
Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P. aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P. aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection. PMID:25085879
Wu, H.; Song, Z.J.; Givskov, Michael Christian;
To understand the importance of quorum sensing in chronic Pseudomonas aeruginosa lung infection, the in vivo pathogenic effects of the wild-type P aeruginosa PAO1 and its double mutant, PAO1 lasI rhlI, in which the signal-generating parts of the quorum sensing systems are defective were compared...
Full Text Available Jacob G Malone1,21John Innes Centre, Norwich, UK; 2School of Biological Sciences, University of East Anglia, Norwich, UKAbstract: Pseudomonas aeruginosa is an opportunistic pathogen that predominates during the later stages of cystic fibrosis (CF lung infections. Over many years of chronic lung colonization, P. aeruginosa undergoes extensive adaptation to the lung environment, evolving both toward a persistent, low virulence state and simultaneously diversifying to produce a number of phenotypically distinct morphs. These lung-adapted P. aeruginosa strains include the small colony variants (SCVs, small, autoaggregative isolates that show enhanced biofilm formation, strong attachment to surfaces, and increased production of exopolysaccharides. Their appearance in the sputum of CF patients correlates with increased resistance to antibiotics, poor lung function, and prolonged persistence of infection, increasing their relevance as a subject for clinical investigation. The evolution of SCVs in the CF lung is associated with overproduction of the ubiquitous bacterial signaling molecule cyclic-di-GMP, with increased cyclic-di-GMP levels shown to be responsible for the SCV phenotype in a number of different CF lung isolates. Here, we review the current state of research in clinical P. aeruginosa SCVs. We will discuss the phenotypic characteristics underpinning the SCV morphotype, the clinical implications of lung colonization with SCVs, and the molecular basis and clinical evolution of the SCV phenotype in the CF lung environment.Keywords: small colony variants, cystic fibrosis, cyclic-di-GMP, Pseudomonas aeruginosa, RsmA, antibiotics
Xu, Xilin; Shao, Bing; Wang, Ran; ZHOU, SIJING; Tang, Zhongzhi; Lu, Weihua; XIONG, SHENGDAO
Background: Pseudomonas aeruginosa may cause severe or even fatal infection in hosts with immunodeficiency. Interleukin-17 (IL-17) is a newly discovered pro-inflammatory cytokine, which promotes the recruitment and activation of neutrophils in the respiratory tract by inducing release of chemokine C-X-C. Objective: This study was conducted to explore the role of IL-17 in host defense against acute pseudomonas aeruginosa infection in lungs. Methods: The expression of IL-17 and its downstream e...
Jiricny, Natalie; Molin, Søren; Foster, Kevin;
Pseudomonas aeruginosa, is an opportunistic, bacterial pathogen causing persistent and frequently fatal infections of the lung in patients with cystic fibrosis. Isolates from chronic infections differ from laboratory and environmental strains in a range of traits and this is widely interpreted as...
Döring, G; Goldstein, W; A. Röll; Schiøtz, P O; Høiby, N; Botzenhart, K.
We investigated the role of Pseudomonas aeruginosa exoenzymes in cystic fibrosis lung infection in the presence and absence of specific serum antibodies. In sputa of 21 cystic fibrosis patients, concentrations of P. aeruginosa proteases and exotoxin A were determined by sensitive radioimmunoassays. In all sputa, detection of exoenzymes was negative (less than or equal to 10 ng). Positive serum antibody titers to bacterial exoenzymes were found in the majority of patients. Purified immunoglobu...
Winstanley, Craig; O'Brien, Siobhan; Brockhurst, Michael A
Pseudomonas aeruginosa populations undergo a characteristic evolutionary adaptation during chronic infection of the cystic fibrosis (CF) lung, including reduced production of virulence factors, transition to a biofilm-associated lifestyle, and evolution of high-level antibiotic resistance. Populations of P. aeruginosa in chronic CF lung infections typically exhibit high phenotypic diversity, including for clinically important traits such as antibiotic resistance and toxin production, and this diversity is dynamic over time, making accurate diagnosis and treatment challenging. Population genomics studies reveal extensive genetic diversity within patients, including for transmissible strains the coexistence of highly divergent lineages acquired by patient-to-patient transmission. The inherent spatial structure and spatial heterogeneity of selection in the CF lung appears to play a key role in driving P. aeruginosa diversification. PMID:26946977
The global rise in antibiotic resistance is a significant problem facing healthcare professionals. In particular within the cystic fibrosis (CF) lung, bacteria can establish chronic infection and resistance to a wide array of antibiotic therapies. One of the principle pathogens associated with chronic infection in the CF lung is Pseudomonas aeruginosa. P. aeruginosa can establish chronic infection in the CF lung partly through the use of the biofilm mode of growth. This biofilm mode of growth...
Wu, H; Song, Z; Hentzer, Morten;
The pathogenesis of Pseudomonas aeruginosa is associated with expression of virulence factors, many of which are controlled by two N:-acylhomoserine lactone (AHL)-based quorum-sensing systems. Escherichia coli strains equipped with a luxR-based monitor system expressing green fluorescent protein...... (GFP) in the presence of exogenous AHL molecules were used to detect the production of AHLs from P. aeruginosa in vivo. Mice were challenged intratracheally with alginate beads containing P. aeruginosa and E. coli and killed on different days after the challenge. By means of confocal scanning laser...... microscopy, GFP-expressing E. coli bacteria could be detected in the lung tissues, indicating production and excretion of AHL molecules in vivo by the infecting P. aeruginosa. AHL signals were detected mainly in lung tissues exhibiting severe pathological changes. These findings support the view that...
A. L. Pukhalsky
Full Text Available Chronic endobronchial inflammation and bacterial infection are the main causes of morbidity and mortality in cystic fibrosis (CF, an autosomal recessive genetic disorder associated with improper function of chloride channels. Inflammation in CF lung is greatly amplified after Pseudomonas aeruginosa infection. In this study the relationship between P. aeruginosa status and inflammatory markers has been investigated. Seventeen CF children in acute lung exacerbation were examined. CF patients without P. aeruginosa infection were characterized by elevated activity of sputum elastase, reduced response of peripheral blood lymphocytes to PHA and significant resistance to the antiproliferative action of glucocorticoids. These parameters were normalized after antibiotic treatment. The patients with prolonged P. aeruginosa infection demonstrated extremely high levels of elastase activity and elevated amounts of sputum IL-8 and TNF-α. Although antibiotic treatment resulted in clinical improvement, it failed to suppress excessive immune response in the lung. The data indicate that CF patients with prolonged P. aeruginosa need the modified treatment, which should include immunomodulating drugs and protease inhibitors as well as antibacterial therapy.
Griswold, Karl E.; Bement, Jenna L; Teneback, Charlotte C; Scanlon, Thomas C.; Wargo, Matthew J.; Leclair, Laurie W.
There is increasing urgency in the battle against drug-resistant bacterial pathogens, and this public health crisis has created a desperate need for novel antimicrobial agents. Recombinant human lysozyme represents one interesting candidate for treating pulmonary infections, but the wild type enzyme is subject to electrostatic mediated inhibition by anionic biopolymers that accumulate in the infected lung. We have redesigned lysozyme’s electrostatic potential field, creating a genetically eng...
Damlund, Dina Silke Malling; Christophersen, Lars; Jensen, Peter Østrup; Alhede, Morten; Høiby, Niels; Moser, Claus
The majority of cystic fibrosis (CF) patients acquire chronic Pseudomonas aeruginosa lung infection, resulting in increased mortality and morbidity. The chronic P. aeruginosa lung infection is characterized by bacteria growing in biofilm surrounded by polymorphonuclear neutrophils (PMNs). However, the infection is not eradicated and the inflammatory response leads to gradual degradation of the lung tissue. In CF patients, a Th2-dominated adaptive immune response with a pronounced antibody response is correlated with poorer outcome. Dendritic cells (DCs) are crucial in bridging the innate immune system with the adaptive immune response. Once activated, the DCs deliver a set of signals to uncommitted T cells that induce development, such as expansion of regulatory T cells and polarization of Th1, Th2 or Th17 subsets. In this study, we characterized DCs in lungs and regional lymph nodes in BALB/c mice infected using intratracheal installation of P. aeruginosa embedded in seaweed alginate in the lungs. A significantly elevated concentration of DCs was detected earlier in the lungs than in the regional lymph nodes. To evaluate whether the chronic P. aeruginosa lung infection leads to activation of DCs, costimulatory molecules CD80 and CD86 were analyzed. During infection, the DCs showed significant elevation of CD80 and CD86 expression in both the lungs and the regional lymph nodes. Interestingly, the percentage of CD86-positive cells was significantly higher than the percentage of CD80-positive cells in the lymph nodes. In addition, cytokine production from Lipopolysaccharides (LPS)-stimulated DCs was analyzed demonstrating elevated production of IL-6, IL-10 and IL-12. However, production of IL-12 was suppressed earlier than IL-6 and IL-10. These results support that DCs are involved in skewing of the Th1/Th2 balance in CF and may be a possible treatment target. PMID:27009697
Lam, J; Chan, R.; Lam, K.; Costerton, J W
Direct electron microscopic examination of postmortem lung material from cystic fibrosis patients infected with Pseudomonas aeruginosa has shown that these bacterial cells form distinct fiber-enclosed microcolonies in the infected alveoli. Similar examination of bronchoscopy material from infected cystic fibrosis patients showed that the fibres of the enveloping matrix are definitely associated with the bacterial cells. The fibers of the extracellular matrix stain with ruthenium red and are t...
Yang, L.; Haagensen, J.A.; Jelsbak, L.; Sternberg, C.; Høiby, Niels; Molin, S.; Johansen, Helle Krogh
The growth dynamics of bacterial pathogens within infected hosts are a fundamental but poorly understood feature of most infections. We have focused on the in situ distribution and growth characteristics of two prevailing and transmissible Pseudomonas aeruginosa clones that have caused chronic lung...... matrix, whereas nonmucoid variants were present mainly as dispersed cells. To obtain estimates of the growth rates of P. aeruginosa in CF lungs, we used quantitative FISH to indirectly measure growth rates of bacteria in sputum samples (reflecting the in vivo lung conditions). The concentration of r......-phase subpopulation seemed to be present in sputa. This was found for both mucoid and nonmucoid variants despite their different organizations in sputum. The results suggest that the bacterial population may be confronted with selection forces that favor optimized growth activities. This scenario constitutes a new...
Ciofu, Oana; Bagge, Niels; Høiby, Niels
To test the hypothesis that antibodies against the chromosomal beta-lactamase of Pseudomonas aeruginosa (a beta ab) might act as beta-lactamase inhibitors in patients with cystic fibrosis and chronic lung infection with P. aeruginosa, we compared in a rat model of chronic lung infection the...... efficacy of treatment with ceftazidime in beta-lactamase-immunized (group I) and non-immunized (group II) rats. Chronic lung infection was established with alginate-embedded P. aeruginosa producing high amounts of beta-lactamase in 133 Lewis rats. Prior to infection, group I (66 rats) was immunized three...... times at 2-week intervals with purified beta-lactamase in incomplete Freund's adjuvant (IFA) and group II (67 rats) received IFA. Ceftazidime treatment was initiated after challenge and continued for 10 days, after which the rats were sacrificed and the lung bacteriology and pathology were analysed. Rat...
Wu, H; Song, Z; Givskov, Michael;
To understand the importance of quorum sensing in chronic Pseudomonas aeruginosa lung infection, the in vivo pathogenic effects of the wild-type P. aeruginosa PAO1 and its double mutant, PAO1 lasI rhlI, in which the signal-generating parts of the quorum sensing systems are defective were compared...
Full Text Available Chronic lung infection by Pseudomonas aeruginosa is the major severe complication in cystic fibrosis (CF patients, where P. aeruginosa persists and grows in biofilms in the endobronchial mucus under hypoxic conditions. Numerous polymorphonuclear leukocytes (PMNs surround the biofilms and create local anoxia by consuming the majority of O2 for production of reactive oxygen species (ROS. We hypothesized that P. aeruginosa acquires energy for growth in anaerobic endobronchial mucus by denitrification, which can be demonstrated by production of nitrous oxide (N2O, an intermediate in the denitrification pathway. We measured N2O and O2 with electrochemical microsensors in 8 freshly expectorated sputum samples from 7 CF patients with chronic P. aeruginosa infection. The concentrations of NO3(- and NO2(- in sputum were estimated by the Griess reagent. We found a maximum median concentration of 41.8 µM N2O (range 1.4-157.9 µM N2O. The concentration of N2O in the sputum was higher below the oxygenated layers. In 4 samples the N2O concentration increased during the initial 6 h of measurements before decreasing for approximately 6 h. Concomitantly, the concentration of NO3(- decreased in sputum during 24 hours of incubation. We demonstrate for the first time production of N2O in clinical material from infected human airways indicating pathogenic metabolism based on denitrification. Therefore, P. aeruginosa may acquire energy for growth by denitrification in anoxic endobronchial mucus in CF patients. Such ability for anaerobic growth may be a hitherto ignored key aspect of chronic P. aeruginosa infections that can inform new strategies for treatment and prevention.
Moser, Claus; van Gennip, Maria; Bjarnsholt, Thomas;
Moser C, van Gennip M, Bjarnsholt T, Jensen PO, Lee B, Hougen HP, Calum H, Ciofu O, Givskov M, Molin S, Hoiby N. Novel experimental Pseudomonas aeruginosa lung infection model mimicking long-term host-pathogen interactions in cystic fibrosis. APMIS 2009; 117: 95-107. The dominant cause of premature...... death in patients suffering from cystic fibrosis (CF) is chronic lung infection with Pseudomonas aeruginosa. The chronic lung infection often lasts for decades with just one clone. However, as a result of inflammation, antibiotic treatment and different niches in the lungs, the clone undergoes...... and 2003) of the chronic lung infection of one CF patient using the seaweed alginate embedment model. The results showed that the non-mucoid clones reduced their virulence over time, resulting in faster clearing of the bacteria from the lungs, improved pathology and reduced pulmonary production...
Ping Yan; Yiqiang Chen; Zhijun Song; Hong Wu; Jinliang Kong; Xuejun Qin
Objective: To establish an animal model of P.aeruginosa biofilm associated with chronic pulmonary infection and investigate the pathogenic effects of biofilm. Methods: Experiments in vitro, measuring the MICS, MBCS of ievofloxacin(LFX), ceftazidime(CAZ) in PAO579 in alginate beads and planktonic PAO579. Rats were challenged with 0.1 ml of PAO579(109CFU/ml) in alginate beads or 0.1 ml of planktonic PAO579(109CFU/ml), 3,7,14 days after challenging, bacteriological, pathological features were observed. Results: The MICS, MBCS of LFX, CAZ in PAO579 in alginate beads were higher than those in planktonic PAO579 in vitro. CFU/lung in alginate beads group was significantly higher than that in planktonic bacteria group(P = 0.002, P =0.004, P = 0.002, respectively); macroscopic lung pathology and the inflammation in alginate beads group were significantly more severe compared to those in planktonic bacteria group in vivo. Conclusion: P.aeruginosa biofilm protected bacterium from killing of antibiotics and might mediate the host immune damage in the lung tissue and made bacterium evade the host immune defense.
Johansen, Helle Krogh; Gøtzsche, Peter C
Chronic pulmonary infection in cystic fibrosis results in progressive lung damage. Once colonisation of the lungs with Pseudomonas aeruginosa occurs, it is almost impossible to eradicate. Vaccines, aimed at reducing infection with Pseudomonas aeruginosa, have been developed.......Chronic pulmonary infection in cystic fibrosis results in progressive lung damage. Once colonisation of the lungs with Pseudomonas aeruginosa occurs, it is almost impossible to eradicate. Vaccines, aimed at reducing infection with Pseudomonas aeruginosa, have been developed....
Full Text Available Pseudomonas aeruginosa can establish life-long airways chronic infection in patients with cystic fibrosis (CF with pathogenic variants distinguished from initially acquired strain. Here, we analysed chemical and biological activity of P. aeruginosa Pathogen-Associated Molecular Patterns (PAMPs in clonal strains, including mucoid and non-mucoid phenotypes, isolated during a period of up to 7.5 years from a CF patient. Chemical structure by MS spectrometry defined lipopolysaccharide (LPS lipid A and peptidoglycan (PGN muropeptides with specific structural modifications temporally associated with CF lung infection. Gene sequence analysis revealed novel mutation in pagL, which supported lipid A changes. Both LPS and PGN had different potencies when activating host innate immunity via binding TLR4 and Nod1. Significantly higher NF-kB activation, IL-8 expression and production were detected in HEK293hTLR4/MD2-CD14 and HEK293hNod1 after stimulation with LPS and PGN respectively, purified from early P. aeruginosa strain as compared to late strains. Similar results were obtained in macrophages-like cells THP-1, epithelial cells of CF origin IB3-1 and their isogenic cells C38, corrected by insertion of cystic fibrosis transmembrane conductance regulator (CFTR. In murine model, altered LPS structure of P. aeruginosa late strains induces lower leukocyte recruitment in bronchoalveolar lavage and MIP-2, KC and IL-1beta cytokine levels in lung homogenates when compared with early strain. Histopathological analysis of lung tissue sections confirmed differences between LPS from early and late P. aeruginosa. Finally, in this study for the first time we unveil how P. aeruginosa has evolved the capacity to evade immune system detection, thus promoting survival and establishing favourable conditions for chronic persistence. Our findings provide relevant information with respect to chronic infections in CF.
Ciofu, Oana; Johansen, Helle Krogh; Aanaes, Kasper; Wassermann, Tina; Alhede, Morten; von Buchwald, Christian; Høiby, Niels
-lung transplantation isolates. RESULTS: The same phenotypes caused by similar mutations and similar gene expression profiles were found in mucoid and non-mucoid isolates from the paranasal sinuses and from the lungs before and after transplantation. CONCLUSION: Bilateral exchange of P. aeruginosa isolates between the...
Hoffmann, Nadine; Rasmussen, Thomas Bovbjerg; Jensen, Peter Østrup;
mice (Cftr(tmlUnc-/-)) and BALB/c mice, as reflected by the detection of a high number of P. aeruginosa organisms in the lung homogenates at 7 days postinfection and alginate biofilms, surrounded by polymorphonuclear leukocytes in the alveoli. In comparison, both an AHL-producing nonmucoid revertant...
Dudhani, Rajesh V.; Turnidge, John D.; Coulthard, Kingsley; Milne, Robert W.; Rayner, Craig R.; Li, Jian; Nation, Roger L.
Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation stud...
Lee, Bao le ri; Schjerling, Charlotte K.; Kirkby, Nikolai;
Phenotypic and genotypic diversifications of Pseudomonas aeruginosa in the airways of patients with cystic fibrosis (CF) promote long-term survival of bacteria during chronic lung infection. Twelve clonally related, sequential mucoid and non-mucoid paired P. aeruginosa isolates obtained from three...
Lavoie, Elise G.; Wangdi, Tamding; Kazmierczak, Barbara I.
Innate immune responses play a critical role in controlling acute infections due to Pseudomonas aeruginosa in both mice and in humans. In this review we focus on innate immune recognition and clearance mechanisms that are important for controlling P. aeruginosa in the mammalian lung, with particular attention to those that influence the outcome of in vivo infection in murine models.
Moser, C; Johansen, H K; Song, Z;
The chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) is characterized by a pronounced antibody response and microcolonies surrounded by numerous polymorphonuclear neutrophils (PMN). Poor prognosis is correlated with a high antibody response to P. aeruginosa antigens. An animal...... was cleared more efficiently in C3H/HeN mice and significantly more C3H/HeN mice showed normal lung histopathology (p
Lange, K H; Hougen, H P; Høiby, N;
In a rat model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis, we investigated the possibility of preventing chronic lung inflammation or decreasing the progression of the infection. We compared the lethality, pathology, bacterial clearance, and immunogenicity after...... stimulation of the non-specific defence mechanisms by Escherichia coli lipopolysaccharide (LPS) or P. aeruginosa sonicate, or the acquired specific immune response by vaccination with the same bacterial antigens. One day prior to challenge with P. aeruginosa embedded in alginate beads, rats were stimulated...... with either E. coli LPS or P. aeruginosa sonicate. Four and two weeks prior to challenge other rats were vaccinated with either E. coli LPS or P. aeruginosa sonicate. Controls did not receive any stimulation or vaccination. The lethality after challenge was lower in rats stimulated with E. coli LPS (p...
d'Angelo, Ivana; Casciaro, Bruno; Miro, Agnese; Quaglia, Fabiana; Mangoni, Maria Luisa; Ungaro, Francesca
Cationic antimicrobial peptides (CAMPs) are very promising in the treatment of multi-drug resistant Pseudomonas aeruginosa lung infections experienced by cystic fibrosis (CF) patients. Nevertheless, there is an urgent need of inhalable formulations able to deliver the intact CAMP in conductive airways and to shield its interactions with airway mucus/bacterial biofilm, thus enhancing CAMP/bacteria interactions. Along these lines, the aim of this work was the design and development of nano-embedded microparticles (NEM) for sustained delivery of CAMPs in the lung. To this purpose, nanoparticles (NPs) made of poly(lactide-co-glycolide) (PLGA) containing a model CAMP, colistin (Col), were produced by emulsion/solvent diffusion technique. Engineering NPs with chitosan (CS) and poly(vinyl alcohol) (PVA) allowed to modulate surface properties and, in so doing, to improve NP transport through artificial CF mucus. In order to achieve a long-term stable dosage form useful for NP inhalation, NPs were spray-dried in different carriers (lactose or mannitol), thus producing NEM. The most promising NEM formulations were selected on the basis of bulk and flow properties, distribution of NPs in the carrier and aerosolization performance upon delivery through a breath-actuated dry powder inhaler. Of note, selected Col-loaded NEM were found to kill P. aeruginosa biofilm and to display a prolonged efficacy in biofilm eradication compared to the free Col. This effect was likely ascribable to the ability of NPs to penetrate into bacterial biofilm, as demonstrated by confocal analysis, and to sustain Col release inside it. Taken all together, our results indicate that adequate engineering of PLGA NPs represents an enticing technological approach to harness novel antimicrobials for P. aeruginosa lung infection, such as CAMPs, especially in CF. PMID:26340361
The intensive antibiotic treatment of cystic fibrosis (CF) patients with chronic lung infection with Pseudomonas aeruginosa has improved the survival rate and the clinical condition of Danish patients. Acquirement of resistance to anti-pseudomonal antibiotics is one of the main drawbacks of this...... therapeutic strategy and our results showed the development of resistance of P. aeruginosa to several antibiotics during 25 years of intensive antibiotic treatment. Our studies have been concentrating on the development of resistance to beta-lactam antibiotics. We have shown an association between the...... induction to even higher levels during treatment with beta-lactam antibiotics, were the most frequent phenotype found among resistant Danish P. aeruginosa CF isolates. We have also shown that the high alginate producing P. aeruginosa isolates, that characterize the chronic lung infection in CF patients, are...
use of conventional antimicrobial compounds in many cases cannot eradicate biofilms, there is an urgent need to develop alternative measures to combat biofilm infections. The present review is focussed on the important opportunistic pathogen and biofilm model organism Pseudomonas aeruginosa. Initially...
Dudhani, Rajesh V; Turnidge, John D; Coulthard, Kingsley; Milne, Robert W; Rayner, Craig R; Li, Jian; Nation, Roger L
Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation studies were conducted over 24 h with a dose range of 5 to 160 mg/kg of body weight/day. The bacterial burden in the thigh or lung was measured at 24 h after the initiation of treatment. Relationships between antibacterial effect and measures of exposure to unbound (f) colistin (area under the concentration-time curve [fAUC/MIC], maximum concentration of drug in plasma [fC(max)]/MIC, and the time that the concentration in plasma is greater than the MIC [fT > MIC]) were examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R(2) = 87%) and the lung infection model (R(2) = 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans. PMID:20028824
Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary growth phase killing of P. aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr -/--mice
Hoffmann, N.; Lee, Bao le ri; Hentzer, Morten;
The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) ...
Calum, Henrik; Moser, Claus; Jensen, Peter Østrup;
infection in cystic fibrosis. Lung cell suspensions were depleted of lymphocytes by magnetic cell sorting. The concentrations of IFN-gamma, IL-1beta and GM-CSF were estimated by ELISA at day 1 and 2 after infection. Non-infected mice were used as controls. Flow cytometry was used to estimate the surface...... expression of Fc receptors was significantly lower on NK cells in C3H/HeN mice at day 1 and 2. In conclusion, the present results show phenotypic differences in NK cells in the two mice strains in chronic P. aeruginosa lung infection, indicating different modulating effects in the Th1/Th2 balance....
Bacteria in natural, industrial and clinical settings predominantly live in biofilms, i.e., sessile structured microbial communities encased in self-produced extracellular matrix material. One of the most important characteristics of microbial biofilms is that the resident bacteria display a...... remarkable increased tolerance toward antimicrobial attack. Biofilms formed by opportunistic pathogenic bacteria are involved in devastating persistent medical device-associated infections, and chronic infections in individuals who are immune-compromised or otherwise impaired in the host defense. Because the...... use of conventional antimicrobial compounds in many cases cannot eradicate biofilms, there is an urgent need to develop alternative measures to combat biofilm infections. The present review is focussed on the important opportunistic pathogen and biofilm model organism Pseudomonas aeruginosa. Initially...
van Gennip, M; Moser, Claus; Christensen, Louise D;
Background: Effects of treatment with tobramycin initiated 1 or 24 h post-infection were investigated in a new version of a pulmonary infection model in mice. The model reflects the differentiated behaviour of Pseudomonas aeruginosa mucoid strains isolated from the lungs of one chronically infected...... cystic fibrosis (CF) patient at different time periods during chronic lung infection. Methods: BALB/c mice were challenged with alginate-embedded mucoid clinical isolates isolated in 1988, 1997 or 2003. Mice were euthanized on day 1, 2 or 3 post-infection for estimation of quantitative bacteriology......: A significant reduction in the number of bacteria was observed when initiating treatment 1 h post-infection compared with initiating treatment after 24 h, although the latest isolate avoided complete clearance. Early antibiotic treatment directed at the mucoid phenotype in mice also reduced the...
Dubin, Patricia J.; Martz, Ashley; Eisenstatt, Jessica R.; Fox, Michael D.; Logar, Alison; Kolls, Jay K.
Pseudomonas aeruginosa is an opportunistic pathogen that is capable of causing acute and chronic pulmonary infection in the immunocompromised host. In the case of cystic fibrosis (CF), chronic P. aeruginosa infection causes increased mortality by promoting overly exuberant airway inflammation and cumulative lung damage. Identifying the key regulators of this inflammation may lead to the development of new therapies that improve P. aeruginosa-related mortality. We report here that interleukin-...
Hansen, Susse Kirkelund; Rau, Martin Holm; Johansen, Helle Krogh;
The opportunistic pathogen Pseudomonas aeruginosa is a frequent colonizer of the airways of patients suffering from cystic fibrosis (CF). Depending on early treatment regimens, the colonization will, with high probability, develop into chronic infections sooner or later, and it is important to es...
suggest that addition of oral ciprofloxacin to inhaled tobramycin may reduce lung inflammation. Clinical trials with new formulations of old antibiotics for inhalation therapy (aztreonam lysine) against chronic P. aeruginosa infection improved patient-reported outcome, lung function, time to acute...... patients without P. aeruginosa infection did not improve lung function. Here I review the recent advances in the treatment of P. aeruginosa lung infections with a focus on inhalation treatments targeted at prophylaxis and chronic suppressive therapy....
Jensen, Peter Østrup; Lykkesfeldt, Jens; Bjarnsholt, Thomas;
Considerable evidence supports the presence of oxidative stress in cystic fibrosis (CF). The disease has long been associated with both increased production of reactive oxygen species and impaired antioxidant status, in particular during the chronic pulmonary infection with Pseudomonas aeruginosa......, which is the main cause of morbidity and mortality in CF. Guinea pigs are unable to synthesize ascorbate (ASC) or vitamin C, a major antioxidant of the lung, and thus like human beings rely on its presence in the diet. On this basis, guinea pigs receiving ASC-deficient diet have been used as a model of...... present in animals on ASC-deficient diet compared with animals on ASC sufficient diet. Measurements of the ASC levels in the lung were significantly decreased in infected compared with non-infected animals. Interestingly, the infection by itself decreased the antioxidant capacity of the plasma (measured...
Alejandro J Moyano; Sofía Feliziani; Julio A Di Rienzo; Smania, Andrea M.
Pseudomonas aeruginosa is an opportunistic pathogen that chronically infects the airways of cystic fibrosis (CF) patients and undergoes a process of genetic adaptation based on mutagenesis. We evaluated the role of mononucleotide G:C and A:T simple sequence repeats (SSRs) in this adaptive process. An in silico survey of the genome sequences of 7 P. aeruginosa strains showed that mononucleotide G:C SSRs but not A:T SSRs were greatly under-represented in coding regions, suggesting a strong coun...
d'Angelo, Ivana; Perfetto, Brunella; Costabile, Gabriella; Ambrosini, Veronica; Caputo, Pina; Miro, Agnese; d'Emmanuele di Villa Bianca, Roberta; Sorrentino, Raffaella; Donnarumma, Giovanna; Quaglia, Fabiana; Ungaro, Francesca
We have recently demonstrated that the specific inhibition of nuclear factor-κB by a decoy oligonucleotide (dec-ODN) delivered through inhalable large porous particles (LPP) made of poly(lactic-co-glycolic acid) (PLGA) may be highly beneficial for long-term treatment of lung inflammation. Nevertheless, besides chronic inflammation, multifunctional systems aimed to control also infection are required in chronic lung diseases, such as cystic fibrosis (CF). In this work, we tested the hypothesis that engineering PLGA-based LPP with branched poly(ethylenimine) (PEI) may improve LPP properties for pulmonary delivery of dec-ODN, with particular regard to the treatment of Pseudomonas aeruginosa lung infections. After getting insight into the role of PEI on the technological properties of PLGA-based LPP for delivery of dec-ODN, the putative synergistic effect of PEI free or PEI released from LPP on in vitro antimicrobial activity of tobramycin (Tb) and aztreonam (AZT) against P. aeruginosa was elucidated. Meanwhile, cytotoxicity studies on A549 cells were carried out. Results clearly demonstrate that the dry powders have promising aerosolization properties and afford a prolonged in vitro release of both dec-ODN and PEI. The encapsulation of PEI into LPP results in a 2-fold reduction of the minimum inhibitory concentration of AZT, while reducing the cytotoxic effect of PEI. Of note, the developed ODN/PLGA/PEI LPP persisted at lung at least for 14 days after intratracheal administration in rats where they can provide sustained and combined release of dec-ODN and PEI. dec-ODN will likely act as an anti-inflammatory drug, while PEI may enhance the therapeutic activity of inhaled antibiotics, which are commonly employed for the treatment of concomitant lung infections. PMID:27002689
Wu, H.; Song, Z.; Hentzer, Morten; Andersen, Jens Bo; Molin, Søren; Givskov, Michael Christian; Høiby, N.
Introduction: Antibiotics are used to treat bacterial infections by killing the bacteria or inhibiting their growth, but resistance to antibiotics can develop readily. The discovery that bacterial quorum-sensing regulates bacterial virulence as well as the formation of biofilms opens up new ways to...... lung infection by targeting bacterial quorum-sensing without directly killing bacteria or inhibiting their growth. Methods: Study I. Mice with Escherichia coli MT102 [luxR-PluxI-gfp(ASV)] lung infection were injected intravenously with N-acyl homoserine lactones with or without furanones to test the...
Wu, H.; Song, Z.; Hentzer, Morten;
Introduction: Antibiotics are used to treat bacterial infections by killing the bacteria or inhibiting their growth, but resistance to antibiotics can develop readily. The discovery that bacterial quorum-sensing regulates bacterial virulence as well as the formation of biofilms opens up new ways to...... control certain bacterial infections. Furanone compounds capable of inhibiting bacterial quorum-sensing systems have been isolated from the marine macro alga Delisea pulchra. Objectives: Two synthetic furanones were tested for their ability to attenuate bacterial virulence in the mouse models of chronic...... lung infection by targeting bacterial quorum-sensing without directly killing bacteria or inhibiting their growth. Methods: Study I. Mice with Escherichia coli MT102 [luxR-PluxI-gfp(ASV)] lung infection were injected intravenously with N-acyl homoserine lactones with or without furanones to test the...
Full Text Available Chronic respiratory infection by Pseudomonas aeruginosa is a major cause of mortality in cystic fibrosis (CF. We investigated the interplay between three key microbiological aspects of these infections: the occurrence of transmissible and persistent strains, the emergence of variants with enhanced mutation rates (mutators and the evolution of antibiotic resistance. For this purpose, 10 sequential isolates, covering up to an 8-year period, from each of 10 CF patients were studied. As anticipated, resistance significantly accumulated overtime, and occurred more frequently among mutator variants detected in 6 of the patients. Nevertheless, highest resistance was documented for the nonmutator CF epidemic strain LES-1 (ST-146 detected for the first time in Spain. A correlation between resistance profiles and resistance mechanisms evaluated [efflux pump (mexB, mexD, mexF, and mexY and ampC overexpression and OprD production] was not always obvious and hypersusceptibility to certain antibiotics (such as aztreonam or meropenem was frequently observed. The analysis of whole genome macrorestriction fragments through Pulsed-Field Gel Electrophoresis (PFGE revealed that a single genotype (clone FQSE-A produced persistent infections in 4 of the patients. Multilocus Sequence typing (MLST identified clone FQSE-A as the CF epidemic clone ST-274, but striking discrepancies between PFGE and MLST profiles were evidenced. While PFGE macrorestriction patterns remained stable, a new sequence type (ST-1089 was detected in two of the patients, differing from ST-274 by only two point mutations in two of the genes, each leading to a nonpreviously described allele. Moreover, detailed genetic analyses revealed that the new ST-1089 is a mutS deficient mutator lineage that evolved from the epidemic strain ST-274, acquired specific resistance mechanisms, and underwent further interpatient spread. Thus, presented results provide the first evidence of interpatient dissemination
Kolpen, Mette; Kühl, Michael; Bjarnsholt, Thomas;
local anoxia by consuming the majority of O2 for production of reactive oxygen species (ROS). We hypothesized that P. aeruginosa acquires energy for growth in anaerobic endobronchial mucus by denitrification, which can be demonstrated by production of nitrous oxide (N2O), an intermediate in the...... denitrification pathway. We measured N2O and O2 with electrochemical microsensors in 8 freshly expectorated sputum samples from 7 CF patients with chronic P. aeruginosa infection. The concentrations of NO3(-) and NO2(-) in sputum were estimated by the Griess reagent. We found a maximum median concentration of 41.......8 µM N2O (range 1.4-157.9 µM N2O). The concentration of N2O in the sputum was higher below the oxygenated layers. In 4 samples the N2O concentration increased during the initial 6 h of measurements before decreasing for approximately 6 h. Concomitantly, the concentration of NO3(-) decreased in sputum...
Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants
Ciofu, Oana; Mandsberg, Lotte F.; Bjarnsholt, Thomas;
During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated...
Johansen, H.K.; Gøtzsche, Peter C.; Johansen, Helle Krogh
BACKGROUND: Chronic pulmonary infection in cystic fibrosis results in progressive lung damage. Once colonisation of the lungs with Pseudomonas aeruginosa occurs, it is almost impossible to eradicate. Vaccines, aimed at reducing infection with Pseudomonas aeruginosa, have been developed. OBJECTIVES......: To assess the effectiveness of vaccination against Pseudomonas aeruginosa in cystic fibrosis. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register using the terms vaccines AND pseudomonas (last search May 2008) and PubMed using the terms vaccin* AND...... cystic fibrosis (last search May 2008). SELECTION CRITERIA: Randomised trials (published or unpublished) comparing Pseudomonas aeruginosa vaccines (oral, parenteral or intranasal) with control vaccines or no intervention in cystic fibrosis. DATA COLLECTION AND ANALYSIS: The authors independently selected...
de Vrankrijker, Angélica M M; Wolfs, Tom F W; Ciofu, Oana;
Pseudomonas aeruginosa causes opportunistic infections in immunocompromised individuals and patients ventilated mechanically and is the major pathogen in patients with cystic fibrosis, in which it causes chronic infections. Epidemiological, in vitro and animal data suggest a role for respiratory...... the lung homogenates when compared to mice which were only infected with P. aeruginosa and lung function changes were more severe in co-infected mice. Control mice receiving RSV alone showed no significant changes in lung function or cytokine production, and no inflammatory changes in the lung...
Moser, Claus; Jensen, Peter Ø; Pressler, Tacjana;
The inflammation in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa lung infection is dominated by polymorphonuclear neutrophils (PMNs). There seems to be a relationship between the PMN-dominated inflammation, pronounced antibody production and a Th2-dominated response. Apart from...... lung function. In addition, an inverse correlation between IL-3 and IFN-gamma was observed. The results indicate involvement of endogenous GM-CSF, G-CSF and IL-3 in the skewed Th response in CF, and change to a Th1-dominated response might be achieved with GM-CSF treatment....
Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants.
Ciofu, Oana; Mandsberg, Lotte F; Bjarnsholt, Thomas; Wassermann, Tina; Høiby, Niels
During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated that mutator populations are amplified in the CF lung by hitchhiking with adaptive mutations. Two of the genes that are frequently mutated in isolates from chronic infection are mucA and lasR. Loss-of-function mutations in these genes determine the phenotypic switch to mucoidy and loss of quorum sensing, which are considered hallmarks of chronic virulence. The aims of our study were to investigate (1) the genetic background of the P. aeruginosa subpopulations with non-mutator, weak or strong mutator phenotype and their dynamics during the chronic lung infection, and (2) the time sequence in which the hypermutable, mucoid and quorum-sensing-negative phenotypes emerge during chronic lung infection. For these purposes the sequences of mutS, mutL, uvrD, mutT, mutY and mutM anti-mutator genes as well as of mucA and lasR were analysed in 70 sequential P. aeruginosa isolates obtained from the respiratory secretions of 10 CF patients (one to three isolates per time point). Analysis of the genetic background of the mutator phenotype showed that mutS was the most commonly affected gene followed by mutL in isolates with strong mutator phenotype. The mutT, mutY, mutM genes were affected in isolates with low fold-changes in the mutation frequencies compared to the reference strain PAO1. Isolates with non-mutator, weak or strong mutator phenotype were represented at all time points showing co-existence of these subpopulations, which suggests parallel evolution of the various mutators in the different focal niches of infection in the CF lung. Mutations in mucA and lasR occurred earlier than mutations in the anti-mutator genes, showing that hypermutability is not a prerequisite for the
Kragh, Kasper Nørskov; Alhede, Morten; Jensen, Peter Ø;
Cystic fibrosis (CF) patients have increased susceptibility to chronic lung infections by Pseudomonas aeruginosa, but the ecophysiology within the CF lung during infections is poorly understood. The aim of this study was to elucidate the in vivo growth physiology of P. aeruginosa within lungs of...... whereby PMNs slow the growth of the bacteria and render them less susceptible to antibiotic treatment while enabling them to persist by anaerobic respiration....
Cornelis, Pierre; Dingemans, Jozef
Pseudomonas aeruginosa is a Gram-negative γ-Proteobacterium which is known for its capacity to colonize various niches, including some invertebrate and vertebrate hosts, making it one of the most frequent bacteria causing opportunistic infections. P. aeruginosa is able to cause acute as well as chronic infections and it uses different colonization and virulence factors to do so. Infections range from septicemia, urinary infections, burn wound colonization, and chronic colonization of the lung...
Bjarnsholt, Thomas; Jensen, Peter Østrup; Rasmussen, Thomas B;
The opportunistic human pathogen Pseudomonas aeruginosa is the predominant micro-organism of chronic lung infections in cystic fibrosis patients. P. aeruginosa colonizes the lungs by forming biofilm microcolonies throughout the lung. Quorum sensing (QS) renders the biofilm bacteria highly tolerant...... garlic-treated biofilm. Garlic extract was administered as treatment for a mouse pulmonary infection model. Mice were treated with garlic extract or placebo for 7 days, with the initial 2 days being prophylactic before P. aeruginosa was instilled in the left lung of the mice. Bacteriology, mortality......, histopathology and cytokine production were used as indicators. The garlic treatment initially provoked a higher degree of inflammation, and significantly improved clearing of the infecting bacteria. The results indicate that a QS-inhibitory extract of garlic renders P. aeruginosa sensitive to tobramycin...
Pier, Gerald B.; Grout, Martha; Zaidi, Tanweer S.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion channel, but its relationship to the primary clinical manifestation of CF, chronic Pseudomonas aeruginosa pulmonary infection, is unclear. We report that CFTR is a cellular receptor for binding, endocytosing, and clearing P. aeruginosa from the normal lung. Murine cells expressing recombinant human wild-type CFTR ingested 30-100 times as many P. aeruginosa as cells lacking CFTR or expressing mutant Δ F508 CFTR protein. Purified CFTR inhibited ingestion of P. aeruginosa by human airway epithelial cells. The first extracellular domain of CFTR specifically bound to P. aeruginosa and a synthetic peptide of this region inhibited P. aeruginosa internalization in vivo, leading to increased bacterial lung burdens. CFTR clears P. aeruginosa from the lung, indicating a direct connection between mutations in CFTR and the clinical consequences of CF.
Jensen, P Ø; Moser, C; Kobayashi, O;
bacterial clearance in the lungs of C3H/HeN mice could be explained by faster activation of the PMNs, as indicated by the higher up-regulation of CD11b. The severe lung inflammation in BALB/c mice may be caused by the early higher content of G-CSF in the sera mobilizing PMNs from the bone marrow and the...... decreased 1 day after bacterial challenge, whereas the expression was increased after 2 days of challenge on PMNs of C3H/HeN mice only. These changes were accompanied by a more severe lung inflammation in BALB/c mice and faster clearance of the bacteria in C3H/HeN mice. In conclusion, the rapid early...
Sordelli, D O; Cerquetti, M C; el-Tawil, G; Ramwell, P W; Hooke, A M; Bellanti, J A
In chronic P. aeruginosa infection, lung tissue damage is induced by either the microorganism or the inflammatory response. We investigated, in an animal model, whether a non-steroidal anti-inflammatory drug, ibuprofen, reduced lung inflammation produced by P. aeruginosa. Lung lavages, pulmonary clearance of P. aeruginosa and lung pathology were studied in CD-1 mice injected with sodium ibuprofenate. A single dose of the drug, injected immediately after 30 min exposure to the P. aeruginosa aerosol, decreased the recruitment of granulocytes into airways in a dose-dependent manner. Pretreatment with 2 doses of the drug 18 and 6 h before the P. aeruginosa challenge was even more effective. The kinetics of changes in prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations in lung lavage fluids after P. aeruginosa aerosol were also modified by ibuprofen. Moreover, ibuprofen treatment did not impair lung clearance of the challenge microorganisms, and the animals had less inflammation of the lungs. PMID:3863757
Moser, C; Jensen, P O; Kobayashi, O;
, resistance to re-infection was paralleled by a shift towards a Th1-dominated response and increased IL-12 production. No significant increase in serum IgG was observed in the re-infected mice. In conclusion, these results indicate a protective role for a Th1-dominated response, independent of antibody...
Song, Z; Johansen, H K; Faber, V;
The predominant pathogen in patients with cystic fibrosis (CF) is Pseudomonas aeruginosa, which results in a chronic lung infection associated with progressive pulmonary insufficiency. In a rat model of chronic P. aeruginosa pneumonia mimicking that in patients with CF, we studied whether the...... inflammation and antibody responses could be changed by treatment with the Chinese herbal medicine ginseng. An aqueous extract of ginseng was injected subcutaneously, and cortisone and saline were used as controls. Two weeks after challenge with P. aeruginosa, the ginseng-treated group showed a significantly...... against P. aeruginosa sonicate and a shift from an acute type to a chronic type of lung inflammation compared to those in the control and cortisone-treated groups were observed. These findings indicate that ginseng treatment of an experimental P. aeruginosa pneumonia in rats promotes a cellular response...
Fothergill, Joanne L; Neill, Daniel R; Loman, Nick; Winstanley, Craig; Kadioglu, Aras
Chronic bacterial infections are a key feature of a variety of lung conditions. The opportunistic bacterium, Pseudomonas aeruginosa, is extremely skilled at both colonizing and persisting in the airways of patients with lung damage. It has been suggested that the upper airways (including the paranasal sinuses and nasopharynx) play an important role as a silent reservoir of bacteria. Over time, P. aeruginosa can adapt to its niche, leading to increased resistance in the face of the immune system and intense therapy regimes. Here we describe a mouse inhalation model of P. aeruginosa chronic infection that can be studied for at least 28 days. We present evidence for adaptation in vivo, in terms of genotype and phenotype including antibiotic resistance. Our data suggest that there is persistence in the upper respiratory tract and that this is key in the establishment of lung infection. This model provides a unique platform for studying evolutionary dynamics and therapeutics. PMID:25179232
Jørgensen, Karin Meinike; Wassermann, Tina; Johansen, Helle Krogh;
and mutations in the global regulator genes mucA, lasR and rpoN. Our aim was to understand the metabolic changes occurring over time and between niches of the CF airways. By applying Phenotype MicroArrays, we investigated changes in the carbon and nitrogen catabolism of subsequently clonally related mucoid...... intermittently colonizing isolates. Fewer differences were observed between sinus and lung isolates, showing a higher degree of isolate similarity between these two niches. Modest respiratory changes were seen for the early isolate/PAO1 comparisons, indicating colonization with environmental isolates. Assignment...
Lorè, Nicola Ivan; Cigana, Cristina; De Fino, Ida; Riva, Camilla; Juhas, Mario; Schwager, Stephan; Eberl, Leo; Bragonzi, Alessandra
The opportunistic pathogen Pseudomonas aeruginosa is able to thrive in diverse ecological niches and to cause serious human infection. P. aeruginosa environmental strains are producing various virulence factors that are required for establishing acute infections in several host organisms; however, the P. aeruginosa phenotypic variants favour long-term persistence in the cystic fibrosis (CF) airways. Whether P. aeruginosa strains, which have adapted to the CF-niche, have lost their competitive fitness in the other environment remains to be investigated. In this paper, three P. aeruginosa clonal lineages, including early strains isolated at the onset of infection, and late strains, isolated after several years of chronic lung infection from patients with CF, were analysed in multi-host model systems of acute infection. P. aeruginosa early isolates caused lethality in the three non-mammalian hosts, namely Caenorhabditis elegans, Galleria mellonella, and Drosophila melanogaster, while late adapted clonal isolates were attenuated in acute virulence. When two different mouse genetic background strains, namely C57Bl/6NCrl and Balb/cAnNCrl, were used as acute infection models, early P. aeruginosa CF isolates were lethal, while late isolates exhibited reduced or abolished acute virulence. Severe histopathological lesions, including high leukocytes recruitment and bacterial load, were detected in the lungs of mice infected with P. aeruginosa CF early isolates, while late isolates were progressively cleared. In addition, systemic bacterial spread and invasion of epithelial cells, which were detected for P. aeruginosa CF early strains, were not observed with late strains. Our findings indicate that niche-specific selection in P. aeruginosa reduced its ability to cause acute infections across a broad range of hosts while maintaining the capacity for chronic infection in the CF host. PMID:22558188
Nicola Ivan Lorè
Full Text Available The opportunistic pathogen Pseudomonas aeruginosa is able to thrive in diverse ecological niches and to cause serious human infection. P. aeruginosa environmental strains are producing various virulence factors that are required for establishing acute infections in several host organisms; however, the P. aeruginosa phenotypic variants favour long-term persistence in the cystic fibrosis (CF airways. Whether P. aeruginosa strains, which have adapted to the CF-niche, have lost their competitive fitness in the other environment remains to be investigated. In this paper, three P. aeruginosa clonal lineages, including early strains isolated at the onset of infection, and late strains, isolated after several years of chronic lung infection from patients with CF, were analysed in multi-host model systems of acute infection. P. aeruginosa early isolates caused lethality in the three non-mammalian hosts, namely Caenorhabditis elegans, Galleria mellonella, and Drosophila melanogaster, while late adapted clonal isolates were attenuated in acute virulence. When two different mouse genetic background strains, namely C57Bl/6NCrl and Balb/cAnNCrl, were used as acute infection models, early P. aeruginosa CF isolates were lethal, while late isolates exhibited reduced or abolished acute virulence. Severe histopathological lesions, including high leukocytes recruitment and bacterial load, were detected in the lungs of mice infected with P. aeruginosa CF early isolates, while late isolates were progressively cleared. In addition, systemic bacterial spread and invasion of epithelial cells, which were detected for P. aeruginosa CF early strains, were not observed with late strains. Our findings indicate that niche-specific selection in P. aeruginosa reduced its ability to cause acute infections across a broad range of hosts while maintaining the capacity for chronic infection in the CF host.
950304 The diagnosis and treatment of pulmonaryaspergilloma in the aged—a report of 17 cases.LI Di-anqin(李殿清),et al.Henan Provincial Pulmon DisHosp,Zhengzhou,450003.Chin J Geriatr 1994;13(6):338-339.Seventeen cases of pulmonary aspergilloma in theaged were reported.The primary diseases were pul-monary tuberculosis in 14 cases and pulmonary cyst,cancer of lung and pulmonary abscess in one each.In14 cases,the clinical manifestation was frequenthemoptysis;the occurrence rate was 82.4%.Among
2009188 Multi-slice spiral CT appearances of pulmonary infections after liver transplantation.XIE Lixuan(谢丽璇),et al.Dept Imaging,Changzheng Hosp,2nd Milit Med Univ,Shanghai 200003.Chin J Radiol,2009;43(1):8-11.
Kuehn Meta J
Full Text Available Abstract Background Pseudomonas aeruginosa is the major pathogen associated with chronic and ultimately fatal lung infections in patients with cystic fibrosis (CF. To investigate how P. aeruginosa-derived vesicles may contribute to lung disease, we explored their ability to associate with human lung cells. Results Purified vesicles associated with lung cells and were internalized in a time- and dose-dependent manner. Vesicles from a CF isolate exhibited a 3- to 4-fold greater association with lung cells than vesicles from the lab strain PAO1. Vesicle internalization was temperature-dependent and was inhibited by hypertonic sucrose and cyclodextrins. Surface-bound vesicles rarely colocalized with clathrin. Internalized vesicles colocalized with the endoplasmic reticulum (ER marker, TRAPα, as well as with ER-localized pools of cholera toxin and transferrin. CF isolates of P. aeruginosa abundantly secrete PaAP (PA2939, an aminopeptidase that associates with the surface of vesicles. Vesicles from a PaAP knockout strain exhibited a 40% decrease in cell association. Likewise, vesicles from PAO1 overexpressing PaAP displayed a significant increase in cell association. Conclusion These data reveal that PaAP promotes the association of vesicles with lung cells. Taken together, these results suggest that P. aeruginosa vesicles can interact with and be internalized by lung epithelial cells and contribute to the inflammatory response during infection.
Full Text Available Abstract Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF patients is caused by biofilm-growing mucoid strains. Biofilms can be prevented by early aggressive antibiotic prophylaxis or therapy, and they can be treated by chronic suppressive therapy. New results from one small trial suggest that addition of oral ciprofloxacin to inhaled tobramycin may reduce lung inflammation. Clinical trials with new formulations of old antibiotics for inhalation therapy (aztreonam lysine against chronic P. aeruginosa infection improved patient-reported outcome, lung function, time to acute exacerbations and sputum density of P. aeruginosa. Other drugs such as quinolones are currently under investigation for inhalation therapy. A trial of the use of anti-Pseudomonas antibiotics for long-term prophylaxis showed no effect in patients who were not already infected. Use of azithromycin to treat CF patients without P. aeruginosa infection did not improve lung function. Here I review the recent advances in the treatment of P. aeruginosa lung infections with a focus on inhalation treatments targeted at prophylaxis and chronic suppressive therapy.
930120 A clinical study of 50 cases of legion-naires disease.WANG Baofa(王保法),et al.Dept Intern Med,2nd Affili Hosp,Hehei MedColl,Shijiazhuang,050000.Chin J Tuberc &Respir Dis 1992;15(5):266-268.The clinical features and X-ray manifesta-tions of 50 cases of legionnaires disease wereanalysed.8 cases might be due to nosocomial in-fection through breathing in flying particles ofthe saliva or phlegm.According to the mainclinical features,this disease could be dividedinto common pneumonia type,acute gastroen-teritis type,encephalopathy type,shock type,and acute renal insufficiency type.The differen-
Hendricks, Matthew R; Lashua, Lauren P; Fischer, Douglas K; Flitter, Becca A; Eichinger, Katherine M; Durbin, Joan E; Sarkar, Saumendra N; Coyne, Carolyn B; Empey, Kerry M; Bomberger, Jennifer M
Clinical observations link respiratory virus infection and Pseudomonas aeruginosa colonization in chronic lung disease, including cystic fibrosis (CF) and chronic obstructive pulmonary disease. The development of P. aeruginosa into highly antibiotic-resistant biofilm communities promotes airway colonization and accounts for disease progression in patients. Although clinical studies show a strong correlation between CF patients' acquisition of chronic P. aeruginosa infections and respiratory virus infection, little is known about the mechanism by which chronic P. aeruginosa infections are initiated in the host. Using a coculture model to study the formation of bacterial biofilm formation associated with the airway epithelium, we show that respiratory viral infections and the induction of antiviral interferons promote robust secondary P. aeruginosa biofilm formation. We report that the induction of antiviral IFN signaling in response to respiratory syncytial virus (RSV) infection induces bacterial biofilm formation through a mechanism of dysregulated iron homeostasis of the airway epithelium. Moreover, increased apical release of the host iron-binding protein transferrin during RSV infection promotes P. aeruginosa biofilm development in vitro and in vivo. Thus, nutritional immunity pathways that are disrupted during respiratory viral infection create an environment that favors secondary bacterial infection and may provide previously unidentified targets to combat bacterial biofilm formation. PMID:26729873
Ciofu, Oana; Riis, Bente; Pressler, Tacjana; Poulsen, Henrik Enghusen; Høiby, Niels
Oxidative stress caused by chronic lung inflammation in patients with cystic fibrosis (CF) and chronic lung infection with Pseudomonas aeruginosa is characterized by the reactive oxygen species (ROS) liberated by polymorphonuclear leukocytes (PMNs). We formulated the hypothesis that oxidation of....../patient) collected from the 1st and up to the 25th year of their chronic lung infection. The level of oxidized guanine moiety 8-oxo-2'-deoxyguanosine (8-oxodG), which is a frequently investigated DNA oxidative lesion, was measured. Hypermutable P. aeruginosa isolates were found in the sputum bacterial population of...
XU Jin-fu; QU Jie-ming; HE Li-xian; OU Zhou-luo
Background The number of immunosupressed patients has increased in the past decades. Among them Pseudomonas aeruginosa (P. aeruginosa) is one of the leading bacteria for pneumonia that are associated with poor prognosis. However, the pathogenesis of P. aeruginosa pneumonia in immunosupressed patients is not understood completely. Previous reports showed keratinocyte growth factor (KGF) is associated with lung injury in immunocompetent hosts. In this study, we investigated the different reactions of lung injury, lung pathology and KGF expressions in P. aeruginosa pneumonia between immunosuppressed and immunocompetent rats.Methods Immunosuppression of male rats was induced by injecting immunosuppressive subcutaneously.Pneumonia was established by instilling P. aeruginous tracheally. The immunocompetent rats were the control group. Survival rate, lung histopathology, pulmonary permeability and oedema, KGF mRNA and protein expressions in lungs of both groups were investigated.Results The survival rate of immunosuppressed group was lower than that of immunocompetent group (33.3%vs 83.3%). After exposure to bacteria, pulmonary permeability and wet/dry ratio in immunosuppressed group were higher than those in immunocompetent group. Pulmonary congestion and haemorrhage were more intensive in immunosuppressed group compared to immunocompetent group. Apoptosis and necrosis were also observed in infected lungs of immunosuppressed rats. Although we detected KGF expressions in lungs of both groups after infection, the expressions of KGF protein and mRNA gene in immunosuppressed group were much lower than in immunocompetent group.Conclusions Compared with immunocompetent group, there was more intensive lung injury in immunosuppressed group. Severe lung injury may contribute to the poor prognosis of pneumonia. KGF expressions of pneumonia in immunosuppressed rats were less than those in immunocompetent ones.
Moser, Claus; Jensen, Peter Ø; Pressler, Tacjana;
mobilizing monocytes and PMNs from the bone marrow, GM-CSF, G-CSF and IL-3 select subsets of dendritic cells, which subsequently induce distinct Th responses. Therefore, the present study examines the correlation between the mobilizing cytokines in serum and the Th responses. The IFN-gamma and IL-4...... production by peripheral blood mononuclear cells, and the concentrations of GM-CSF and G-CSF in serum as well as lung function, were determined in 37 CF patients with and 6 CF patients without chronic P. aeruginosa lung infection. The GM-CSF/G-CSF ratio correlated both with the IFN-gamma production and good...... lung function. In addition, an inverse correlation between IL-3 and IFN-gamma was observed. The results indicate involvement of endogenous GM-CSF, G-CSF and IL-3 in the skewed Th response in CF, and change to a Th1-dominated response might be achieved with GM-CSF treatment....
Johansson, Ewa; Welinder-Olsson, Christina; Gilljam, Marita
Lung infection with Pseudomonas aeruginosa is common in lung transplant recipients and may lead to severe complications. Bacteriological surveillance aims to detect transmission of microbes between hospital environment and patients. We sought to determine whether genotyping of P. aeruginosa isolates could improve identifications of pathways of infection. From 2004 to 2009, we performed genotyping with multiple-locus variable number of tandem repeats analysis (MLVA) and pulsed-field gel electrophoresis (PFGE) of P. aeruginosa isolates cultured from lung transplant recipients at Sahlgrenska University Hospital, Gothenburg. During a small outbreak in 2008, cultivation and genotyping of isolates from sink and drains samples from the hospital ward were performed. Pseudomona aeruginosa from 11/18 patients were genotyped to unique strains. The remaining seven patients were carriers of a P. aeruginosa strain of cluster A genotype. Pseudomona aeruginosa was isolated in 4/8 water samples, typed by MLVA also as cluster A genotype and confirmed by PFGE to be similar or identical to the isolates from four transplanted patients. In conclusion, genotyping of isolates revealed a clonal relationship between patient and water isolates, indicating in-hospital transmission of P. aeruginosa. We suggest genotyping with MLVA for rapid routine surveillance, with the PFGE method used for extended, confirmatory analyses. PMID:24450429
Full Text Available Objective To investigate the effects of lasR/rhlR gene on Foxp3, TGF-β1 and IL-10 of lung tissue in rat tracheal intubation model with biofilm infection of Pseudomonas aeruginosa (Ps. aer wild strain (PAO1 and quorum sensing (QS deficient strain (ΔlasRΔrhlR. Methods Twenty-one SD rats were randomly assigned into 3 groups (7 each: ΔlasRΔrhlR-treated group, PAO1-treated group and sterile control group. Biofilms (BF were cultured in vitro, and the BF coated tube (infected respectively with Ps. aer PAO1 strain, ΔlasRΔrhlR strain, or with asepsis was inserted into the trachea to establish the rat model. The rats were sacrificed on the 7th day after intubation. Colony count of lung tissue homogenate (cfu and lung HE staining were performed, and IL-10 content in bronchoalveolar lavage fluid (BALF, TGF-β1 in lung tissue, and the expression of Foxp3 mRNA in lung cells were determined. Results The bacterial counts were significantly higher in PAO1 and ΔlasRΔrhlR groups than that in sterile control group, and the counts were obviously higher in PAO1 group (10 400.00±6313.70/g lung tissue than that in ΔlasRΔrhlR group (975.00±559.97/g lung tissue, P<0.05. There was no significant pathological changes in lung tissue in sterile control group, while the bronchi and blood vessels in PAO1 group were infiltrated by a large number of inflammatory cells and complicated with alveolar septum thickening and local abscess and necrosis. The pathological changes were milder in ΔlasRΔrhlR group than in PAO1 group; the expression of Foxp3 mRNA was higher in the two Ps. aer infected groups than that in sterile control group (0.65±0.32, and it was significantly higher in PAO1 group (4.62±1.07 than in ΔlasRΔrhlR group (2.15±1.43, P<0.05. The accumulated optical density value of TGF-β1 was significantly higher in the two Ps. aer infected groups than in sterile control group (3721.66±1412.95, and significantly higher in PAO1 group (65 090.56±33
Anas, Adam A; van Lieshout, Miriam H P; Claushuis, Theodora A M; de Vos, Alex F; Florquin, Sandrine; de Boer, Onno J; Hou, Baidong; Van't Veer, Cornelis; van der Poll, Tom
Pseudomonas aeruginosa is a flagellated pathogen frequently causing pneumonia in hospitalized patients and sufferers of chronic lung disease. Here we investigated the role of the common Toll-like receptor (TLR) adaptor myeloid differentiation factor (MyD)88 in myeloid vs. lung epithelial cells in clearance of P. aeruginosa from the airways. Mice deficient for MyD88 in lung epithelial cells (Sftpccre-MyD88-lox mice) or myeloid cells (LysMcre-MyD88-lox mice) and bone marrow chimeric mice deficient for TLR5 (the receptor recognizing Pseudomonas flagellin) in either parenchymal or hematopoietic cells were infected with P. aeruginosa via the airways. Sftpccre-MyD88-lox mice demonstrated a reduced influx of neutrophils into the bronchoalveolar space and an impaired early antibacterial defense after infection with P. aeruginosa, whereas the response of LysMcre-MyD88-lox mice did not differ from control mice. The immune-enhancing role of epithelial MyD88 was dependent on recognition of pathogen-derived flagellin by epithelial TLR5, as demonstrated by an unaltered clearance of mutant P. aeruginosa lacking flagellin from the lungs of Sftpccre-MyD88-lox mice and an impaired bacterial clearance in bone marrow chimeric mice lacking TLR5 in parenchymal cells. These data indicate that early clearance of P. aeruginosa from the airways is dependent on flagellin-TLR5-MyD88-dependent signaling in respiratory epithelial cells. PMID:27288486
Objective: To determine the prevalence of Pseudomonas aeruginosa in post-operative wound infection. Results: Out of the 60 bacterial isolates found in post-operative wound infection, 20 (33.3%) were Pseudomonas aeruginosa, followed by Staphylococcus aureus 13(21.7%), Klebsiella species 10(16.7%), Escherichia coli 7(11.7%), Atypical coliform 4(6.7%), Proteus species 4(6.7%), Streptococcus pyogenes 1(1.7%) and Enterococcus faecalis 1(1.7%) in the order. Pseudomonas aeruginosa infections was higher in female than male, ratio 3:2 and was found more among young and elderly debilitated patients. The in vitro sensitivity pattern of 20 isolates of Pseudomonas aeruginosa showed colistin (100%), gentamicin (75%), streptomycin (30%), and tetracycline (10%). Conclusion: The role of Pseudomonas aeruginosa as an agent of nosocomial infection is re-emphasised. (author)
Giladi, Moshe; Porat, Yaara; Blatt, Alexandra; Shmueli, Esther; Wasserman, Yoram; Kirson, Eilon D; Palti, Yoram
High-frequency, low-intensity electric fields generated by insulated electrodes have previously been shown to inhibit bacterial growth in vitro. In the present study, we tested the effect of these antimicrobial fields (AMFields) on the development of lung infection caused by Pseudomonas aeruginosa in mice. We demonstrate that AMFields (10 MHz) significantly inhibit bacterial growth in vivo, both as a stand-alone treatment and in combination with ceftazidime. In addition, we show that peripher...
Hengzhuang, Wang; Wu, Hong; Ciofu, Oana;
planktonic and biofilm P. aeruginosa cells in vivo. Colistin showed concentration-dependent killing, while imipenem showed time-dependent killing on both planktonic and biofilm P. aeruginosa cells in vivo. The parameter best correlated to the elimination of bacteria in lung by colistin was the area under the...... concentration was above the MBIC (T(MBIC)) for biofilm cells. However, the AUC/MIC of imipenem showed a better correlation with the efficacy of imipenem for biofilm infections (R(2) = 0.89) than planktonic cell infections (R(2) = 0.38). The postantibiotic effect (PAE) of colistin and imipenem was shorter in...
Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary growth phase killing of P. aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr -/--mice
Hoffmann, N.; Lee, Bao le ri; Hentzer, Morten; Rasmussen, Thomas Bovbjerg; Song, Z.; Johansen, H. K.; Givskov, Michael Christian; Høiby, N.
the complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa alginate by the incomplete precipitation of polymerized alginate and high levels of readily dialyzable uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became...
Ciofu, Oana; Mandsberg, Lotte F; Wang, Hengzhuang;
During chronic lung infection of patients with cystic fibrosis, Pseudomonas aeruginosa can survive for long periods of time under the challenging selective pressure imposed by the immune system and antibiotic treatment as a result of its biofilm mode of growth and adaptive evolution mediated by...... importance of biofilm prevention strategies by early aggressive antibiotic prophylaxis or therapy before phenotypic diversification during chronic lung infection of patients with cystic fibrosis....
Mathee, Kalai; Ciofu, Oana; Sternberg, Claus; Lindum, Peter W.; Campbell, Joan I. A.; Jensen, Per; Johnsen, Anders H.; Givskov, Michael Christian; Ohman, Dennis E.; Molin, Søren; Høiby, Niels; Kharazmi, Arsalan
The leading cause of mortality in patients with cystic fibrosis (CF) is respiratory failure due in large part to chronic lung infection with Pseudomonas aeruginosa strains that undergo mucoid conversion, display a biofilm mode of growth in vivo and resist the infiltration of polymorphonuclear leu...
Clancy, J P; Dupont, L; Konstan, M W; Billings, J; Fustik, S; Goss, C H; Lymp, J; Minic, P; Quittner, A L; Rubenstein, R C; Young, K R; Saiman, L; Burns, J L; Govan, J R W; Ramsey, B; Gupta, R
Rationale Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. Objectives To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. Methods 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire—Revised (CFQ-R). Results The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs −0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). Conclusions Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection. PMID:23749840
Scoffield, Jessica A; Wu, Hui
Pseudomonas aeruginosa is the major aetiological agent of chronic pulmonary infections in cystic fibrosis (CF) patients. However, recent evidence suggests that the polymicrobial community of the CF lung may also harbour oral streptococci, and colonization by these micro-organisms may have a negative impact on P. aeruginosa within the CF lung. Our previous studies demonstrated that nitrite abundance plays an important role in P. aeruginosa survival during co-infection with oral streptococci. Nitrite reductase is a key enzyme involved in nitrite metabolism. Therefore, the objective of this study was to examine the role nitrite reductase (gene nirS) plays in P. aeruginosa survival during co-infection with an oral streptococcus, Streptococcus parasanguinis. Inactivation of nirS in both the chronic CF isolate FRD1 and acute wound isolate PAO1 reduced the survival rate of P. aeruginosa when co-cultured with S. parasanguinis. Growth of both mutants was restored when co-cultured with S. parasanguinis that was defective for H2O2 production. Furthermore, the nitrite reductase mutant was unable to kill Drosophila melanogaster during co-infection with S. parasanguinis. Taken together, these results suggest that nitrite reductase plays an important role for survival of P. aeruginosa during co-infection with S. parasanguinis. PMID:26673783
James Chloe E
Full Text Available Abstract Background Pseudomonas aeruginosa is the most common bacterial pathogen infecting the lungs of patients with cystic fibrosis (CF. The Liverpool Epidemic Strain (LES is transmissible, capable of superseding other P. aeruginosa populations and is associated with increased morbidity. Previously, multiple inducible prophages have been found to coexist in the LES chromosome and to constitute a major component of the accessory genome not found in other sequenced P. aerugionosa strains. LES phages confer a competitive advantage in a rat model of chronic lung infection and may, therefore underpin LES prevalence. Here the infective properties of three LES phages were characterised. Results This study focuses on three of the five active prophages (LESφ2, LESφ3 and LESφ4 that are members of the Siphoviridae. All were induced from LESB58 by norfloxacin. Lytic production of LESφ2 was considerably higher than that of LESφ3 and LESφ4. Each phage was capable of both lytic and lysogenic infection of the susceptible P. aeruginosa host, PAO1, producing phage-specific plaque morphologies. In the PAO1 host background, the LESφ2 prophage conferred immunity against LESφ3 infection and reduced susceptibility to LESφ4 infection. Each prophage was less stable in the PAO1 chromosome with substantially higher rates of spontaneous phage production than when residing in the native LESB58 host. We show that LES phages are capable of horizontal gene transfer by infecting P. aeruginosa strains from different sources and that type IV pili are required for infection by all three phages. Conclusions Multiple inducible prophages with diverse infection properties have been maintained in the LES genome. Our data suggest that LESφ2 is more sensitive to induction into the lytic cycle or has a more efficient replicative cycle than the other LES phages.
Ghoul, Melanie; West, Stuart A.; Johansen, Helle Krogh;
, especially human pathogens, remains to be tested. We examined the role of bacteriocins in competition using Pseudomonas aeruginosa strains infecting lungs of humans with cystic fibrosis (CF). We assessed the ability of different strains to kill each other using phenotypic assays, and sequenced their genomes...
Pseudomonas aeruginosa (Pa) is the predominant pathogen infecting the airways of patients with cystic fibrosis (CF). Initial colonization is usually transient and associated with non-mucoid strains, which can be eradicated if identified early. This strategy can prevent, or at least delay, chronic Pa infection, which eventually develops in the majority of patients by their late teens or early adulthood. This article discusses the management and latest treatment developments of Pa lung infection in patients with CF, with a focus on nebulized antibiotic therapy.
Rybtke, Morten T; Jensen, Peter Østrup; Høiby, Niels;
Biofilm formation by bacteria is recognized as a major problem in chronic infections due to their recalcitrance against the immune defense and available antibiotic treatment schemes. The opportunistic pathogen Pseudomonas aeruginosa has drawn special attention in this regard due to its severity of...
Full Text Available HIV-1 depletes CD4+ T cells in the blood, lymphatic tissues, gut and lungs. Here we investigated the relationship between depletion and infection of CD4+ T cells in the lung parenchyma. The lungs of 38 Indian rhesus macaques in early to later stages of SIVmac251 infection were examined, and the numbers of CD4+ T cells and macrophages plus the frequency of SIV RNA+ cells were quantified. We showed that SIV infected macrophages in the lung parenchyma, but only in small numbers except in the setting of interstitial inflammation where large numbers of SIV RNA+ macrophages were detected. However, even in this setting, the number of macrophages was not decreased. By contrast, there were few infected CD4+ T cells in lung parenchyma, but CD4+ T cells were nonetheless depleted by unknown mechanisms. The CD4+ T cells in lung parenchyma were depleted even though they were not productively infected, whereas SIV can infect large numbers of macrophages in the setting of interstitial inflammation without depleting them. These observations point to the need for future investigations into mechanisms of CD4+ T cell depletion at this mucosal site, and into mechanisms by which macrophage populations are maintained despite high levels of infection. The large numbers of SIV RNA+ macrophages in lungs in the setting of interstitial inflammation indicates that lung macrophages can be an important source for SIV persistent infection.
Phennicie, Ryan T.; Sullivan, Matthew J.; Singer, John T.; Yoder, Jeffrey A.; Kim, Carol H.
Cystic fibrosis (CF) is a genetic disease caused by recessive mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is associated with prevalent and chronic Pseudomonas aeruginosa lung infections. Despite numerous studies that have sought to elucidate the role of CFTR in the innate immune response, the links between CFTR, innate immunity, and P. aeruginosa infection remain unclear. The present work highlights the zebrafish as a powerful model organism for human infectious disease, particularly infection by P. aeruginosa. Zebrafish embryos with reduced expression of the cftr gene (Cftr morphants) exhibited reduced respiratory burst response and directed neutrophil migration, supporting a connection between cftr and the innate immune response. Cftr morphants were infected with P. aeruginosa or other bacterial species that are commonly associated with infections in CF patients, including Burkholderia cenocepacia, Haemophilus influenzae, and Staphylococcus aureus. Intriguingly, the bacterial burden of P. aeruginosa was found to be significantly higher in zebrafish Cftr morphants than in controls, but this phenomenon was not observed with the other bacterial species. Bacterial burden in Cftr morphants infected with a P. aeruginosa ΔLasR mutant, a quorum sensing-deficient strain, was comparable to that in control fish, indicating that the regulation of virulence factors through LasR is required for enhancement of infection in the absence of Cftr. The zebrafish system provides a multitude of advantages for studying the pathogenesis of P. aeruginosa and for understanding the role that innate immune cells, such as neutrophils, play in the host response to acute bacterial infections commonly associated with cystic fibrosis. PMID:20732993
Full Text Available Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1β in lung pathology using the experimental F508del-CFTR murine model on C57BL/6 genetic background (Cftr(tm1eur or d/d, on double deficient for d/d and type 1 interleukin-1 receptor (d/d X IL-1R1-/-, and antibody neutralization. At steady state, young adult d/d mice did not show any signs of spontaneous lung inflammation. However, IL-1R1 deficiency conferred partial protection to repeated P. aeruginosa endotoxins/LPS lung instillation in d/d mice, as 50% of d/d mice succumbed to inflammation, whereas all d/d x IL-1R1-/- double mutants survived with lower initial weight loss and less pulmonary collagen and mucus production, suggesting that the absence of IL-1R1 signaling is protective in d/d mice in LPS-induced lung damage. Using P. aeruginosa acute lung infection we found heightened neutrophil recruitment in d/d mice with higher epithelial damage, increased bacterial load in BALF, and augmented IL-1β and TNF-α in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1β signaling in response to P. aeruginosa. IL-1β antibody neutralization had no effect on lung homeostasis in either d/d or WT mice, however P. aeruginosa induced lung inflammation and bacterial load were diminished by IL-1β antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1β production and reduced bacterial clearance. Further, we show that neutralization of IL-1β in d/d mice through the double mutation d/d x IL-1R1-/- and in WT via antibody neutralization attenuates inflammation. This supports the notion that intervention in the IL-1R1/IL-1β pathway may be detrimental in CF patients.
Glasser, Stephan W; Senft, Albert P; Whitsett, Jeffrey A; Maxfield, Melissa D; Ross, Gary F; Richardson, Theresa R; Prows, Daniel R; Xu, Yan; Korfhagen, Thomas R
To determine the role of surfactant protein C (SP-C) in host defense, SP-C-deficient (Sftpc-/-) mice were infected with the pulmonary pathogen Pseudomonas aeruginosa by intratracheal injection. Survival of young, postnatal day 14 Sftpc-/- mice was decreased in comparison to Sftpc+/+ mice. The sensitivity to Pseudomonas bacteria was specific to the 129S6 strain of Sftpc-/- mice, a strain that spontaneously develops interstitial lung disease-like lung pathology with age. Pulmonary bacterial load and leukocyte infiltration were increased in the lungs of Sftpc-/- mice 24 h after infection. Early influx of polymorphonuclear leukocytes in the lungs of uninfected newborn Sftpc-/- mice relative to Sftpc+/+ mice indicate that the lack of SP-C promotes proinflammatory responses in the lung. Mucin expression, as indicated by Alcian blue staining, was increased in the airways of Sftpc-/- mice following infection. Phagocytic activity of alveolar macrophages from Sftpc-/- mice was reduced. The uptake of fluorescent beads in vitro and the number of bacteria phagocytosed by alveolar macrophages in vivo was decreased in the Sftpc-/- mice. Alveolar macrophages from Sftpc-/- mice expressed markers of alternative activation that are associated with diminished pathogen response and advancing pulmonary fibrosis. These findings implicate SP-C as a modifier of alveolar homeostasis. SP-C plays an important role in innate host defense of the lung, enhancing macrophage-mediated Pseudomonas phagocytosis, clearance and limiting pulmonary inflammatory responses. PMID:18566429
Lorè, Nicola Ivan; Cigana, Cristina; De Fino, Ida; Riva, Camilla; Juhas, Mario; Schwager, Stephan; Eberl, Leo; Bragonzi, Alessandra
The opportunistic pathogen Pseudomonas aeruginosa is able to thrive in diverse ecological niches and to cause serious human infection. P. aeruginosa environmental strains are producing various virulence factors that are required for establishing acute infections in several host organisms; however, the P. aeruginosa phenotypic variants favour long-term persistence in the cystic fibrosis (CF) airways. Whether P. aeruginosa strains, which have adapted to the CF-niche, have lost their competitive...
Nilsson, Elin; Kollberg, Hans; Johannesson, Marie; Wejåker, Per-Erik; Carlander, David; Larsson, Anders
Immunotherapy with specific antibodies is an alternative to antibiotics for the prevention of infections in humans and animals. We have used orally administered immunoglobulin Y (IgY) preparations, purified from eggs of hens immunized with Pseudomonas aeruginosa bacteria, to prevent pulmonary P. aeruginosa infections in a group of patients with cystic fibrosis (CF). Respiratory infections are major problems for CF patients because of the thick mucus in the airways, and chronic P. aeruginosa lung infections occur in virtually all CF patients and cause morbidity and mortality. The IgY-treated group had only 2.5 P. aeruginosa-positive sputum cultures per 100 months, and none of the IgY-treated patients became chronically colonized with P. aeruginosa. In the control group, 13.7 of the cultures per 100 months were positive for P. aeruginosa, and 24% of patients became chronically colonized with P. aeruginosa. The first enrolled patient in this study has now been treated continuously for more than 10 years. During the first 8 years she only had four P. aeruginosa-positive cultures. After 8 years she became chronically infected, but still after 10 years the bacteria have not turned mucoid. No negative side effects of IgY treatment have been noted during these 10 years. To our knowledge this is the longest treatment with specific yolk antibodies for therapeutic purposes. PMID:17651078
Nam, Seong-Won; Chen, Xiaoqiang; Lim, Jeesun; Kim, So Hyun; Kim, Sang-Tae; Cho, You-Hee; Yoon, Juyoung; Park, Sungsu
Background Pseudomonas aeruginosa (PA) and Burkholderia cepacia complex (Bcc), commonly found in the lungs of cystic fibrosis (CF) patients, often produce cyanide (CN), which inhibits cellular respiration. CN in sputa is a potential biomarker for lung infection by CF pathogens. However, its actual concentration in the infected lungs is unknown. Methods and Findings This work reports observation of CN in the lungs of mice infected with cyanogenic PA or Bcc strains using a CN fluorescent chemos...
Full Text Available Pseudomonas aeruginosa is the leading cause of chronic lung infection and following pulmonary worsening of cystic fibrosis patients. To verify whether bacterial modifications regarding motility, mucoidy, and serum susceptibility proceeded from an adaptation to chronic infection or a replacement with a new strain, sequential P. aeruginosa isolates of known phenotype collected from 5 cystic fibrosis patients were typed by pulsed-field gel electophoresis (PFGE. Antimicrobial susceptibility testing of all isolates was performed by the disc diffusion method. PFGE typing demonstrated that strains dissimilar in colony morphotype and of different antibiotic susceptibility patterns could be of the same genotype. Some patients were colonized with a rather constant P. aeruginosa flora, with strains of different phenotypes but of one genotype. Instead, some patients may be colonized by more than one genotype. Secretion of mucoid exopolysaccharide and acquisition of a new antibiotic susceptibility phenotype in these strain appear to evolve during chronic colonization in cystic fibrosis patients from specific adaptation to infection rather than from acquisition of new bacterial strains.
Bjarnsholt, Thomas; Jensen, Peter Østrup; Rasmussen, Thomas B;
to otherwise lethal doses of antibiotics, and protects against the bactericidal activity of polymorphonuclear leukocytes (PMNs). It has been previously demonstrated that QS is inhibited by garlic extract. In this study, the synergistic effects of garlic and tobramycin, and PMNs activities have been...... evaluated. P. aeruginosa was grown in vitro in continuous-culture once-through flow chambers with and without garlic extract. The garlic-treated biofilms were susceptible to both tobramycin and PMN grazing. Furthermore, the PMNs showed an increase in respiratory burst activation, when incubated with the...... garlic-treated biofilm. Garlic extract was administered as treatment for a mouse pulmonary infection model. Mice were treated with garlic extract or placebo for 7 days, with the initial 2 days being prophylactic before P. aeruginosa was instilled in the left lung of the mice. Bacteriology, mortality...
Full Text Available Chronic lung infections with Pseudomonas aeruginosa are associated with the diversification of the persisting clone into niche specialists and morphotypes, a phenomenon called 'dissociative behaviour'. To explore the potential of P. aeruginosa to change its morphotype by single step loss-of-function mutagenesis, a signature-tagged mini-Tn5 plasposon library of the cystic fibrosis airway isolate TBCF10839 was screened for colony morphology variants under nine different conditions in vitro. Transposon insertion into 1% of the genome changed colony morphology into eight discernable morphotypes. Half of the 55 targets encode features of primary or secondary metabolism whereby quinolone production was frequently affected. In the other half the transposon had inserted into genes of the functional categories transport, regulation or motility/chemotaxis. To mimic dissociative behaviour of isogenic strains in lungs, pools of 25 colony morphology variants were tested for competitive fitness in an acute murine airway infection model. Six of the 55 mutants either grew better or worse in vivo than in vitro, respectively. Metabolic proficiency of the colony morphology variant was a key determinant for survival in murine airways. The most common morphotype of self-destructive autolysis did unexpectedly not impair fitness. Transposon insertions into homologous genes of strain PAO1 did not reproduce the TBCF10839 mutant morphotypes for 16 of 19 examined loci pointing to an important role of the genetic background on colony morphology. Depending on the chosen P. aeruginosa strain, functional genome scans will explore other areas of the evolutionary landscape. Based on our discordant findings of mutant phenotypes in P. aeruginosa strains PAO1, PA14 and TBCF10839, we conclude that the current focus on few reference strains may miss modes of niche adaptation and dissociative behaviour that are relevant for the microevolution of complex traits in the wild.
Guan, Wei-Jie; Gao, Yong-Hua; Xu, Gang; Lin, Zhi-Ya; Tang, Yan; Li, Hui-Min; Li, Zhi-Min; Zheng, Jin-Ping
Background Current status of Pseudomonas aeruginosa (PA) infection in clinically stable bronchiectasis in mainland China remains unclear. Objective To compare the inflammation and lung function impairment in bronchiectasis patients isolated or infected with PA, potentially pathogenic microorganisms (PPMs) and commensals, and to identify factors associated with PA isolation and infection. Methods Patients with steady-state bronchiectasis and healthy subjects were recruited. Peripheral blood and sputum were sampled to determine inflammatory markers and bacterial loads in steady-state bronchiectasis and health. Spirometry and diffusing capacity were also measured. Results We enrolled 144 bronchiectasis patients and 23 healthy subjects. PA isolation and infection accounted for 44 and 39 patients, who demonstrated significant inflammatory responses and markedly impaired spirometry, but not diffusing capacity, compared with healthy subjects and patients isolated with other PPMs and commensals (all P, 4 or more exacerbations within 2 years (OR: 3.74 for PA isolation, OR: 2.95 for PA infection) and cystic bronchiectasis (OR: 3.63 for PA isolation, OR: 4.47 for PA infection) were the factors consistently associated with PA isolation and infection. Conclusions PA elicits intense inflammation and lung function impairment in steady-state bronchiectasis. The density of PA does not correlate with most clinical indices. PA infection is associated with females, frequent exacerbations and cystic bronchiectasis. PMID:25973228
Full Text Available Pseudomonas aeruginosa is a well-known pathogenic bacterium that forms biofilms and produces virulence factors, thus leading to major problems in many fields, such as clinical infection, food contamination and marine biofouling. In this study, we report the purification and characterization of an exopolysaccharide EPS273 from the culture supernatant of marine bacterium Pseudomonas stutzeri 273. The exopolysaccharide EPS273 not only effectively inhibits biofilm formation but also disperses preformed biofilm of Pseudomonas aeruginosa PAO1. High performance liquid chromatography traces of the hydrolyzed polysaccharides shows that EPS273 primarily consists of glucosamine, rhamnose, glucose and mannose. Further investigation demonstrates that EPS273 reduces the production of the virulence factors pyocyanin, exoprotease and rhamnolipid, and the virulence of P. aeruginosa PAO1 to human lung cells A549 and zebrafish embryos is also obviously attenuated by EPS273. In addition, EPS273 also greatly reduces the production of hydrogen peroxide (H2O2 and extracellular DNA (eDNA, which are important factors for biofilm formation. Furthermore, EPS273 exhibits strong antioxidant potential by quenching hydroxyl and superoxide anion radicals. Notably, the antibiofouling activity of EPS273 is observed in the marine environment up to two weeks according to the amounts of bacteria and diatoms in the glass slides submerged in the ocean. Taken together, the properties of EPS273 indicate that it has a promising prospect in combating bacterial biofilm-associated infection, food-processing contamination and marine biofouling.
Rybtke, Morten Theil; Jensen, Peter Ø; Høiby, Niels; Givskov, Michael Christian; Tolker-Nielsen, Tim; Bjarnsholt, Thomas
Biofilm formation by bacteria is recognized as a major problem in chronic infections due to their recalcitrance against the immune defense and available antibiotic treatment schemes. The opportunistic pathogen Pseudomonas aeruginosa has drawn special attention in this regard due to its severity of...... extracellular matrix encasing the biofilm-associated bacteria as well as the elaborate signaling mechanisms employed by the bacterium enables it to withstand the continuous stresses imposed by the immune defense and administered antibiotics resulting in a state of chronic inflammation that damages the host. The...... immune response leading to this chronic inflammation is described. Finally, novel treatment strategies againstP. aeruginosa are described including, quorum-sensing inhibition and induced biofilm-dispersion. The tolerance towards currently available antimicrobials calls for development of alternative...
Schaber, J. Andy; Triffo, W.J.; Suh, Sang J.; Oliver, Jeffrey W.; Hastert, Mary C.; Griswold, John A.; Auer, Manfred; Hamood, Abdul N.; Rumbaugh, Kendra P.
Biofilms are bacterial communities residing within a polysaccharide matrix that are associated with persistence and antibiotic resistance in chronic infections. We show that the opportunistic pathogen Pseudomonas aeruginosa forms biofilms within 8 hours of infection in thermally-injured mice, demonstrating that biofilms contribute to bacterial colonization in acute infections. P. aeruginosa biofilms were visualized within burned tissue surrounding blood vessels and adipose cells. Although quorum sensing (QS), a bacterial signaling mechanism, coordinates differentiation of biofilms in vitro, wild type and QS-deficient P. aeruginosa formed similar biofilms in vivo. Our findings demonstrate that P. aeruginosa forms biofilms on specific host tissues independent of QS.
Diaz Caballero, Julio; Clark, Shawn T.; Coburn, Bryan; Zhang, Yu; Wang, Pauline W.; Donaldson, Sylva L.; Tullis, D Elizabeth; Yau, Yvonne C. W.; Waters, Valerie J; Hwang, David M.; Guttman, David S.
ABSTRACT Pulmonary infections caused by Pseudomonas aeruginosa are a recalcitrant problem in cystic fibrosis (CF) patients. While the clinical implications and long-term evolutionary patterns of these infections are well studied, we know little about the short-term population dynamics that enable this pathogen to persist despite aggressive antimicrobial therapy. Here, we describe a short-term population genomic analysis of 233 P. aeruginosa isolates collected from 12 sputum specimens obtained...
Bisgaard, H; Pedersen, S S; Nielsen, K G;
The efficacy and safety of anti-inflammatory treatment with inhaled glucocorticosteroids in patients with cystic fibrosis (CF) and complicating chronic Pseudomonas aeruginosa (P.a.) lung infection was studied in a placebo-controlled, parallel, double-blind single center trial. Active treatment......-trial histamine reactivity and the change in FEV1 in the first period in patients on budesonide. We conclude that inhaled glucocorticosteroids can be of short-term benefit in patients with CF and chronic P.a. infection and that those patients most likely to benefit from this treatment are patients with...... hyperreactive airways. Prolonged studies in larger number of patients are necessary to determine the long-term efficacy of this treatment....
Hassett, Daniel J; Korfhagen, Thomas R; Irvin, Randall T;
CF airway mucus can be infected by opportunistic microorganisms, notably Pseudomonas aeruginosa. Once organisms are established as biofilms, even the most potent antibiotics have little effect on their viability, especially during late-stage chronic infections. Better understanding of the mechani...... mechanisms used by P. aeruginosa to circumvent host defenses and therapeutic intervention strategies is critical for advancing novel treatment strategies....
Glasser, Stephan W.; Senft, Albert P; Jeffrey A Whitsett; Melissa D. Maxfield; Ross, Gary F.; Richardson, Theresa R.; Prows, Daniel R.; Xu, Yan; Korfhagen, Thomas R.
To determine the role of surfactant protein C (SP-C) in host defense, SP-C-deficient (Sftpc−/−) mice were infected with the pulmonary pathogen Pseudomonas aeruginosa by intratracheal injection. Survival of young, postnatal day 14 Sftpc−/−ice was decreased in comparison to Sftpc+/+ mice. The sensitivity to Pseudomonas bacteria was specific to the 129S6 strain of Sftpc−/− mice, a strain that spontaneously develops interstitial lung disease-like lung pathology with age. Pulmonary bacterial load ...
Mathee, K; Ciofu, O; Sternberg, C;
The leading cause of mortality in patients with cystic fibrosis (CF) is respiratory failure due in large part to chronic lung infection with Pseudomonas aeruginosa strains that undergo mucoid conversion, display a biofilm mode of growth in vivo and resist the infiltration of polymorphonuclear......Da protein associated with alginate overproducing strains was identified as AlgE (Alg76) by N-terminal sequence analysis. Thus, the common phenotype of the mucoid variants, which included a genetically engineered mucA22 mutant, suggested that the only mutation incurred as a result of H2O2 treatment was in...
Mathee, Kalai; Ciofu, Oana; Sternberg, Claus;
The leading cause of mortality in patients with cystic fibrosis (CF) is respiratory failure due in large part to chronic lung infection with Pseudomonas aeruginosa strains that undergo mucoid conversion, display a biofilm mode of growth in vivo and resist the infiltration of polymorphonuclear......Da protein associated with alginate overproducing strains was identified as AlgE (Alg76) by N-terminal sequence analysis. Thus, the common phenotype Of the mucoid variants, which included a genetically engineered mucA22 mutant, suggested that the only mutation incurred as a result of H(2)O(2) treatment was...
Tramper-Stranders, G. A.; van der Ent, C. K.; Molin, Søren;
were analysed that were either eradicated rapidly or persisted despite multiple antimicrobial treatments. Eighty-six early infection episodes were studied. First P. aeruginosa isolates from patients with eradication (36) or persistent infection (16) were included; isolates from patients with...
Brouqui, P; Rousseau, M C; Stein, A.; Drancourt, M; D. Raoult
Indwelling device infections are associated with considerable morbidity and extremely high cost. Pseudomonas aeruginosa is the most frequent gram-negative etiologic agent associated with infections of indwelling catheters and foreign body implants. It is generally agreed that eradication of infection in the presence of a foreign body requires removal of the foreign body. Using a combination of ceftazidime and ciprofloxacin, we cured nine of nine patients with P. aeruginosa-infected osteosynth...
Pseudomonas aeruginosa is the most commonly identified opportunistic pathogen associated with pool acquired bather disease. To better understand why this microorganism poses this protracted problem we recently appraised P. aeruginosa pool risk management. Much is known about the ...
Schaber, J. Andy; Triffo, W.J.; Suh, Sang J.; Oliver, Jeffrey W.; Hastert, Mary C.; Griswold, John A.; Auer, Manfred; Hamood, Abdul N; Rumbaugh, Kendra P.
Biofilms are bacterial communities residing within a polysaccharide matrix that are associated with persistence and antibiotic resistance in chronic infections. We show that the opportunistic pathogen Pseudomonas aeruginosa forms biofilms within 8 h of infection in thermally injured mice, demonstrating that biofilms contribute to bacterial colonization in acute infections as well. Using light, electron, and confocal scanning laser microscopy, P. aeruginosa biofilms were visualized within burn...
Wahab, Asrul Abdul; Rahman, M.M.
Pseudomonas aeruginosa is a gram-negative bacillus that causes wide spectrum clinical infections. However, it is most frequently associated with hospital-acquired infection. In this case a 58-year-old male with underlying hypertension and dyslipidaemia was admitted for acute right leg cellulitis. Pseudomonas aeruginosa was identified from the case, though it was not a usual suspected organism. It might be due to community-acquired infection.
Daniel J Smith
Full Text Available BACKGROUND: Primary defects in host immune responses have been hypothesised to contribute towards an inability of subjects with cystic fibrosis (CF to effectively clear pulmonary infections. Innate T-lymphocytes provide rapid pathogen-specific responses prior to the development of classical MHC class I and II restricted T-cell responses and are essential to the initial control of pulmonary infection. We aimed to examine the relationship between peripheral blood lymphocyte phenotype and clinical outcomes in adults with CF. METHODS: We studied 41 subjects with CF and 22, age matched, non-smoking healthy control subjects. Lymphocytes were extracted from peripheral blood samples and phenotyped by flow-cytometry. Lymphocyte phenotype was correlated with sputum microbiology and clinical parameters. RESULTS: In comparison to healthy control subjects, mucosal associated invariant T (MAIT-lymphocytes were significantly reduced in the peripheral blood of subjects with CF (1.1% versus 2.0% of T-lymphocytes, P = 0.002. MAIT cell concentration was lowest in CF subjects infected with P. aeruginosa and in subjects receiving treatment for a pulmonary exacerbation. Furthermore a reduced MAIT cell concentration correlated with severity of lung disease. CONCLUSION: Reduced numbers of MAIT cells in subjects with CF were associated with P. aeruginosa pulmonary infection, pulmonary exacerbations and more severe lung disease. These findings provide the impetus for future studies examining the utility of MAIT cells in immunotherapies and vaccine development. Longitudinal studies of MAIT cells as biomarkers of CF pulmonary infection are awaited.
Limoli, D H; Yang, J; Khansaheb, M K; Helfman, B; Peng, L; Stecenko, A A; Goldberg, J B
Cystic fibrosis-related diabetes (CFRD) patients suffer from accelerated rates of pulmonary decline compared to cystic fibrosis (CF) patients with normal glucose tolerance (NGT). However, the mechanisms underlying this difference are unknown. While CFRD is associated with increased respiratory infections, a link between infection and enhanced pulmonary dysfunction remains unclear. The development of glucose intolerance is spectral, resulting in impaired glucose tolerance (IGT) prior to the diagnosis of CFRD. Inclusion of IGT patients within the NGT group may diminish the ability to identify correlations with CFRD. With this in mind, this study aimed to determine if the association between CFRD and respiratory infections is correlated with pulmonary decline. Respiratory cultures from 234 CF patients with confirmed diagnosis of NGT or CFRD were analyzed to measure rates of infection, focusing on the two most prevalent bacteria in CF, Staphylococcus aureus and Pseudomonas aeruginosa. Infection status was correlated with pulmonary function and confounding clinical variables including age, gender, blood glucose levels, and CF transmembrane conductance regulator (CFTR) phenotype were considered in multivariate analyses. CFRD patients, particularly those with extremely high blood glucose levels, were more likely than NGT patients to be co-infected with S. aureus and P. aeruginosa, compared to infection with only one pathogen. Co-infection was associated with decreased lung function and increased frequency of pulmonary exacerbations, even after adjustment for confounding variables. Alterations in the microbial community composition, as opposed to the presence of a single pathogen, may account for greater pulmonary decline in CFRD patients. PMID:26993289
Singh, Sonali; Barr, Helen; Liu, Yi-Chia; Robins, Adrian; Heeb, Stephan; Williams, Paul; Fogarty, Andrew; Cámara, Miguel; Martínez-Pomares, Luisa
Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ventilation or recurrent infections, particularly in cystic fibrosis (CF) patients. CF patients have been proposed to have a Th2 and Th17-biased immune response suggesting that the lack of Th1 and/or over exuberant Th17 responses could contribute to the establishment of chronic P. aeruginosa infection and deterioration of lung function. Accordingly, we have observed that interferon (IFN)-γ production by peripheral blood mononuclear cells from CF patients positively correlated with lung function, particularly in patients chronically infected with P. aeruginosa. In contrast, IL-17A levels tended to correlate negatively with lung function with this trend becoming significant in patients chronically infected with P. aeruginosa. These results are in agreement with IFN-γ and IL-17A playing protective and detrimental roles, respectively, in CF. In order to explore the protective effect of IFN-γ in CF, the effect of IFN-γ alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), on the ability of human macrophages to control P. aeruginosa growth, resist the cytotoxicity induced by this bacterium or promote inflammation was investigated. Treatment of macrophages with IFN-γ, in the presence and absence of GM-CSF, failed to alter bacterial growth or macrophage survival upon P. aeruginosa infection, but changed the inflammatory potential of macrophages. IFN-γ caused up-regulation of monocyte chemoattractant protein-1 (MCP-1) and TNF-α and down-regulation of IL-10 expression by infected macrophages. GM-CSF in combination with IFN-γ promoted IL-6 production and further reduction of IL-10 synthesis. Comparison of TNF-α vs. IL-10 and IL-6 vs. IL-10 ratios revealed the following hierarchy in regard to the pro-inflammatory potential of human macrophages
Salomonsen Charlotte M
Full Text Available Abstract Background Hemorrhagic pneumonia is a disease of farmed mink (Neovison vison caused by Pseudomonas aeruginosa. The disease is highly seasonal in Danish mink with outbreaks occurring almost exclusively in the autumn. Human respiratory syncytial virus (RSV has been shown to augment infection with P. aeruginosa in mice and to promote adhesion of P. aeruginosa to human respiratory cells. Findings We tested 50 lung specimens from mink with hemorrhagic pneumonia for bovine RSV by reverse transcriptase polymerase chain reaction (PCR and for human RSV by a commercial real-time PCR. RSV was not found. Conclusions This study indicates that human and bovine RSV is not a major co-factor for development of hemorrhagic pneumonia in Danish mink.
Dingemans, Jozef; Monsieurs, Pieter; Yu, Sung-Huan; Crabbé, Aurélie; Förstner, Konrad U.; Malfroot, Anne
ABSTRACT Chronic colonization of the lungs by Pseudomonas aeruginosa is one of the major causes of morbidity and mortality in cystic fibrosis (CF) patients. To gain insights into the characteristic biofilm phenotype of P. aeruginosa in the CF lungs, mimicking the CF lung environment is critical. We previously showed that growth of the non-CF-adapted P. aeruginosa PAO1 strain in a rotating wall vessel, a device that simulates the low fluid shear (LS) conditions present in the CF lung, leads to the formation of in-suspension, self-aggregating biofilms. In the present study, we determined the phenotypic and transcriptomic changes associated with the growth of a highly adapted, transmissible P. aeruginosa CF strain in artificial sputum medium under LS conditions. Robust self-aggregating biofilms were observed only under LS conditions. Growth under LS conditions resulted in the upregulation of genes involved in stress response, alginate biosynthesis, denitrification, glycine betaine biosynthesis, glycerol metabolism, and cell shape maintenance, while genes involved in phenazine biosynthesis, type VI secretion, and multidrug efflux were downregulated. In addition, a number of small RNAs appeared to be involved in the response to shear stress. Finally, quorum sensing was found to be slightly but significantly affected by shear stress, resulting in higher production of autoinducer molecules during growth under high fluid shear (HS) conditions. In summary, our study revealed a way to modulate the behavior of a highly adapted P. aeruginosa CF strain by means of introducing shear stress, driving it from a biofilm lifestyle to a more planktonic lifestyle. PMID:27486191
Bianconi, Irene; Milani, Andrea; Cigana, Cristina; Paroni, Moira; Levesque, Roger C.; Bertoni, Giovanni; Bragonzi, Alessandra
The opportunistic pathogen Pseudomonas aeruginosa can establish life-long chronic infections in the airways of cystic fibrosis (CF) patients. Persistent lifestyle is established with P. aeruginosa patho-adaptive variants, which are clonal with the initially-acquired strains. Several reports indicated that P. aeruginosa adapts by loss-of-function mutations which enhance fitness in CF airways and sustain its clonal expansion during chronic infection. To validate this model of P. aeruginosa adap...
Full Text Available Background: Type I interferon (IFN-I predisposes to bacterial superinfections, an important problem during viral infection or treatment with interferon-alpha (IFN-α. IFN-I-induced neutropenia is one reason for the impaired bacterial control; however there is evidence that more frequent bacterial infections during IFN-α-treatment occur independently of neutropenia. Methods: We analyzed in a mouse model, whether Pseudomonas aeruginosa control is influenced by co-infection with the lymphocytic choriomeningitis virus (LCMV. Bacterial titers, numbers of neutrophils and the gene-expression of liver-lysozyme-2 were determined during a 24 hours systemic infection with P. aeruginosa in wild-type and Ifnar-/- mice under the influence of LCMV or poly(I:C. Results: Virus-induced IFN-I impaired the control of Pseudomonas aeruginosa. This was associated with neutropenia and loss of lysozyme-2-expression in the liver, which had captured P. aeruginosa. A lower release of IFN-I by poly(I:C-injection also impaired the bacterial control in the liver and reduced the expression of liver-lysozyme-2. Low concentration of IFN-I after infection with a virulent strain of P. aeruginosa alone impaired the bacterial control and reduced lysozyme-2-expression in the liver as well. Conclusion: We found that during systemic infection with P. aeruginosa Kupffer cells quickly controlled the bacteria in cooperation with neutrophils. Upon LCMV-infection this cooperation was disturbed.
Paula E Beaumont
Full Text Available Cathelicidins are multifunctional cationic host-defence peptides (CHDP; also known as antimicrobial peptides and an important component of innate host defence against infection. In addition to microbicidal potential, these peptides have properties with the capacity to modulate inflammation and immunity. However, the extent to which such properties play a significant role during infection in vivo has remained unclear. A murine model of acute P. aeruginosa lung infection was utilised, demonstrating cathelicidin-mediated enhancement of bacterial clearance in vivo. The delivery of exogenous synthetic human cathelicidin LL-37 was found to enhance a protective pro-inflammatory response to infection, effectively promoting bacterial clearance from the lung in the absence of direct microbicidal activity, with an enhanced early neutrophil response that required both infection and peptide exposure and was independent of native cathelicidin production. Furthermore, although cathelicidin-deficient mice had an intact early cellular inflammatory response, later phase neutrophil response to infection was absent in these animals, with significantly impaired clearance of P. aeruginosa. These findings demonstrate the importance of the modulatory properties of cathelicidins in pulmonary infection in vivo and highlight a key role for cathelicidins in the induction of protective pulmonary neutrophil responses, specific to the infectious milieu. In additional to their physiological roles, CHDP have been proposed as future antimicrobial therapeutics. Elucidating and utilising the modulatory properties of cathelicidins has the potential to inform the development of synthetic peptide analogues and novel therapeutic approaches based on enhancing innate host defence against infection with or without direct microbicidal targeting of pathogens.
Sordelli, D O; Zeligs, B J; Cerquetti, M C; Morris Hooke, A; Bellanti, J A
The changes in pulmonary cell population in response to aerosols containing either Pseudomonas aeruginosa or Staphylococcus aureus were studied in a murine model. The lungs of inbred DBA/2J mice received an inoculum of 2 X 10(5) colony-forming units of the microorganism and lung lavages were performed at various time intervals thereafter. P. aeruginosa aerosols produced an immediate decrease in the number of resident alveolar macrophages (AM), followed by a two-waved recruitment of cells into the respiratory tract; the first wave was composed of polymorphonuclear leukocytes (PMN) and the second of monocyte-like peroxidase-positive AM. The change in cell populations was transient and returned to baseline values within a week after aerosolization. In contrast, aerosolized S. aureus initially induced a slight increase in mononuclear cells, and by 60 min after aerosol exposure, the cell population was not different from that of control animals. PMID:3920067
Seeger, W; Walmrath, D; Neuhof, H.; Lutz, F.
The effects of Pseudomonas aeruginosa cytotoxin on the pulmonary microvasculature were studied in blood-free, perfused, isolated rabbit lungs. Cytotoxin was administered to the recirculating Krebs Henseleit albumin (1%) buffer during two consecutive 30-min-perfusion phases (phases 1 and 2) at a concentration of 13 micrograms/ml, followed by a third perfusion phase (phase 3) without toxin. After perfusion phases 2 and 3, the capillary filtration coefficient (Kf,c) and vascular compliance were ...
Full Text Available Infections with Pseudomonas aeruginosa have been a long-standing challenge for clinical therapy because of complex pathogenesis and resistance to antibiotics, thus attaching importance to explore effective vaccines for prevention and treatment. In the present study, we constructed a novel DNA vaccine by inserting mutated gene toxAm encoding Pseudomonas Exotoxin A and gene pcrV encoding tip protein of the type III secretion system into respective sites of a eukaryotic plasmid pIRES, named pIRES-toxAm-pcrV, and next evaluated the efficacy of the vaccine in murine acute Pseudomonas pneumonia models. Compared to DNA vaccines encoding single antigen, mice vaccinated with pIRES-toxAm-pcrV elicited higher levels of antigen-specific serum immunoglobulin G (IgG, enhanced splenic cell proliferation and cytokine secretion in response to Pseudomonas aeruginosa antigens, additionally PAO1 challenge in mice airway resulted in reduced bacteria burden and milder pathologic changes in lungs. Besides, it was observed that immunogenicity and protection could be promoted by the CpG ODN 1826 adjuvant. Taken together, it's revealed that recombinant DNA vaccine pIRES-toxAm-pcrV was a potential candidate for immunotherapy of Pseudomonas aeruginosa infection and the CpG ODN 1826 a potent stimulatory adjuvant for DNA vaccination.
Abd-Alla, Mohamed H.; Bashandy, Shymaa R.
Eighteen organic compounds were present in growing onion bulbs cultivar Giza 6 infected with P. aeruginosa, but only fourteen of them are present in dry infected onion bulbs; however, four compounds were missing in dry onion. The missing compounds in dry infected onion bulbs are pantolactone, 4,5-dihydro-4,5-dimethylfuran-2(3H)-one, myristic acid, and linoleic acid. All of them were detected in growing onion (living cell) during Pseudomonas aeruginosa infection, and it is hypothesized that it...
Chest radiography in two teenage boys, one with Wiscott-Aldrich's syndrome and one with acute lymphatic leucemia in remission showed increased interstitial pattern. In both computed tomography (CT) of the lungs showed heavy interstitial pneumonia, rather different in appearance but in both cases equal to the CT findings in opportunistic lung infections known from immunoincompetent patients with for instance pneumocystis carinii and/or cytomegalo virus infections. In both patients the CT findings led to lung biopsy establishing the etiologic agent. (orig.)
Ciofu, Oana; Tolker-Nielsen, Tim; Jensen, Peter Østrup;
Lung infection is the main cause of morbidity and mortality in patients with cystic fibrosis and is mainly dominated by Pseudomonas aeruginosa. The biofilm mode of growth makes eradication of the infection impossible, and it causes a chronic inflammation in the airways. The general mechanisms of...... biofilm formation and antimicrobial tolerance and resistance are reviewed. Potential anti-biofilm therapeutic targets such as weakening of biofilms by quorum-sensing inhibitors or antibiotic killing guided by pharmacokinetics and pharmacodynamics of antibiotics are presented. The vicious circle of...... adaptive evolution of the persisting bacteria imposes important therapeutic challenges and requires development of new drug delivery systems able to reach the different niches occupied by the bacteria in the lung of cystic fibrosis patients....
Full Text Available BACKGROUND: Fosfomycin is a cell wall inhibitor used efficiently to treat uncomplicated urinary tract and gastrointestinal infections. A very convenient feature of fosfomycin, among others, is that although the expected frequency of resistant mutants is high, the biological cost associated with mutation impedes an effective growth rate, and bacteria cannot offset the obstacles posed by host defenses or compete with sensitive bacteria. Due to the current scarcity of new antibiotics, fosfomycin has been proposed as an alternative treatment for other infections caused by a wide variety of bacteria, particularly Pseudomonas aeruginosa. However, whether fosfomycin resistance in P. aeruginosa provides a fitness cost still remains unknown. PRINCIPAL FINDINGS: We herein present experimental evidence to show that fosfomycin resistance cannot only emerge easily during treatment, but that it is also cost-free for P. aeruginosa. We also tested if, as has been reported for other species such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, fosfomycin resistant strains are somewhat compromised in their virulence. As concerns colonization, persistence, lung damage, and lethality, we found no differences between the fosfomycin resistant mutant and its sensitive parental strain. The probability of acquisition in vitro of resistance to the combination of fosfomycin with other antibiotics (tobramycin and imipenem has also been studied. While the combination of fosfomycin with tobramycin makes improbable the emergence of resistance to both antibiotics when administered together, the combination of fosfomycin plus imipenem does not avoid the appearance of mutants resistant to both antibiotics. CONCLUSIONS: We have reached the conclusion that the use of fosfomycin for P. aeruginosa infections, even in combined therapy, might not be as promising as expected. This study should encourage the scientific community to assess the in vivo cost of resistance
Brouqui, P; Rousseau, M C; Stein, A; Drancourt, M; Raoult, D
Indwelling device infections are associated with considerable morbidity and extremely high cost. Pseudomonas aeruginosa is the most frequent gram-negative etiologic agent associated with infections of indwelling catheters and foreign body implants. It is generally agreed that eradication of infection in the presence of a foreign body requires removal of the foreign body. Using a combination of ceftazidime and ciprofloxacin, we cured nine of nine patients with P. aeruginosa-infected osteosynthetic material and four of five patients with hip and knee prostheses without removing the foreign material. Follow-up was for a mean of 21 months (range, 6 to 60 months). Some patients experienced minor side effects (arthralgia in one patient and rash in another patient). We conclude that this combination is effective and safe and should be useful in the treatment of P. aeruginosa-infected orthopedic implants. PMID:8585720
Keith H Turner
Full Text Available Opportunistic infections caused by Pseudomonas aeruginosa can be acute or chronic. While acute infections often spread rapidly and can cause tissue damage and sepsis with high mortality rates, chronic infections can persist for weeks, months, or years in the face of intensive clinical intervention. Remarkably, this diverse infectious capability is not accompanied by extensive variation in genomic content, suggesting that the genetic capacity to be an acute or a chronic pathogen is present in most P. aeruginosa strains. To investigate the genetic requirements for acute and chronic pathogenesis in P. aeruginosa infections, we combined high-throughput sequencing-mediated transcriptome profiling (RNA-seq and genome-wide insertion mutant fitness profiling (Tn-seq to characterize gene expression and fitness determinants in murine models of burn and non-diabetic chronic wound infection. Generally we discovered that expression of a gene in vivo is not correlated with its importance for fitness, with the exception of metabolic genes. By combining metabolic models generated from in vivo gene expression data with mutant fitness profiles, we determined the nutritional requirements for colonization and persistence in these infections. Specifically, we found that long-chain fatty acids represent a major carbon source in both chronic and acute wounds, and P. aeruginosa must biosynthesize purines, several amino acids, and most cofactors during infection. In addition, we determined that P. aeruginosa requires chemotactic flagellar motility for fitness and virulence in acute burn wound infections, but not in non-diabetic chronic wound infections. Our results provide novel insight into the genetic requirements for acute and chronic P. aeruginosa wound infections and demonstrate the power of using both gene expression and fitness profiling for probing bacterial virulence.
Hsu, Daniel; Taylor, Patricia; Fletcher, Dave; van Heeckeren, Rolf; Eastman, Jean; van Heeckeren, Anna; Davis, Pamela; Chmiel, James F; Pearlman, Eric; Bonfield, Tracey L
Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated with Pseudomonas aeruginosa colonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17. Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected with P. aeruginosa had robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed with P. aeruginosa infection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency of Cftr and ongoing inflammation. These studies demonstrate the in vivo contribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis. PMID:27271746
Xu, Zhi-Gang; Gao, Yu; He, Jian-Guo; Xu, Wei-Feng; Jiang, Mei; JIN, HUAN-SHENG
Pseudomonas aeruginosa is a common pathogenic bacterium in urinary tract infections (UTIs), particularly catheter-associated UTIs. The aim of this study was to investigate the effect of azithromycin (AZM) on P. aeruginosa isolated from UTIs. Isolates were identified by biochemical assays and the Vitek system. Antimicrobial susceptibility was determined using the disk diffusion assay. Biofilm formation and adhesion were assayed using a crystal violet staining method. The swimming motility was ...
Vasilev, Ch L; Veleva, K V; Tekelieva, R Kh; Pencheva, P I
The antibody levels in 18 batches of the preparations of human immunoglobulin, Immunovenin and Immunovenin-Intact, for intravenous injection were determined in the enzyme immunoassay with the use of the mixture of P. aeruginosa lipopolysaccharide antigens of seven immunotypes. The average antibody titers in these preparations were identical. The preparations were found to have protective action against P. aeruginosa experimental infection in mice. PMID:1907793
Pires, Diana P.; Vilas Boas, Diana; Sillankorva, Sanna
Antimicrobial resistance constitutes one of the major worldwide public health concerns. Bacteria are becoming resistant to the vast majority of antibiotics, and nowadays, a common infection can be fatal. To address this situation, the use of phages for the treatment of bacterial infections has been extensively studied as an alternative therapeutic strategy. Since Pseudomonas aeruginosa is one of the most common causes of health care-associated infections, many studies have reported the in vitro and in vivo antibacterial efficacy of phage therapy against this bacterium. This review collects data of all the P. aeruginosa phages sequenced to date, providing a better understanding about their biodiversity. This review further addresses the in vitro and in vivo results obtained by using phages to treat or prevent P. aeruginosa infections as well as the major hurdles associated with this therapy. PMID:25972556
Full Text Available Staphylococcus (S. aureus and Pseudomonas (Ps. aeruginosa are two of the most frequently opportunistic pathogens isolated in nosocomial infections, responsible for severe infections in immunocompromised hosts. The frequent emergence of antibiotic-resistant S. aureus and Ps. aeruginosa strains has determined the development of new strategies in order to elucidate the different mechanisms used by these bacteria at different stages of the infectious process, providing the scientists with new procedures for preventing, or at least improving, the control of S. aureus and Ps. aeruginosa infections. The purpose of this study was to characterize the molecular markers of virulence in S. aureus and Ps. aeruginosa strains isolated from different clinical specimens. We used multiplex and uniplex PCR assays to detect the genes encoding different cell-wall associated and extracellular virulence factors, in order to evaluate potential associations between the presence of putative virulence genes and the outcome of infections caused by these bacteria. Our results demonstrate that all the studied S. aureus and Ps. aeruginosa strains synthesize the majority of the investigated virulence determinants, probably responsible for different types of infections.
Rančić Milan; Ristić Lidija; Stanković Ivana
Introduction. This study was aimed at analyzing the site, kind and type of infection which develop in patients having lung cancer at hospital treatment. Material and methods. Clinical data of the patients hospitalized for lung cancer were analyzed at the Clinic for Lung Diseases and Tuberculosis in Knez Selo in the period from January 2002 till December 2007. A great number of patients (1296-75.9%) had non-small cell lung cancer. In 1708 patients with lung cancer, 773 febrile episodes were re...
Chouake, Jason; Schairer, David; Kutner, Allison; Sanchez, David A; Makdisi, Joy; Blecher-Paz, Karin; Nacharaju, Parimala; Tuckman-Vernon, Chaim; Gialanella, Phil; Friedman, Joel M; Nosanchuk, Joshua D; Friedman, Adam J
Pseudomonas aeruginosa is a community-acquired, nosocomial pathogen that is an important cause of human morbidity and mortality; it is intrinsically resistant to several antibiotics and is capable of developing resistance to newly developed drugs via a variety of mechanisms. P aeruginosa's ubiquity and multidrug resistance (MDR) warrants the development of innovative methods that overcome its ability to develop resistance. We have previously described a nitric oxide-releasing nanoparticle (NO-np) platform that effectively kills gram-positive and gram-negative organisms in vitro and accelerates clinical recovery in vivo in murine wound and abscess infection models. We have also demonstrated that when glutathione (GSH) is added to NO-np, the nitroso intermediate S-nitrosoglutathione (GSNO) is formed, which has greater activity against P aeruginosa and other gram-negative organisms compared with NO-np alone. In the current study, we evaluate the potential of NO-np to generate GSNO both in vitro and in vivo in a murine excisional wound model infected with an MDR clinical isolate of P aeruginosa. Whereas NO-np alone inhibited P aeruginosa growth in vitro for up to 8 hours, NO-np+GSH completely inhibited P aeruginosa growth for 24 hours. Percent survival in the NO-np+GSH-treated isolates was significantly lower than in the NO-np (36.1% vs 8.3%; P=.004). In addition, NO-np+GSH accelerated wound closure in P aeruginosa-infected wounds, and NO-np+GSH-treated wounds had significantly lower bacterial burden when compared to NO-np-treated wounds (P<.001). We conclude that GSNO is easily generated from our NO-np platform and has the potential to be used as an antimicrobial agent against MDR organisms such as P aeruginosa. PMID:23377518
Jonathon P Audia
Full Text Available Herein we describe a pathogenic role for the Pseudomonas aeruginosa type three secretion system (T3SS needle tip complex protein, PcrV, in causing lung endothelial injury. We first established a model in which P. aeruginosa wild type strain PA103 caused pneumonia-induced sepsis and distal organ dysfunction. Interestingly, a PA103 derivative strain lacking its two known secreted effectors, ExoU and ExoT [denoted PA103 (ΔU/ΔT], also caused sepsis and modest distal organ injury whereas an isogenic PA103 strain lacking the T3SS needle tip complex assembly protein [denoted PA103 (ΔPcrV] did not. PA103 (ΔU/ΔT infection caused neutrophil influx into the lung parenchyma, lung endothelial injury, and distal organ injury (reminiscent of sepsis. In contrast, PA103 (ΔPcrV infection caused nominal neutrophil infiltration and lung endothelial injury, but no distal organ injury. We further examined pathogenic mechanisms of the T3SS needle tip complex using cultured rat pulmonary microvascular endothelial cells (PMVECs and revealed a two-phase, temporal nature of infection. At 5-hours post-inoculation (early phase infection, PA103 (ΔU/ΔT elicited PMVEC barrier disruption via perturbation of the actin cytoskeleton and did so in a cell death-independent manner. Conversely, PA103 (ΔPcrV infection did not elicit early phase PMVEC barrier disruption. At 24-hours post-inoculation (late phase infection, PA103 (ΔU/ΔT induced PMVEC damage and death that displayed an apoptotic component. Although PA103 (ΔPcrV infection induced late phase PMVEC damage and death, it did so to an attenuated extent. The PA103 (ΔU/ΔT and PA103 (ΔPcrV mutants grew at similar rates and were able to adhere equally to PMVECs post-inoculation indicating that the observed differences in damage and barrier disruption are likely attributable to T3SS needle tip complex-mediated pathogenic differences post host cell attachment. Together, these infection data suggest that the T3SS needle
Lefebvre, Annick; Quantin, Catherine; Vanhems, Philippe; Lucet, Jean-Christophe; Bertrand, Xavier; Astruc, Karine; Chavanet, Pascal; Aho-Glélé, Ludwig S.
Aim: We aimed to study the impact of new water systems, which were less contaminated with P. aeruginosa, on the incidence of healthcare-associated P. aeruginosa cases (colonizations or infections) in care units that moved to a different building between 2005 and 2014. Methods: Generalized Estimated Equations were used to compare the incidence of P. aeruginosa healthcare-associated cases according to the building. Results: Twenty-nine units moved during the study period and 2,759 cases occurred in these units. No difference was observed when the new building was compared with older buildings overall. Conclusion: Our results did not support our hypothesis of a positive association between water system contamination and the incidence of healthcare-associated P. aeruginosa cases. These results must be confirmed by linking results of water samples and patients’ data.
A major purpose of treating patients with cystic fibrosis (CF) is to prevent or delay chronic lung infections with CF-pathogenic Gram-negative bacteria. In the intermittent stage, bacteria can usually be eradicated from the lungs with antibiotics, but following eradication, the next lung...... CF patients. This is important since urgent treatment reduces morbidity when CF patients are early colonised with P. aeruginosa, however, there is a lack of diagnostic tools for detecting the early colonisation in the lungs and in the sinuses. We initiated a treatment strategy for CF patients to...... strategy, sinus bacteria could be eradicated in a large proportion of patients. Essentially, growth of CF-pathogenic bacteria from the lower respiratory tract was decreased following the treatment. Furthermore, a number of patients have been free from CF-pathogenic bacteria for more than one year after...
Full Text Available BACKGROUND: Pseudomonas aeruginosa (PA and Burkholderia cepacia complex (Bcc, commonly found in the lungs of cystic fibrosis (CF patients, often produce cyanide (CN, which inhibits cellular respiration. CN in sputa is a potential biomarker for lung infection by CF pathogens. However, its actual concentration in the infected lungs is unknown. METHODS AND FINDINGS: This work reports observation of CN in the lungs of mice infected with cyanogenic PA or Bcc strains using a CN fluorescent chemosensor (4',5'-fluorescein dicarboxaldehyde with a whole animal imaging system. When the CN chemosensor was injected into the lungs of mice intratracheally infected with either PA or B. cepacia strains embedded in agar beads, CN was detected in the millimolar range (1.8 to 4 mM in the infected lungs. CN concentration in PA-infected lungs rapidly increased within 24 hours but gradually decreased over the following days, while CN concentration in B. cepacia-infected lungs slowly increased, reaching a maximum at 5 days. CN concentrations correlated with the bacterial loads in the lungs. In vivo efficacy of antimicrobial treatments was tested in live mice by monitoring bacteriogenic CN in the lungs. CONCLUSIONS: The in vivo imaging method was also found suitable for minimally invasive testing the efficacy of antibiotic compounds as well as for aiding the understanding of bacterial cyanogenesis in CF lungs.
Klitten, Laura Line; Alhede, Morten; Kolpen, Mette;
reported that O2 is mainly consumed by the activated PMNs, while O2 consumption by aerobic respiration is diminutive and nitrous oxide (N2O) is produced in infected CF sputum. This suggests that the reported growth rates of P. aeruginosa in lungs and sputum may result from anaerobic respiration using...... denitrification. The growth rate of P. aeruginosa achieved by denitrification at physiological levels (~400 μM) of nitrate (NO(-) 3) is however, not known. Therefore, we have measured growth rates of anoxic cultures of PAO1 and clinical isolates (n = 12) in LB media supplemented with NO(-) 3 and found a...... significant increase of growth when supplementing PAO1 and clinical isolates with ≥150 μM NO(-) 3 and 100 μM NO(-) 3, respectively. An essential contribution to growth by denitrification was demonstrated by the inability to establish a significantly increased growth rate by a denitrification deficient Δnir...
Turner, Keith H.; Jake Everett; Urvish Trivedi; Rumbaugh, Kendra P.; Marvin Whiteley
Opportunistic infections caused by Pseudomonas aeruginosa can be acute or chronic. While acute infections often spread rapidly and can cause tissue damage and sepsis with high mortality rates, chronic infections can persist for weeks, months, or years in the face of intensive clinical intervention. Remarkably, this diverse infectious capability is not accompanied by extensive variation in genomic content, suggesting that the genetic capacity to be an acute or a chronic pathogen is present in ...
Merches, Katja; Khairnar, Vishal; Knuschke, Torben; et al.
BACKGROUND: Type I interferon (IFN-I) predisposes to bacterial superinfections, an important problem during viral infection or treatment with interferon-alpha (IFN-α). IFN-I-induced neutropenia is one reason for the impaired bacterial control; however there is evidence that more frequent bacterial infections during IFN-α-treatment occur independently of neutropenia. METHODS: We analyzed in a mouse model, whether Pseudomonas aeruginosa control is influenced by co-infection with the lymphocy...
Vogt, Stefanie L.; Green, Christopher; Stevens, Katarzyna M.; Day, Brad; Erickson, David L.; Woods, Donald E.; Storey, Douglas G.
The stringent response is a regulatory system that allows bacteria to sense and adapt to nutrient-poor environments. The central mediator of the stringent response is the molecule guanosine 3′,5′-bispyrophosphate (ppGpp), which is synthesized by the enzymes RelA and SpoT and which is also degraded by SpoT. Our laboratory previously demonstrated that a relA mutant of Pseudomonas aeruginosa, the principal cause of lung infections in cystic fibrosis patients, was attenuated in virulence in a Dro...
Full Text Available Introduction. This study was aimed at analyzing the site, kind and type of infection which develop in patients having lung cancer at hospital treatment. Material and methods. Clinical data of the patients hospitalized for lung cancer were analyzed at the Clinic for Lung Diseases and Tuberculosis in Knez Selo in the period from January 2002 till December 2007. A great number of patients (1296-75.9% had non-small cell lung cancer. In 1708 patients with lung cancer, 773 febrile episodes were recorded, i.e. 687 states of infections. Results. Most of the infections were recorded in the tracheobronchial tree (60.9%. The infection was confirmed microbiologically in 38% of infectious states. Predominant Gram positive pathogens were Staphylococcus aureus and Streptococcus, but among Gram negative pathogens there were Escherichia coli and Haemophilus influenzae. Discussion. A significantly better therapy response to antibiotics was found in the group of patients where microbiological agents were isolated (p<0.05. The predominant site of infection in the patients with lung cancer is the tracheobronchial tree without a significant difference between frequency of Gram positive and Gram negative pathogens.
The antimicrobial activity and other medical benefits of garlic oil have been attributed to the presence of sulphides in it. Pseudomonas aeruginosa is a multidrug resistance opportunistic human pathogen that infect many patients .To control these infections, there is a need for other agents with greater antimicrobial activity and less toxicity. In this study, the effect of irradiated and non-irradiated garlic oil has been evaluated. The irradiation of garlic oil at 10.0 kGy decreased slightly its antibacterial activity against the tested Pseudomonas aeruginosa. The results revealed that there was no effect of garlic oil either irradiated or non-irradiated on the adherent cells formed by Pseudomonas aeruginosa tested organism on tissue culture plate. Garlic oil (irradiated or nonirradiated) was administrated subcutaneously as treatment for a mouse infection model. Bacteriological examination and mortality rate were used as indicators. The treatment with non-irradiated garlic oil decreased the number of bacteria in the infected group in contrast with the placebo group (saline), while, irradiation of garlic oil with 10.0 kGy had no effect on the infected bacteria. Also, the results indicated that, the treatment with non-irradiated garlic oil decreased the mortality in comparison with irradiated garlic oil which did not show any effect. Scanning electron microscopy study revealed that there were morphological changes in the Pseudomonas aeruginosa treated with non- irradiated garlic oil in comparison with untreated one
Cramer, Nina; Wiehlmann, Lutz; Ciofu, Oana;
The molecular epidemiology of the chronic airway infections with Pseudomonas aeruginosa in individuals with cystic fibrosis (CF) was investigated by cross-sectional analysis of bacterial isolates from 51 CF centers and by longitudinal analysis of serial isolates which had been collected at the CF...
Kolmos, H J; Lerche, A; Kristoffersen, Kirsten Lydia; Rosdahl, V T
Pseudomonas aeruginosa was isolated from bronchoalveolar lavage fluid from 8 consecutive patients undergoing bronchoscopy at an infectious diseases unit. None of the patients developed signs of respiratory tract infection that could be ascribed to the organism. The source of contamination was the...
Kerr, J. R.
Three surgery patients were monitored postoperatively, with particular reference to lung infection. In each case there was a clinical impression that Pseudomonas aeruginosa suppressed the growth of Candida albicans in patients with clinically significant lung infections from whom both of these organisms were isolated from serial sputum samples. Regrowth of C. albicans after P. aeruginosa eradication occurred in two patients, despite fluconazole therapy, to which both C. albicans isolates were...
Johansen, Helle Krogh; Moskowitz, Samuel M; Ciofu, Oana;
BACKGROUND: Colistin resistant Pseudomonas aeruginosa have rarely been reported in cystic fibrosis (CF) patients. METHODS: We performed a 17-year prospective study on colistin susceptibility and compared our findings with clinical variables. RESULTS: The first outbreak started in 1995 and lasted 5...... the first outbreak. Most resistant isolates belonged to two major clones that had similar genotypes in the two outbreaks. The P. aeruginosa isolates were all non-mucoid and they appeared in a group of chronically infected patients that had been admitted to the same ward for antibiotic treatment and...
Histoplasmosis is a primarily pulmonary originated mycosis which is acquired by inhalation. In the majority of the cases infection goes unnoticed or gets manifested by slight respiratory symptoms. Histoplasmoma is a relatively common form of acute lung histoplasmosis, in form of nodules, which is generally accompanied by calcification that can increase in size and simulate a lung neoplasia. This article describes a case of an immunocompromised patient with this kind of pulmonary mycosis
Ciofu, O; Petersen, T D; Jensen, P;
BACKGROUND: In order to study the impact on the lung function of patients with cystic fibrosis of the avidity of antipseudomonal antibodies, the avidity of antibodies against the chromosomal beta-lactamase of Pseudomonas aeruginosa (a beta ab) and against the 60-65 kDa heat shock protein of P...... function the avidity of a beta ab was higher than in patients with poor lung function (p = 0.018). No significant difference in the avidity of the anti-GroEL antibodies was observed between the two groups of patients. CONCLUSION: In patients with cystic fibrosis a high avidity of a beta ab could contribute...
Yue, Lei; Xie, Zhongping; Li, Hua; Pang, Zheng; Junkins, Robert D; Tremblay, Michel L; Chen, Xiaochun; Lin, Tong-Jun
Pseudomonas aeruginosa is a major opportunistic pathogen in immune-compromised individuals. Mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator in P. aeruginosa infection. PTP1B-deficient mice display greatly enhanced bacterial clearance and reduced disease scores, which are accompanied by increased neutrophil infiltration and cytokine production. Interestingly, PTP1B deficiency mainly up-regulates the production of interferon-stimulated response elements-regulated cytokines and chemokines, including chemokine ligand 5 (regulated on activation normal T cell expressed and secreted), CXCL10 (interferon γ-inducible protein 10), and interferon-β production. Further studies reveal that PTP1B deficiency leads to increased interferon regulatory factor 7 (IRF7) expression and activation. These findings demonstrate a novel regulatory mechanism of the immune response to P. aeruginosa infection through PTP1B-IRF7 interaction. This novel PTP1B-IRF7-interferon-stimulated response elements pathway may have broader implications in Toll-like receptor-mediated innate immunity. PMID:27105736
Bjarnsholt, Thomas; Jensen, Peter Østrup; Burmølle, Mette; Hentzer, Morten; Haagensen, Janus Anders Juul; Hougen, Hans Petter; Calum, Henrik; Madsen, Kit G; Moser, Claus; Molin, Søren; Høiby, Niels; Givskov, Michael Christian
The opportunistic human pathogen Pseudomonas aeruginosa is the predominant micro-organism of chronic lung infections in cystic fibrosis (CF) patients. P. aeruginosa colonizes the CF lungs by forming biofilm structures in the alveoli. In the biofilm mode of growth the bacteria are highly tolerant to...
Bjarnsholt, Thomas; Jensen, Peter Østrup; Fiandaca, Mark J; Pedersen, Jette; Hansen, Christine Rønne; Andersen, Claus Bøgelund; Pressler, Tacjana; Givskov, Michael; Høiby, Niels
The present study was undertaken to investigate the appearance and location of Pseudomonas aeruginosa in the cystic fibrosis (CF) lung and in sputum. Samples include preserved tissues of CF patients who died due to chronic P. aeruginosa lung infection prior to the advent of intensive antibiotic...
Christensen, Louise D; Moser, Claus; Jensen, Peter Ø; Rasmussen, Thomas B; Christophersen, Lars; Kjelleberg, Staffan; Kumar, Naresh; Høiby, Niels; Givskov, Michael Christian; Bjarnsholt, Thomas
Pseudomonas aeruginosa is an opportunistic human pathogen that causes chronic biofilm-based infections in host organisms. P. aeruginosa employs quorum sensing (QS) to control expression of its virulence, and to establish and maintain chronic infections. Under such conditions, the biofilm mode of...... growth contributes significantly to P. aeruginosa tolerance to the action of the innate and adaptive defence system and numerous antibiotics. In the present study, an in vivo foreign-body infection model was established in the peritoneal cavity of mice. Experimental data showed that QS-deficient P...
Francis J. Gilchrist
Full Text Available Hydrogen cyanide is readily detected in the headspace above Pseudomonas aeruginosa cultures and in the breath of cystic fibrosis (CF patients with chronic (P. aeruginosa infection. We investigated if exhaled breath HCN is an early marker of P. aeruginosa infection. 233 children with CF who were free from P. aeruginosa infection were followed for 2 years. Their median (interquartile range age was 8.0 (5.0–12.2 years. At each study visit, an exhaled breath sample was collected for hydrogen cyanide analysis. In total, 2055 breath samples were analysed. At the end of the study, the hydrogen cyanide concentrations were compared to the results of routine microbiology surveillance. P. aeruginosa was isolated from 71 children during the study with an incidence (95% CI of 0.19 (0.15–0.23 cases per patient-year. Using a random-effects logistic model, the estimated odds ratio (95% CI was 3.1 (2.6–3.6, which showed that for a 1- ppbv increase in exhaled breath hydrogen cyanide, we expected a 212% increase in the odds of P. aeruginosa infection. The sensitivity and specificity were estimated at 33% and 99%, respectively. Exhaled breath hydrogen cyanide is a specific biomarker of new P. aeruginosa infection in children with CF. Its low sensitivity means that at present, hydrogen cyanide cannot be used as a screening test for this infection.
Jensen, P. Ø.; Bjarnsholt, Thomas; Phipps, Richard Kerry;
. aeruginosa induced rapid necrosis of the PMNs. This mechanism was also observed in mouse lungs infected with P. aeruginosa, and in sputum obtained from P.-aeruginosa-infected patients with cystic fibrosis. Evidence is presented that the necrotic effect was caused by rhamnolipids, production of which is QS...... controlled. The results demonstrate the potential of the QS system to facilitate infections with P. aeruginosa by disabling the PMNs, which are a major first line of defence of the host. Furthermore, the study emphasizes the inhibition of QS as a target for the treatment of infections with P. aeruginosa....
Aviles, Hernan; Belay, Tesfaye; Fountain, Kimberly; Vance, Monique; Sonnenfeld, Gerald
It has been reported that spaceflight conditions alter the immune system and resistance to infection [Belay T, Aviles H, Vance M, Fountain K, and Sonnenfeld G. J Allergy Clin Immunol 170: 262-268, 2002; Hankins WR and Ziegelschmid JF. In: Biomedical Results of Apollo. Washington, DC: NASA, 1975, p. 43-81. (NASA Spec. Rep. SP-368)]. Ground-based models, including the hindlimb-unloading model, have become important tools for increasing understanding of how spaceflight conditions can influence physiology. The objective of the present study was to determine the effect of hindlimb unloading on the susceptibility of mice to Pseudomonas aeruginosa infection. Hindlimb-unloaded and control mice were subcutaneously infected with 1 LD50 of P. aeruginosa. Survival, bacterial organ load, and antibody and corticosterone levels were compared among the groups. Hindlimb unloading had detrimental effects for infected mice. Animals in the hindlimb-unloaded group, compared with controls, 1). showed significantly increased mortality and reduced time to death, 2). had increased levels of corticosterone, and 3). were much less able to clear bacteria from the organs. These results suggest that hindlimb unloading may induce the production of corticosterone, which may play a critical role in the modulation of the immune system leading to increased susceptibility to P. aeruginosa infection.
Hawdon, Nicole A; Aval, Pouya Sadeghi; Barnes, Rebecca J;
Pseudomonas aeruginosa is the major cause of chronic pulmonary disease in cystic fibrosis (CF) patients. During chronic infection, P. aeruginosa lose certain virulence factors, transform into a mucoid phenotype, and develop antibiotic resistance. We hypothesized that these genetic and phenotypic...
Johansen, Helle Krogh; Gøtzsche, Peter C
update of a previously published review. OBJECTIVES: To assess the effectiveness of vaccination against Pseudomonas aeruginosa in cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register using the terms vaccines AND pseudomonas (last search 30...... fibrosis. DATA COLLECTION AND ANALYSIS: The authors independently selected trials, assessed them and extracted data. MAIN RESULTS: Six trials were identified. Two trials were excluded since they were not randomised and one old, small trial because it was not possible to assess whether is was randomised....... The three included trials comprised 483, 476 and 37 patients, respectively. No data have been published from one of the large trials, but the company stated in a press release that the trial failed to confirm the results from an earlier study and that further clinical development was suspended. In the...
Estahbanati, Hamid Karimi; Kashani, Parnian Pour; Ghanaatpisheh, Fahimeh
Pseudomonas aeruginosa plays a prominent role as an etiological agent involved in serious infections in burned patients. In this study P. aeruginosa infections were analyzed at the Motahari Burn Center in Tehran (from 22 December 1998 to April 1999) to estimate their frequency, antibiotic susceptibility and serotypes. One hundred and eighty-four positive cultures and 205 bacterial strains were isolated among swabs or biopsy specimens during the study period. Pseudomonas was found to be the most common (57%) followed by Acinetobacter (17%), Escherichia coli (12%), Staphylococcus aureus (8%) and other organisms (6%). The frequency of P. aeruginosa resistance to gentamicin, ceftizoxime, carbenicillin, cephalothin and ceftazidime was over 90%. The antibiotics to which P. aeruginosa was most sensitive were amikacin and tetracyclin. The "O" serotypes isolated from the 117 Pseudomona aeroginosa isolates were serotypes O:2, O:5, O:6, O:8, O:11, O:12 and O:16. The most common serotype was O:6 (20/17%) followed by O:11 (18/15%) and O:5 (14/12%). The serotype most resistant was O:16 (8%) and the most sensitive was O:8 (2%). Since treatment of infection with available antibiotics according to the results attained proved to be difficult, prevention of infection in the burned patients is considered as an appropriate means of conquering overcoming infection problems. The sum of frequencies of serotypes O:6, O:11, O:5 and O:16 was more than 60%, therefore vaccination of burn patients with polyvalent antiserum to these serotypes could possibly produce immunity in more than half of the burned patients. PMID:12052372
Mamoudou, Savadogo; Lassina, Dao; Fla, Koueta
Nous rapportons deux cas d'infection à Pseudomonas aeruginosa: un cas de méningite et un cas d'infection urinaire. Les auteurs rappellent qu’à côté des étiologies classiques des méningites et des infections urinaires, des germes résistants comme Pseudomonas aeruginosa peuvent être responsables d'infections à localisation méningées et urinaires et dont il faut connaître pour une bonne prise en charge. Le traitement de ces infections requiert un antibiogramme au regard de la grande capacité de résistance de Pseudomonas aeruginosa en milieu hospitalier. La limitation des gestes invasifs et l'application rigoureuse des mesures de prévention des infections en milieu hospitalier contribueront à lutter efficacement contre ces infections en milieu de soins. PMID:26491521
Mishra, Prabhakar; R S, Suresh Kumar; Jerobin, Jayakumar; Thomas, John; Mukherjee, Amitava; Chandrasekaran, Natarajan
Presence of several biochemical constituents in neem makes it an efficient antimicrobial agent for pathogenic diseases. The current investigation was aimed to assess the therapeutic potential of neem nanoemulsion as a control measure for Pseudomonas aeruginosa infection in freshwater fish Labeo rohita. The median lethal concentration (LC50) for the neem oil and neem nanoemulsion was 73.9 and 160.3 mg/L, respectively. The biomarker enzymes of treated fish tissues showed a significant difference in the level of glutathione reductase, catalase, and lipid peroxidation in neem oil-treated samples than in neem nanoemulsion-treated samples at Pneem nanoemulsion was more effective in both in vitro and in vivo methods. Present findings suggest that neem-based nanoemulsion has negligible toxicity to Rohu fishes. This makes neem-based nanoemulsion as an efficient therapeutic agent against P. aeruginosa infection, leading to its possible usage in the aquaculture industry. PMID:24502533
Mamoudou, Savadogo; Lassina, Dao; Fla, Koueta
Nous rapportons deux cas d'infection à Pseudomonas aeruginosa: un cas de méningite et un cas d'infection urinaire. Les auteurs rappellent qu’à côté des étiologies classiques des méningites et des infections urinaires, des germes résistants comme Pseudomonas aeruginosa peuvent être responsables d'infections à localisation méningées et urinaires et dont il faut connaître pour une bonne prise en charge. Le traitement de ces infections requiert un antibiogramme au regard de la grande capacité de ...
Bjarnsholt, Thomas; Givskov, Michael Christian
, and, particularly, higher organisms We have focused on Pseudomonas aeruginosa, an opportunistic pathogen producing more than 30 QS-regulated virulence factors. P. aeruginosa causes several types of nosocomial infection, and lung infection in cystic fibrosis (CF) patients. We review the role of QS in...
Lee, Baoleri; Haagensen, Janus Anders Juul; Ciofu, O.; Andersen, Jens Bo; Hoiby, N.; Molin, Søren
Biofilms are thought to play a key role in the occurrence of lung infections by Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In this study, 20 nonmucoid P. aeruginosa isolates collected during different periods of chronic infection from eight CF patients were assessed with respect...
Wenzel Richard P
Full Text Available Abstract Background Some studies of nosocomial bloodstream infection (nBSI have demonstrated a higher mortality for polymicrobial bacteremia when compared to monomicrobial nBSI. The purpose of this study was to compare differences in systemic inflammatory response and mortality between monomicrobial and polymicrobial nBSI with Pseudomonas aeruginosa. Methods We performed a historical cohort study on 98 adults with P. aeruginosa (Pa nBSI. SIRS scores were determined 2 days prior to the first positive blood culture through 14 days afterwards. Monomicrobial (n = 77 and polymicrobial BSIs (n = 21 were compared. Results 78.6% of BSIs were caused by monomicrobial P. aeruginosa infection (MPa and 21.4% by polymicrobial P. aeruginosa infection (PPa. Median APACHE II score on the day of BSI was 22 for MPa and 23 for PPa BSIs. Septic shock occurred in 33.3% of PPa and in 39.0% of MPa (p = 0.64. Progression to septic shock was associated with death more frequently in PPa (OR 38.5, CI95 2.9–508.5 than MPa (OR 4.5, CI95 1.7–12.1. Maximal SIR (severe sepsis, septic shock or death was seen on day 0 for PPa BSI vs. day 1 for MPa. No significant difference was noted in the incidence of organ failure, 7-day or overall mortality between the two groups. Univariate analysis revealed that APACHE II score ≥20 at BSI onset, Charlson weighted comorbidity index ≥3, burn injury and respiratory, cardiovascular, renal and hematologic failure were associated with death, while age, malignant disease, diabetes mellitus, hepatic failure, gastrointestinal complications, inappropriate antimicrobial therapy, infection with imipenem resistant P. aeruginosa and polymicrobial nBSI were not. Multivariate analysis revealed that hematologic failure (p Conclusion In this historical cohort study of nBSI with P. aeruginosa, the incidence of septic shock and organ failure was high in both groups. Additionally, patients with PPa BSI were not more acutely ill, as judged by APACHE II
Harmer, Christopher J; Wynn, Matthew; Pinto, Rachel; Cordwell, Stuart; Rose, Barbara R; Harbour, Colin; Triccas, James A; Manos, Jim
Some Pseudomonas aeruginosa strains including Australian Epidemic Strain-1 (AES-1 or AUS-01) cause persistent chronic infection in cystic fibrosis (CF) patients, with greater morbidity and mortality. Factors conferring persistence are largely unknown. Previously we analysed the transcriptomes of AES-1 grown in Luria broth, nematode growth medium for Caenorhabditis elegans assay (both aerobic) and artificial sputum medium (mainly hypoxic). Transcriptional comparisons included chronic AES-1 strains against PAO1 and acute AES-1 (AES-1R) against its chronic isogen (AES-1M), isolated 10.5 years apart from a CF patient and not eradicated in the meantime. Prominent amongst genes downregulated in AES-1M in all comparisons was homogentisate-1-2-dioxygenase (hmgA); an oxygen-dependent gene known to be mutationally deactivated in many chronic infection strains of P. aeruginosa. To investigate if hmgA downregulation and deactivation gave similar virulence persistence profiles, a hmgA mutant made in UCBPP-PA14 utilising RedS-recombinase and AES-1M were assessed in the C. elegans virulence assay, and the C57BL/6 mouse for pulmonary colonisation and TNF-α response. In C. elegans, hmgA deactivation resulted in significantly increased PA14 virulence while hmgA downregulation reduced AES-1M virulence. AES-1M was significantly more persistent in mouse lung and showed a significant increase in TNF-α (p<0.0001), sustained even with no detectable bacteria. PA14ΔhmgA did not show increased TNF-α. This study suggests that hmgA may have a role in P. aeruginosa persistence in chronic infection and the results provide a starting point for clarifying the role of hmgA in chronic AES-1. PMID:26252386
Full Text Available Pulmonary infections frequently occur following hip fracture surgery in aged patients. However, the underlying reasons are not fully understood. The present study investigates the systemic inflammatory response and pulmonary conditions following hip fracture surgery as a means of identifying risk factors for lung infections using an aged rodent model. Aged, male Sprague-Dawley rats (8 animals per group underwent a sham procedure or hip fracture plus femoral intramedullary pinning. Animals were sacrificed 1, 3, and 7 days after the injury. Markers of systemic inflammation and pulmonary injury were analyzed. Both sham-operated and injured/surgical group animals underwent intratracheal inoculation with Pseudomonas aeruginosa 1, 3, and 7 days after surgery. P. aeruginosa counts in blood and bronchoalveolar lavage (BAL fluid and survival rates were recorded. Serum TNF-α, IL-6, IL-1β, and IL-10 levels and markers of pulmonary injury were significantly increased at 1 and 3 days following hip fracture and surgery. Animals challenged with P. aeruginosa at 1 and 3 days after injury had a significantly decreased survival rate and more P. aeruginosa recovered from blood and BAL fluid. This study shows that hip fracture and surgery in aged rats induced a systemic inflammatory response and lung injury associated with increased susceptibility to infection during the acute phase after injury and surgery.
Rybtke, Morten; Hultqvist, Louise Dahl; Givskov, Michael;
Studies of biopsies from infectious sites, explanted tissue and medical devises have provided evidence that biofilms are the underlying cause of a variety of tissue-associated and implant-associated recalcitrant human infections. With a need for novel anti-biofilm treatment strategies, research i...
Full Text Available Candida pneumonia is a rare infection of the lungs, with the majority of cases occurring secondary to hematological dissemination of Candida organisms from a distant site, usually the gastrointestinal tract or skin. We report a case of a 77-year-old male who is life-long smoker with a history of rheumatoid arthritis and polymyalgia rheumatica, but did not take immunosuppressants for those conditions. Here, we present an extremely rare case of isolated pulmonary parenchymal Candida infection in the form pulmonary nodules without evidence of systemic disease which has only been described in a few previous reports.
Increasing incidence of resistance of gram-negative bacteria against even newer antibiotic including carbapenem has generated interest in the old antibiotic colistin, which are being used as salvage therapy in the treatment of multidrug resistant infection. Colistin has excellent bactericidal activity against most gram-negative bacilli. It has shown persist level in the liver, kidney, heart, and muscle; while it is poorly distributed to the bones, cerebrospinal fluid, lung parenchyma, and ple...
Döring, Gerd; Flume, Patrick; Heijerman, Harry;
In patients with cystic fibrosis (CF) lung damage secondary to chronic infection is the main cause of death. Treatment of lung disease to reduce the impact of infection, inflammation and subsequent lung injury is therefore of major importance. Here we discuss the present status of antibiotic...
To determine if radiolabeled specific antibodies directed against bacterial antigens could be used to detect sites of infection, gamma camera imaging studies were performed in animals infected with Pseudomonas aeruginosa. Murine monoclonal antibodies (Mabs) directed against Fisher Immunotype 1 Pseudomonas aeruginosa and a nonmicrobial, nonmammalian haptene, p-arsanilic acid, were labeled with 125I by the lodogen-Bead method. Unilateral, deep thigh infections were created by innoculation with 2 X 10(8) Fisher Immunotype 1 P. aeruginosa. Twenty-four hours later, one of the radiolabeled antibodies was injected intravenously at a dose of 0.25 mg/kg (100-150 microCi). Serial gamma imaging was then carried out beginning at 4 hr and at approximately 24-hr intervals thereafter. Beginning as early as 4 hr postinjection, the area of inflammation could be visualized with either the specific or nonspecific Mab, with the images continuing to intensify until 24-48 hr postinjection. At 48 hr, the contrast between lesion and background with the nonspecific Mab began to fade, while the contrast in the specific Mab-generated images continued to intensify until approximately 192 hr postinjection. Clear-cut differentiation between specific and nonspecific Mab-generated images was possible by 72 hr postinjection. We conclude that specific immune imaging of localized infection with Mab's directed against specific microbial antigens is possible and should be clinically useful. In addition, images created by the localization of immunoglobulin non-specifically at the site of inflammation in the first 24-48 hr postinjection may also provide useful information as to the anatomic location of hidden abscesses
Full Text Available Purpose: Several studies have shown that HIV patients are at higher risk of lung cancer. Our aim is to analyse the prevalence and features of lung cancer in HIV-infected patients. Methods: The clinical charts of 4,721 HIV-infected patients seen in three hospitals of southeast Spain (study period 1992–2012 were reviewed, and all patients with a lung cancer were analysed. Results: There were 61 lung cancers, giving a prevalence of 1.2%. There was a predominance of men (82.0%, and smokers (96.6%; mean pack-years 35.2, with a median age of 48.0 (41.7–52.9 years, and their distribution according to risk group for HIV was: intravenous drug use 58.3%, homosexual 20.0%, and heterosexual 16.7%. Thirty-four (56.7% patients were Aids cases, and 29 (47.5% had prior pulmonar events: tuberculosis 16, bacterial pneumonia 9, and P. jiroveci pneumonia 4. The median nadir CD4 count was 149/mm3 (42–232, the median CD4 count at the time of diagnosis of the lung cancer was 237/mm3 (85–397, and 66.1%<350/mm3. 66.7% were on ART, and 70% of them had undetectable HIV viral load. The most common histological types of lung cancer were adenocarcinoma and epidermoid, with 24 (40.0% and 23 (38.3% cases, respectively. There were 49 (80.3% cases with advanced stages (III and IV at diagnosis. The distribution of treatments was: only palliative 23 (39.7%, chemotherapy 14 (24.1%, surgery and chemotherapy 8 (13.8%, radiotherapy 7 (12.1%, surgery 4 (6.9%, and other combined treatments 2 (3.4%. Forty-six (76.7% patients died, with a median survival time of 3 months. The Kaplan-Meier survival rate at 6 months was 42.7% (at 12 months 28.5%. Conclusions: The prevalence of lung cancer in this cohort of HIV-patients is high. People affected are mainly men, smokers, with transmission of HIV by intravenous drug use, and around half of them with prior opportunistic pulmonary events. Most patients had low nadir CD4 count, and were immunosuppressed at the time of diagnosis
Full Text Available Green nail syndrome (GNS caused by Pseudomonas aeruginosa is the most common bacterial nail infection. The treatment of GNS is challenging in many cases and recommendations based on clinical trials are lacking. We report two cases with GNS successfully treated with off-label use of topical nadifloxacin, a fluoroquinolone approved for acne and bacterial skin infections in some countries.
Highly hazardous DNA double-strand breaks can be induced in eukaryotic cells by a number of agents including pathogenic bacterial strains. We have investigated the genotoxic potential of Pseudomonas aeruginosa, an opportunistic pathogen causing devastating nosocomial infections in cystic fibrosis or immunocompromised patients. Our data revealed that infection of immune or epithelial cells by P. aeruginosa triggered DNA strand breaks and phosphorylation of histone H2AX (γH2AX), a marker of DNA double-strand breaks. Moreover, it induced formation of discrete nuclear repair foci similar to gamma-irradiation-induced foci, and containing γH2AX and 53BP1, an adaptor protein mediating the DNA-damage response pathway. Gene deletion, mutagenesis, and complementation in P. aeruginosa identified ExoS bacterial toxin as the major factor involved in γH2AX induction. Chemical inhibition of several kinases known to phosphorylate H2AX demonstrated that Ataxia Telangiectasia Mutated (ATM) was the principal kinase in P. aeruginosa-induced H2AX phosphorylation. Finally, infection led to ATM kinase activation by an auto-phosphorylation mechanism. Together, these data show for the first time that infection by P. aeruginosa activates the DNA double-strand break repair machinery of the host cells. This novel information sheds new light on the consequences of P. aeruginosa infection in mammalian cells. As pathogenic Escherichia coli or carcinogenic Helicobacter pylori can alter genome integrity through DNA double-strand breaks, leading to chromosomal instability and eventually cancer, our findings highlight possible new routes for further investigations of P. aeruginosa in cancer biology and they identify ATM as a potential target molecule for drug design. (authors)
Ju-Hua Ye; Jun-Wu Huang; Hong-Yun Shi
Objective:To study the promoting effect of ozone water rinse on wound healing in rats with Pseudomonas aeruginosa infection.Methods:Wistar male rats were selected as experimental animals and randomly divided into control group, chlorhexidine group and ozone water group,Pseudomonas aeruginosa-infected wounds were made and cleaned with normal saline, chlorhexidine and ozone water respectively; would healing of three groups was observed, wound tissue was collected and contents of inflammatory factors, apoptosis molecules and autophagy markers were detected.Results:Wound healing rates of chlorhexidine group and ozone water group were higher than that of control group and wound healing time was shorter than that of control group, wound healing rate of ozone water group was higher than that of chlorhexidine group and wound healing time was shorter than that of chlorhexidine group; TNF-α, IL-1, IL-2, Fas, FasL and Beclin-1 contents and LC3Ⅱ/LC3Ⅰ ratios in wound tissue of chlorhexidine group and ozone water group were lower than those of control group, and TNF-α, IL-1, IL-2, Fas, FasL and Beclin-1 contents and LC3Ⅱ/LC3Ⅰ ratios in wound tissue of ozone water group were lower than those of chlorhexidine group.Conclusions:Compared with normal saline and chlorhexidine, ozone water rinse helps to promote wound healing, improve wound healing rate and shorten wound healing time in rats withPseudomonas aeruginosa infection, and meanwhile it can inhibit cell apoptosis and autophagy in the wounds.
Hengzhuang, Wang; Høiby, Niels; Ciofu, Oana
efficient dosing regimen and to minimize the development of antimicrobial tolerance and resistance in biofilm infections. Unfortunately, most previous PK/PD studies of antibiotics have been done on planktonic cells, and extrapolation of the results on biofilms is problematic as bacterial biofilms differ...... from planktonic grown cells in the growth rate, gene expression, and metabolism. Here, we set up several protocols for the studies of PK/PD of antibiotics in biofilm infections of P. aeruginosa in vitro and in vivo. It should be underlined that none of the protocols in biofilms have yet been......Although progress on biofilm research has been obtained during the past decades, the treatment of biofilm infections with antibiotics remains a riddle. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of an antimicrobial agent provide important information helping to establish an...
Nguyen, Angela T; Oglesby-Sherrouse, Amanda G
Pseudomonas aeruginosa and Staphylococcus aureus are versatile bacterial pathogens and common etiological agents in polymicrobial infections. Microbial communities containing both of these pathogens are shaped by interactions ranging from parasitic to mutualistic, with the net impact of these interactions in many cases resulting in enhanced virulence. Polymicrobial communities of these organisms are further defined by multiple aspects of the host environment, with important implications for disease progression and therapeutic outcomes. This mini-review highlights the impact of these interactions on the host and individual pathogens, the molecular mechanisms that underlie these interactions, and host-specific factors that drive interactions between these two important pathogens. PMID:27236810
Full Text Available BACKGROUND: The colonization of burn wounds by Pseudomonas aeruginosa can lead to septic shock, organ injuries, and high mortality rates. We hypothesized that negative pressure wound therapy (NPWT would decrease invasion and proliferation of P. aeruginosa within the burn wound and reduce mortality. METHODS: Thermal injuries were induced in anesthetized mice, and P. aeruginosa was applied to the wound surface for 24 h. After removing the burn eschar and debridement, the animals were subjected to either NPWT or wet-to-dry (WTD treatment protocols. The bacterial loads on the wound surface were assessed during 7 d of treatment, as were the concentrations of inflammatory cytokines in the peripheral blood samples. Survival was monitored daily for 14 d after burn induction. Finally, samples of wounded skin, lung, liver, and kidney were collected and subjected to histopathological examination. RESULTS: Applying P. aeruginosa to the burn wound surface led to sepsis. During early stages of treatment, NPWT reduced the mortality of the septic animals and levels of P. aeruginosa within the burn wound compared with WTD-treated animals. Circulating levels of cytokines and cytoarchitectural abnormalities were also significantly reduced via NPWT. CONCLUSIONS: Our data indicate that NPWT inhibits the invasion and proliferation of P. aeruginosa in burn-wounded tissue and decreases early mortality in a murine model of burn-wound sepsis. These therapeutic benefits likely result from the ability of NPWT to decrease bacterial proliferation on the wound surface, reduce cytokine serum concentrations, and prevent damage to internal organs.
Vidya, P; Smith, L; Beaudoin, T; Yau, Y C; Clark, S; Coburn, B; Guttman, D S; Hwang, D M; Waters, V
Early eradication treatment with inhaled tobramycin is successful in the majority of children with cystic fibrosis (CF) with incident Pseudomonas aeruginosa infection. However, in 10-40 % of cases, eradication fails and the reasons for this are poorly understood. The purpose of this study was to determine whether specific microbial characteristics could explain eradication treatment failure. This was a cross-sectional study of CF patients (aged 0-18 years) with incident P. aeruginosa infection from 2011 to 2014 at the Hospital for Sick Children, Toronto, Canada. Phenotypic assays were done on all incident P. aeruginosa isolates, and eradicated and persistent isolates were compared using the Mann-Whitney test or the two-sided Chi-square test. A total of 46 children with CF had 51 incident P. aeruginosa infections. In 72 % (33/46) of the patients, eradication treatment was successful, while 28 % failed eradication therapy. Persistent isolates were less likely to be motile, with significantly less twitch motility (p=0.001), were more likely to be mucoid (p=0.002), and more likely to have a tobramycin minimum inhibitory concentration (MIC) ≥ 128 μg/mL (p=0.02) compared to eradicated isolates. Although biofilm production was similar, there was a trend towards more persistent isolates with deletions in quorum-sensing genes compared with eradicated isolates (p=0.06). Initial acquisition of P. aeruginosa with characteristics of chronic infection is associated with failure of eradication treatment. PMID:26492874
Aanaes, Kasper; Johansen, Helle Krogh; Poulsen, Steen Seier; Pressler, Tacjana; Buchwald, Christian; Høiby, Niels
BACKGROUND: Pseudomonas aeruginosa sinusitis may be the focus for intermittent lung colonization in patients with cystic fibrosis (CF). The sinusitis may induce elevated IgA levels in nasal secretion and saliva against P. aeruginosa. METHODS: 120 CF patients chronically infected, intermittently...... colonized or without P. aeruginosa in the lungs participated in this cross-sectional study. IgA and IgG against P. aeruginosa sonicate and alginate were measured in nasal secretions, saliva, and in serum by ELISA. RESULTS: The intermittently colonized patients had significantly higher IgA levels in nasal...
Christensen, Louise Dahl; Moser, Claus; Jensen, Peter Ø;
growth contributes significantly to P. aeruginosa tolerance to the action of the innate and adaptive defence system and numerous antibiotics. In the present study, an in vivo foreign-body infection model was established in the peritoneal cavity of mice. Experimental data showed that QS-deficient P......Pseudomonas aeruginosa is an opportunistic human pathogen that causes chronic biofilm-based infections in host organisms. P. aeruginosa employs quorum sensing (QS) to control expression of its virulence, and to establish and maintain chronic infections. Under such conditions, the biofilm mode of...... the placebo-treated group. These results were obtained with both an inbred (BALB/c) and an outbred (NMRI) mouse strain. The present results support a model by which functional QS systems play a pivotal role in the ability of bacteria to resist clearing by the innate immune system and strongly suggest...
Høiby, Niels; Ciofu, Oana; Bjarnsholt, Thomas
The persistence of chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) patients is due to biofilm-growing mucoid (alginate-producing) strains. A biofilm is a structured consortium of bacteria, embedded in a self-produced polymer matrix consisting of polysaccharide, protein and...
Guillot, M; Amiour, M; El Hachem, C; Harchaoui, S; Ribault, V; Paris, C
Long-term low dose azithromycin treatment in cystic fibrosis patients with chronic Pseudomonas aeruginosa infection is safe and reduces the decline in lung function, the number of acute exacerbations and improves nutritional status; underlying efficacy mechanisms are multiple and synergistic. PMID:17370396
Song, Z.; Kong, K.F; Wu, H; Maricic, N.; Ramalingam, B.; Priestap, H.; Quirke, J.M.E.; Høiby, N.; Mathee, K
Virulent factors produced by pathogens play an important role in the infectious process, which is regulated by a cell-to-cell communication mechanism called quorum sensing (QS). Pseudomonas aeruginosa is an important opportunistic human pathogen, which causes infections in patients with compromised immune systems and cystic fibrosis. The QS systems of P. aeruginosa use N-acylated homoserine lactone (AHL) as signal molecules. Previously we have demonstrated that Panax ginseng treatment allowed...
Fu, Panfeng; Mohan, Vijay; Mansoor, Syed; Tiruppathi, Chinnaswamy; Sadikot, Ruxana T.; Natarajan, Viswanathan
Earlier studies indicated a role for reactive oxygen species (ROS) in host defense against Pseudomonas aeruginosa infection. However, the role of nicotinamide adenine dinucleotide phosphate–reduced (NADPH) oxidase (NOX) proteins and the mechanism of activation for NADPH oxidase in P. aeruginosa infection are not well-defined. Here, we investigated the role of NOX2 and NOX4 proteins in P. aeruginosa infection, ROS generation, and endothelial barrier function in murine lungs and in human lung m...
Bielecki, P.; Komor, U.; Bielecka, A.; Müsken, M.; Puchalka, J.; Pletz, M.W.; Ballmann, M.; Martins Dos Santos, V.A.P.; Weiss, S.; Häussler, S.
The opportunistic bacterium Pseudomonas aeruginosa is a major nosocomial pathogen causing both devastating acute and chronic persistent infections. During the course of an infection, P.¿ aeruginosa rapidly adapts to the specific conditions within the host. In the present study, we aimed at the ident
Yang, Liang; Hengzhuang, Wang; Wu, Hong;
Chronic lung infection by mucoid Pseudomonas aeruginosa is one of the major pathologic features in patients with cystic fibrosis. Mucoid P. aeruginosa is notorious for its biofilm forming capability and resistance to immune attacks. In this study, the roles of extracellular polymeric substances f...
Jensen, E T; Giwercman, B; Ojeniyi, B; Bangsborg, Jette Marie; Hansen, A; Koch, C; Fiehn, N E; Høiby, N
Cystic fibrosis (CF) patients often suffer from Pseudomonas aeruginosa lung infection yet the source of this organism is not known. In order to determine whether CF patients might be contaminated with P. aeruginosa from dental equipment, a total of 103 water samples from 25 dental sessions in...
Wu, Hong; Lee, Baoleri; Yang, Liang;
Biofilm-associated chronic Pseudomonas aeruginosa lung infections in patients with cystic fibrosis are virtually impossible to eradicate with antibiotics because biofilm-growing bacteria are highly tolerant to antibiotics and host defense mechanisms. Previously, we found that ginseng treatments....... aeruginosa, but significantly prevented P. aeruginosa from forming biofilm. Exposure to 0.5% ginseng aqueous extract for 24 h destroyed most 7-day-old mature biofilms formed by both mucoid and nonmucoid P. aeruginosa strains. Ginseng treatment enhanced swimming and twitching motility, but reduced swarming of...... P. aeruginosa at concentrations as low as 0.25%. Oral administration of ginseng extracts in mice promoted phagocytosis of P. aeruginosa PAO1 by airway phagocytes, but did not affect phagocytosis of a PAO1-filM mutant. Our study suggests that ginseng treatment may help to eradicate the biofilm...
Full Text Available Abstract Background Pseudomonas aeruginosa adhesion to animal/human cells for infection establishment involves adhesive proteins, including its galactose- and fucose-binding lectins PA-IL (LecA and PA-IIL (LecB. The lectin binding to the target-cell receptors may be blocked by compatible glycans that compete with those of the receptors, functioning as anti-adhesion glycodecoys. The anti-adhesion treatment is of the utmost importance for abrogating devastating antibiotic-resistant P. aeruginosa infections in immunodeficient and cystic fibrosis (CF patients. This strategy functions in nature in protecting embryos and neonates. We have shown that PA-IL, PA-IIL, and also CV-IIL (a PA-IIL homolog produced in the related pathogen Chromobacterium violaceum are highly useful for revealing natural glycodecoys that surround embryos in diverse avian eggs and are supplied to neonates in milks and royal jelly. In the present study, these lectins were used as probes to search for seed embryo-protecting glycodecoys. Methods The lectin-blocking glycodecoy activities were shown by the hemagglutination-inhibition test. Lectin-binding glycoproteins were detected by Western blotting with peroxidase-labeled lectins. Results The present work reports the finding - by using PA-IL, PA-IIL, and CV-IIL - of rich glycodecoy activities of low ( 10 kDa compounds (including glycoproteins in extracts of cashew, cocoa, coffee, pumpkin, and tomato seeds, resembling those of avian egg whites, mammal milks, and royal jelly. Conclusions Edible seed extracts possess lectin-blocking glycodecoys that might protect their embryos from infections and also might be useful for hampering human and animal infections.
Jensen, P Ø; Moser, C; Kharazmi, A;
Chronic Pseudomonas aeruginosa lung infection is the major reason for premature death in patients with cystic fibrosis (CF). Infected patients experience a progressive deterioration of the lung tissue caused by a persistent accumulation of PMNs. We investigated if the pulmonary accumulation of PM...
Frydenlund Michelsen, Charlotte; Hossein Khademi, Seyed Mohammad; Krogh Johansen, Helle; Ingmer, Hanne; Dorrestein, Pieter C; Jelsbak, Lars
The effect of polymicrobial interactions on pathogen physiology and how it can act either to limit pathogen colonization or to potentiate pathogen expansion and virulence are not well understood. Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens commonly found together in polymicrobial human infections. However, we have previously shown that the interactions between these two bacterial species are strain dependent. Whereas P. aeruginosa PAO1, a commonly used laboratory strain, effectively suppressed S. aureus growth, we observed a commensal-like interaction between the human host-adapted strain, DK2-P2M24-2003, and S. aureus. In this study, characterization by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) and mass spectral (MS) molecular networking revealed a significant metabolic divergence between P. aeruginosa PAO1 and DK2-P2M24-2003, which comprised several virulence factors and signaling 4-hydroxy-2-alkylquinoline (HAQ) molecules. Strikingly, a further modulation of the HAQ profile was observed in DK2-P2M24-2003 during interaction with S. aureus, resulting in an area with thickened colony morphology at the P. aeruginosa-S. aureus interface. In addition, we found an HAQ-mediated protection of S. aureus by DK2-P2M24-2003 from the killing effect of tobramycin. Our findings suggest a model where the metabolic divergence manifested in human host-adapted P. aeruginosa is further modulated during interaction with S. aureus and facilitate a proto-cooperative P. aeruginosa-S. aureus relationship. PMID:26684729
Fluge, G; Ojeniyi, B; Høiby, N;
OBJECTIVES: Typing of Pseudomonas aeruginosa isolates from Norwegian cystic fibrosis (CF) patients with chronic Pseudomonas lung infection in order to see whether cross-infection might have occurred. METHODS: Isolates from 60 patients were collected during the years 1994-98, and typed by pulsed...... between cystic fibrosis patients has occurred....
Full Text Available Objective. Aloe vera is an herbal medicinal plant with biological activities, such as antimicrobial, anticancer, anti-inflammatory, and antidiabetic ones, and immunomodulatory properties. The purpose of this study was investigation of in vitro antimicrobial activity of A. vera gel against multidrug-resistant (MDR Pseudomonas aeruginosa isolated from patients with burn wound infections. Methods. During a 6-month study, 140 clinical isolates of P. aeruginosa were collected from patients admitted to the burn wards of a hospital in Tehran, Iran. Antimicrobial susceptibility test was carried out against the pathogens using the A. vera gel and antibiotics (imipenem, gentamicin, and ciprofloxacin. Results. The antibiogram revealed that 47 (33.6% of all isolates were MDR P. aeruginosa. The extract isolated from A. vera has antibacterial activity against all of isolates. Also, 42 (89.4% isolates were inhibited by A. vera gel extract at minimum inhibitory concentration (MIC ≤ 200 µg/mL. MIC value of A. vera gel for other isolates (10.6% was 800 µg/mL. All of MDR P. aeruginosa strains were inhibited by A. vera at similar MIC50 and MIC90 200 µg/mL. Conclusion. Based on our results, A. vera gel at various concentrations can be used as an effective antibacterial agent in order to prevent wound infection caused by P. aeruginosa.
Mohammadi-Samani, Soliman; Kouroshfard, Shahriyar; Azarpira, Negar
This study was designed to investigate the effect of inorganic phosphate supplementation on invasive behavior of Pseudomonas aeruginosa in burn wound infections. An emulsion-based lotion containing sodium dihydrogen phosphate was formulated and then 50 female Sprague-Dawley rats with burn wounds were used to assess the effect of phosphate supplementation on swarming motility of P. aeruginosa. On the second day after burn, four groups of rats were inoculated with P. aeruginosa and one group was left as negative control. The treatment was started on day 3 and the animals were followed up for 4 weeks. Significant improvement in wound healing was observed in the phosphate-receiving group after the 4-week follow-up, compared to the negative control, positive control, and silver sulfadiazine-receiving groups. Histopathological assessment of the tissue samples also indicated the healing process in phosphate-enriched lotion receiving group. The results showed that inorganic phosphate supplementation results in alteration of the virulence behavior of P. aeruginosa and improvement in the wound healing process. In conclusion, phosphate supplementation would be a rational strategy in the eradication of P. aeruginosa wound infection. PMID:26787129
Härtl, A; Möllmann, U; Schrinner, E; Stelzner, A
Embryonated hens' eggs can be reliably infected by Pseudomonas aeruginosa in laboratory experiments. Therapy tests with the antibiotics azlocillin (CAS 37091-66-0) and gentamicin (CAS 13291-74-2) on this type of infected hens' eggs demonstrate that this test system offers a realistic alternative to septic experiments with small laboratory rodents. Chick embryos survive a lethal Pseudomonas infection when azlocillin or gentamicin in a relevant therapeutic dose are administered immediately after the infective agent. The use of Pseudomonas infected chick embryos in the screening for new antiinfectives allows, therefore, a considerable reduction of the number of laboratory rodents required. PMID:9342424
The complete DNA sequence of a new lytic T7-like bacteriophage phiKMV is presented. It is the first genome sequence of a member of the Podoviridae that infects Pseudomonas aeruginosa. The linear G + C-rich (62.3%) double-stranded DNA genome of 42,519 bp has direct terminal repeats of 414 bp and contains 48 open reading frames that are all transcribed from the same strand. Despite absence of homology at the DNA level, 11 of the 48 phiKMV-encoded putative proteins show sequence similarity to known T7-type phage proteins. Eighteen open reading frame products have been assigned, including an RNA polymerase, proteins involved in DNA replication, as well as structural, phage maturation, and lysis proteins. Surprisingly, the major capsid protein completely lacks sequence homology to any known protein. Also, the strong virulence toward many clinical P. aeruginosa isolates and a short replication time make phiKMV attractive for phage therapy or a potential source for antimicrobial proteins
Murugan, Nandagopal; Malathi, Jambulingam; Umashankar, Vetrivel; Madhavan, Hajib NarahariRao
Pseudomonas aeruginosa (P. aeruginosa) bacteremia causes significant mortality rate due to emergence of multidrug resistant (MDR) nosocomial infections. We report the draft genome sequence of P. aeruginosa strain VRFPA09, a human bloodstream isolate, phenotypically proven as MDR strain. Whole genome sequencing on VRFPA09, deciphered betalactamase encoding blav(eb-1) and bla(OXA-10) genes and multiple drug resistance, virulence factor encoding genes. PMID:26413042
NING Fang-gang; ZHAO Xiao-zhuo; BIAN Jing; ZHANG Guo-an
Background Infection due to pandrug-resistant Pseudomonas aeruginosa (PDRPA) has become a challenge in clinical practice. The aim of this research was to summarize the treatment of large-area burns (60%-80%) with PDRPA infection and respiratory failure in our hospital over the last two years, and to explore a feasible treatment protocol for such patients.Methods We retrospectively analyzed the treatment of five patients with large-area burns accompanied by PDRPA infection and respiratory failure transferred to our hospital from burn units in hospitals in other Chinese cities from January 2008 to February 2010. Before PDRPA infection occurred, all five patients had open wounds with large areas of granulation because of the failure of surgery and dissolving of scar tissue; they had also undergone long-term administration of carbapenems. This therapy included ventilatory support, rigorous repair of wounds, and combined antibiotic therapy targeted at drug-resistance mechanisms, including carbapenems, ciprofloxacin, macrolide antibiotics and β-lactamase inhibitors.Results Four patients recovered from bums and one died after therapy.Conclusions First, compromised immunity caused by delayed healing of burn wounds in patients with large-area bums and long-term administration of carbapenems may be the important factors in the initiation and progression of PDRPA infection. Second, if targeted at drug-resistance mechanisms, combined antibiotic therapy using carbapenems,ciprofloxacin, macrolide antibiotics and β-lactamase inhibitors could effectively control PDRPA infection. Third, although patients with large-area burns suffered respiratory failure and had high risks from anesthesia and surgery, only aggressive skin grafting with ventilatory support could control the infection and save lives. Patients may not be able to tolerate a long surgical procedure, so the duration of surgery should be minimized, and the frequency of surgery increased.
Song, Z; Kong, K F; Wu, H;
ginseng are mutually exclusive as it is a complex mixture, as shown with the HPLC analysis of the hot water extract. Though ginseng is a promising natural synergetic remedy, it is important to isolate and evaluate the ginseng compounds associated with the anti-QS activity....... immune systems and cystic fibrosis. The QS systems of P. aeruginosa use N-acylated homoserine lactone (AHL) as signal molecules. Previously we have demonstrated that Panax ginseng treatment allowed the animals with P. aeruginosa pneumonia to effectively clear the bacterial infection. We postulated that...... the ability to impact the outcome of infections is partly due to ginseng having direct effect on the production of P. aeruginosa virulence factors. The study explores the effect of ginseng on alginate, protease and AHL production. The effect of ginseng extracts on growth and expression of QS...
Full Text Available Abstract Chorioamnionitis is frequently associated with preterm deliveries before 30 weeks gestation. Chorioamnionitis correlates both with an increased risk of bronchopulmonary dysplasia and with a decreased risk of respiratory distress syndrome. Both interleukin-1α and endotoxin can induce inflammation in the fetal lungs and lung maturation after preterm birth when given by intra-amniotic injection. Inflammation can also result in an arrest of alveolarization, and this lung developmental abnormality is prominent in the lungs of preterm infants that die of bronchopulmonary dysplasia. The mechanisms by which infection/inflammation can have both beneficial and injurious effects on the preterm lung remain to be characterized.
Thépaut, Marion; Grandjean, Teddy; Hober, Didier; Lobert, Pierre-Emmanuel; Bortolotti, Perrine; Faure, Karine; Dessein, Rodrigue; Kipnis, Eric; Guery, Benoit
The murine norovirus (MNV) is a recently discovered mouse pathogen, representing the most common contaminant in laboratory mouse colonies. Nevertheless, the effects of MNV infection on biomedical research are still unclear. We tested the hypothesis that MNV infection could alter immune response in mice with acute lung infection. Here we report that co-infection with MNV increases survival of mice with Pseudomonas aeruginosa acute lung injury and decreases in vivo production of pro-inflammatory cytokines. Our results suggest that MNV infection can deeply modify the parameters studied in conventional models of infection and lead to false conclusions in experimental models. PMID:26338794
Mandsberg, Lotte F; Ciofu, Oana; Kirkby, N;
The chronic Pseudomonas aeruginosa infection of the lungs of cystic fibrosis (CF) patients is characterized by the biofilm mode of growth and chronic inflammation dominated by polymorphonuclear leukocytes (PMNs). A high percentage of P. aeruginosa strains show high frequencies of mutations (hyper...
Feliziani, Sofia; Marvig, Rasmus Lykke; Lujan, Adela M.; Moyano, Alejandro J.; Di Rienzo, Julio A.; Johansen, Helle Krogh; Molin, Søren; Smania, Andrea M.
The advent of high-throughput sequencing techniques has made it possible to follow the genomic evolution of pathogenic bacteria by comparing longitudinally collected bacteria sampled from human hosts. Such studies in the context of chronic airway infections by Pseudomonas aeruginosa in cystic...... to investigate within-host population diversity or long-term evolution of mutators in CF airways. We sequenced the genomes of 13 and 14 isolates of P. aeruginosa mutator populations from an Argentinian and a Danish CF patient, respectively. Our collection of isolates spanned 6 and 20 years of patient...... infection history, respectively. We sequenced 11 isolates from a single sample from each patient to allow in-depth analysis of population diversity. Each patient was infected by clonal populations of bacteria that were dominated by mutators. The in vivo mutation rate of the populations was similar to 100...
Kolpen, Mette; Bjarnsholt, Thomas; Moser, Claus;
Objective: Chronic Pseudomonas aeruginosa lung infection in CF patients is characterized by persisting mucoid biofilm in hypoxic endobronchial mucus. These biofilms are surrounded by numerous polymorphonuclear leukocytes (PMNs), which are the major consumers of O2 for production of O2-. In this s...
Head, Nathan E.; Yu, Hongwei
Chronic lung infections with Pseudomonas aeruginosa biofilms are associated with refractory and fatal pneumonia in cystic fibrosis (CF). In this study, a group of genomically diverse P. aeruginosa isolates were compared with the reference strain PAO1 to assess the roles of motility, twitching, growth rate, and overproduction of a capsular polysaccharide (alginate) in biofilm formation. In an in vitro biofilm assay system, P. aeruginosa displayed strain-specific biofilm formation that was not ...
Full Text Available Background and Objectives: Antibiotic resistance of Pseudomonas aeruginosa remains a major problem in burn patients. The main objective of this study was to determine the antibiotic resistance pattern and frequency of class 1 integrons among P. aeruginosa strains isolated from patients with burn wound infections in a new Burn Centre in Guilan, Iran.Materials and Methods: The bacterial isolates were collected from 182 patients with burn wound infections and P. aeruginosa species were identified by standard bacteriological methods. The drug susceptibility test, using 11 antimicrobial agents, was performed for all the isolates via agar disk diffusion method. PCR was carried out for the detection of integrons.Results: Out of a total of 182 hospitalized patients in the burn center assessed, 86 (47% found to have P. aeruginosa in their isolates. Resistance rates to various antibiotics were as follows: cloxacillin (91.8%, cotrimoxazole (86%, cephazolin (83.7%, carbenicillin (74.4%, piperacillin (69.9%, ceftazidime (68.8%, ciprofloxacin (66.3%, tobramycin (58.2%, amikacin (48.8% and gentamicin (37.2%, while the most effective antibiotic was imipenem with a resistance rate of 23.3%. Thirty nine (45.3% isolates were detected as multi-drug resistant. The PCR results showed that 37 (43% P. aeruginosa isolates and 27 (69.2% multi-drug resistant strains harbored class 1 integrons. A significant correlation was obtained between the presence of integrons and resistance against imipenem, ceftazidime, piperacillin and ciprofloxacin (P < 0.001.Conclusion: Optimization of using antimicrobial agents and control of infection is recommended to prevent the increasing population of drug resistant organisms in the new burn centre setting in this study. Furthermore, the high frequency of class 1 integrons among multi-drug resistant strains might be responsible for dissemination of antibiotic resistance gene.
Keravec, Marlene; Mounier, Jerome; Prestat , Emmanuel; Vallet, Sophie; Jansson, Janet K.; Bergaud , Gaetaqn; Rosec, Silvain; Gourious, Stephanie; Rault, Gilles; Coton, Emmanuel; Barbier, George; Hery-Arnaud, Geneveieve
Abstract Pseudomonas aeruginosa plays a major role in cystic fibrosis (CF) progression. Therefore, it is important to understand the initial steps of P. aeruginosa infection. The structure and dynamics of CF respiratory tract microbial communities during the early stages of P. aeruginosa colonization were characterized by pyrosequencing and cloning-sequencing. The respiratory microbiota showed high diversity, related to the young age of the CF cohort (mean age 10 years). Wide inter- and intra-individual variations were revealed. A common core microbiota of 5 phyla and 13 predominant genera was found, the majority of which were obligate anaerobes. A few genera were significantly more prevalent in patients never infected by P. aeruginosa. Persistence of an anaerobic core microbiota regardless of P. aeruginosa status suggests a major role of certain anaerobes in the pathophysiology of lung infections in CF. Some genera may be potential biomarkers of pulmonary infection state.
Simpson, A J; Wallace, W A; Marsden, M E; Govan, J R; Porteous, D J; Haslett, C; Sallenave, J M
During acute pulmonary infection, tissue injury may be secondary to the effects of bacterial products or to the effects of the host inflammatory response. An attractive strategy for tissue protection in this setting would combine antimicrobial activity with inhibition of human neutrophil elastase (HNE), a key effector of neutrophil-mediated tissue injury. We postulated that genetic augmentation of elafin (an endogenous inhibitor of HNE with intrinsic antimicrobial activity) could protect the lung against acute inflammatory injury without detriment to host defense. A replication-deficient adenovirus encoding elafin cDNA significantly protected A549 cells against the injurious effects of both HNE and whole activated human neutrophils in vitro. Intratracheal replication-deficient adenovirus encoding elafin cDNA significantly protected murine lungs against injury mediated by Pseudomonas aeruginosa in vivo. Genetic augmentation of elafin therefore has the capacity to protect the lung against the injurious effects of both bacterial pathogens resistant to conventional antibiotics and activated neutrophils. PMID:11466403
Delaval, Mathilde; Boland, Sonja; Solhonne, Brigitte; Nicola, Marie-Anne; Mornet, Stéphane; Baeza-Squiban, Armelle; Sallenave, Jean-Michel; Garcia-Verdugo, Ignacio
Background The lung epithelium constitutes the first barrier against invading pathogens and also a major surface potentially exposed to nanoparticles. In order to ensure and preserve lung epithelial barrier function, the alveolar compartment possesses local defence mechanisms that are able to control bacterial infection. For instance, alveolar macrophages are professional phagocytic cells that engulf bacteria and environmental contaminants (including nanoparticles) and secrete pro-inflammator...
Millena R.S. Pinheiro
Full Text Available A retrospective case-control study was conducted to investigate the risk factors for death among intensive care unit patients with Pseudomonas aeruginosa infection. Out of 131 patients investigated, 67 (51.1% died within 30 days of being diagnosed with this infection. The mean duration of hospital stay before this diagnosis was 28.5 ± 26.5 days. No association was found between bacterial resistance and death in this study (multiresistant p= 0.26; panresistant p= 0.42, but the adequacy of the initial treatment was inversely proportional to the degree of resistance. There was a tendency towards greater mortality among patients who received combination therapy (empirical p= 0.09; definitive p= 0.08, despite the greater frequency of appropriate treatment in these patients and the similar degree of severity in the two groups. This finding may be explained by pharmacodynamic parameters that were not studied or by the extensive use of aminoglycosides in the combination therapy, which play a controversial role in combination therapy due to their potential for renal toxicity. The multivariate analysis in our study demonstrated that age [odds ratio (OR 1.04], septic shock (OR 15.4 and hypoalbuminemia (OR 0.32 were independent risk factors for death.
Anvarinejad, Mojtaba; Japoni, Aziz; Rafaatpour, Noroddin; Mardaneh, Jalal; Abbasi, Pejman; Amin Shahidi, Maneli; Dehyadegari, Mohammad Ali; Alipour, Ebrahim
Background: Metallo-beta-lactamase (MBL) producing Pseudomonas aeruginosa in the burn patients is a leading cause of morbidity and mortality and remains a serious health concern among the clinicians. Objectives: The aim of this study was to detect MBL-producing P. aeruginosa in burn patients and determine multidrug-resistant (MDR) strains, and respective resistance patterns. Patients and Methods: In this cross-sectional study, 270 strains of P. aeruginosa were isolated from the burn patients ...
Audia, Jonathon P.; Ashley S. Lindsey; Housley, Nicole A.; Ochoa, Courtney R.; Chun Zhou; Michie Toba; Masahiko Oka; Annamdevula, Naga S.; Fitzgerald, Meshann S.; Frank, Dara W.; Alvarez, Diego F.
Herein we describe a pathogenic role for the Pseudomonas aeruginosa type three secretion system (T3SS) needle tip complex protein, PcrV, in causing lung endothelial injury. We first established a model in which P. aeruginosa wild type strain PA103 caused pneumonia-induced sepsis and distal organ dysfunction. Interestingly, a PA103 derivative strain lacking its two known secreted effectors, ExoU and ExoT [denoted PA103 (ΔU/ΔT)], also caused sepsis and modest distal organ injury whereas an isog...
Sato, Asahi; Kaido, Toshimi; Iida, Taku; Yagi, Shintaro; Hata, Koichiro; Okajima, Hideaki; Takakura, Shunji; Ichiyama, Satoshi; Uemoto, Shinji
Infection is a life-threatening complication after liver transplantation (LT). A recent outbreak of multidrug-resistant Pseudomonas aeruginosa triggered changes in our infection control measures. This study investigated the usefulness of our bundled interventions against postoperative infection after LT. This before-and-after analysis enrolled 130 patients who underwent living donor or deceased donor LT between January 2011 and October 2014. We initiated 3 measures after January 2013: (1) we required LT candidates to be able to walk independently; (2) we increased the hand hygiene compliance rate and contact precautions; and (3) we introduced procalcitonin (PCT) measurement for a more precise determination of empirical antimicrobial treatment. We compared factors affecting the emergence of drug-resistant microorganisms, such as the duration of antimicrobial and carbapenem therapy and hospital stay, and outcomes such as bacteremia and death from infection between before (n = 77) and after (n = 53) the LT suspension period. The utility of PCT measurement was also evaluated. Patients' backgrounds were not significantly different before and after the protocol revision. Incidence of bacteremia (44% versus 25%; P = 0.02), detection rate of multiple bacteria (18% versus 4%; P = 0.01), and deaths from infections (12% versus 2%; P = 0.04) significantly decreased after the protocol revision. Duration of antibiotic (42.3 versus 25.1 days; P = 0.002) and carbapenem administration (15.1 versus 5.2 days; P < 0.001) and the length of postoperative hospital stay (85.4 versus 63.5 days; P = 0.048) also decreased after the protocol revision. PCT mean values were significantly higher in the bacteremia group (10.10 ng/mL), compared with the uneventful group (0.65 ng/mL; P = 0.002) and rejection group (2.30 ng/mL; P = 0.02). One-year overall survival after LT significantly increased in the latter period (71% versus 94%; P = 0
Hansen, C. R.; Pressler, T.; Nielsen, K. G.;
BACKGROUND: Achromobacter xylosoxidans infection may cause conspicuous chronic pulmonary inflammation in cystic fibrosis (CF) patients similar to Pseudomonas aeruginosa and the Burkholderia cepacia complex (Bcc). Evolution in lung function was compared in chronically infected patients. Cytokine...
Luiz Vicente Ribeiro Ferreira da Silva Filho
Full Text Available Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. The use of levels of evidence allows the reader to identify the quality of scientific information that supports the recommendations made by experts. The objective of this review was to address current concepts related to the clinical impact, diagnosis, and treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. For the preparation of this review, the authors defined a group of questions that would be answered in accordance with the principles of PICO–an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. For each question, a structured review of the literature was performed using the Medline database in order to identify the studies with the methodological design most appropriate to answering the question. The questions were designed so that each of the authors could write a response. A first draft was prepared and discussed by the group. Recommendations were then made on the basis of the level of scientific evidence, in accordance with the classification system devised by the Oxford Centre for Evidence-Based Medicine, as well as the level of agreement among the members of the group.
Rubin, J; Walker, R D; Blickenstaff, K; Bodeis-Jones, S; Zhao, S
Infections with antimicrobial-resistant bacteria are a great challenge in both human and veterinary medicine. The purpose of this study was to determine antimicrobial susceptibility of 106 strains of Pseudomonas aeruginosa isolated from dogs with otitis and pyoderma from 2003 to 2006 in the United States. Three antimicrobial panels, including 6 classes and 32 antimicrobial agents, were used. A wide range of susceptibility patterns were noted with some isolates being resistant to between 8 and 28 (mean 16) of the antimicrobials tested. Among the beta-lactams, all isolates were resistant to ampicillin, cefoxitin, cefpodoxime, cephalothin and cefazolin followed by amoxicillin/clavulanic acid (99%), ceftiofur (97%), ceftriaxone (39%), cefotaxime (26%), and cefotaxime/clavulanic acid (20%), whereas less than 7% of isolates were resistant to ceftazidime/clavulanic acid, ceftazidime, piperacillin/tazobactam or cefepime. Two isolates were resistant to the carbapenems. Among the quinolones and fluoroquinolones, the most isolates were resistant to naladixic acid (96%), followed by orbifloxacin (52%), difloxacin (43%), enrofloxacin (31%), marbofloxacin (27%), gatifloxacin (23%), levofloxacin (21%), and ciprofloxacin (16%). Among the aminoglycosides, the most resistance was seen to kanamycin (90%), followed by streptomycin (69%), gentamicin (7%), and amikacin (3%). Of the remaining antimicrobials 100% of the isolates were resistant to chloramphenicol followed by tetracycline (98%), trimethoprim/sulfamethoxazole (57%), and sulfisoxazole (51%). Point mutations were present in gyrA, gyrB, parC, and/or parE genes among 34 of the 102 naladixic acid-resistant isolates. Two isolates contained class 1 integrons carrying aadA gene conferring streptomycin and spectinomycin resistance. The findings suggest that many antimicrobial agents commonly used in companion animals may not constitute appropriate therapy for canine pseudomonas infections. PMID:18395369
Machado, Mary C; Webster, Thomas J
Ventilator-associated pneumonia (VAP) is a serious complication of mechanical ventilation that has been shown to be associated with increased mortality rates and medical costs in the pediatric intensive care unit. Currently, there is no cost-effective solution to the problems posed by VAP. Endotracheal tubes (ETTs) that are resistant to bacterial colonization and that inhibit biofilm formation could provide a novel solution to the problems posed by VAP. The objective of this in vitro study was to evaluate differences in the growth of Pseudomonas aeruginosa on unmodified polyvinyl chloride (PVC) ETTs and on ETTs etched with a fungal lipase, Rhizopus arrhizus, to create nanoscale surface features. These differences were evaluated using an in vitro model of the pediatric airway to simulate a ventilated patient in the pediatric intensive care unit. Each experiment was run for 24 hours and was supported by computational models of the ETT. Dynamic conditions within the ETT had an impact on the location of bacterial growth within the tube. These conditions also quantitatively affected bacterial growth especially within the areas of tube curvature. Most importantly, experiments in the in vitro model revealed a 2.7 log reduction in the number (colony forming units/mL) of P. aeruginosa on the nanoroughened ETTs compared to the untreated PVC ETTs after 24 hours. This reduction in total colony forming units/mL along the x-axis of the tube was similar to previous studies completed for Staphylococcus aureus. Thus, this dynamic study showed that lipase etching can create surface features of nanoscale roughness on PVC ETTs that decrease bacterial attachment of P. aeruginosa without the use of antibiotics and may provide clinicians with an effective and inexpensive tool to combat VAP. PMID:27563242
Full Text Available Introduction. During the last two decadesthe larval therapy has reemerged as a safe andreliable alternative for the healing of cutaneousulcers that do not respond to the conventionaltreatments.Objective. To evaluate the use of the larvaeof Lucilia sericata as a treatment for infectedwounds with Pseudomonas aeruginosa in ananimal model.Materials and methods. Twelve rabbits wererandomly distributed in 3 groups: the firstgroup was treated with larval therapy; the secondwas treated with antibiotics therapy and to thethird no treatment was applied, therefore wasestablished as a control group. To each animala wound was artificially induced, and then asuspension of P. aeruginosa was inoculated intothe lesion. Finally, every rabbit was evaluateduntil the infection development was recognizedand treatment was set up for the first twogroups according with the protocols mentionedabove. Macroscopic evaluation of the woundswas based on the presence of edema, exudates,bad odor, inflammation around the wound andthe presence of granulation tissue. The healingprocess was evaluated by monitoring histologicalchanges in the dermal tissue.Results. Differences in the time requiredfor wound healing were observed between thefirst group treated with larval therapy (10 daysand the second group treated with conventionalantibiotics therapy (20 days.Conclusion. The L. sericata larva is and efficienttool as a therapy for infected wounds withP. aeruginosa.
Cadranel, J.; GARFIELD D; Lavolé, A; Wislez, M.; Milleron, B.; Mayaud, C.
AIDS related mortality has fallen sharply in industrialised countries since 1996 following the introduction of highly active antiretroviral therapy. This has been accompanied by an increase in the proportion of deaths attributable to non‐AIDS defining solid tumours, especially lung cancer. The risk of developing lung cancer seems to be higher in HIV infected subjects than in the general population of the same age, partly because the former tend more frequently to be smokers and, especially, i...
Katherine E Price
Full Text Available Cystic Fibrosis (CF is a human genetic disease that results in the accumulation of thick, sticky mucus in the airways, which results in chronic, life-long bacterial biofilm infections that are difficult to clear with antibiotics. Pseudomonas aeruginosa lung infection is correlated with worsening lung disease and P. aeruginosa transitions to an antibiotic tolerant state during chronic infections. Tobramycin is an aminoglycoside currently used to combat lung infections in individuals with CF. While tobramycin is effective at eradicating P. aeruginosa in the airways of young patients, it is unable to completely clear the chronic P. aeruginosa infections in older patients. A recent report showed that co-addition of tobramycin and mannitol enhanced killing of P. aeruginosa grown in vitro as a biofilm on an abiotic surface. Here we employed a model system of bacterial biofilms formed on the surface of CF-derived airway cells to determine if mannitol would enhance the antibacterial activity of tobramycin against P. aeruginosa grown on a more clinically relevant surface. Using this model system, which allows the growth of robust biofilms with high-level antibiotic tolerance analogous to in vivo biofilms, we were unable to find evidence for enhanced antibacterial activity of tobramycin with the addition of mannitol, supporting the observation that this type of co-treatment failed to reduce the P. aeruginosa bacterial load in a clinical setting.
... CDC.gov . Healthcare-associated Infections (HAIs) Share Compartir Pseudomonas aeruginosa in Healthcare Settings On this Page What ... and/or help treat infections? What is a Pseudomonas infection? Pseudomonas infection is caused by strains of ...
Full Text Available The susceptibility of 105 Pseudomonas aeruginosa isolates collected from patients with urinary tract infectionswas assessed by determination of minimum inhibitory concentration (MICs using agar dilution method against thefollowing agents: norfloxacin, ofloxacin, ciprofloxacin and pefloxacin.Resistance rates of P. aeruginosa to tested fluoroquinolones was fairly uniformly distributed between compounds asfollowed: norfloxacin - 52.4%, ofloxacin- 49.5%, ciprofloxacin - 51.4%, pefloxacin - 49.5%. Analysis of cross-resistancein P. aeruginosa showed a correlated magnitude of resistance between fluoroquinolones. Among the P.aeruginosa strainsthe number of those showing simultaneously resistance to all tested agents is high (n=50.The significant increase in fluoroquinolone resistance probably reflects the widspread use of this agent and the clinicaluse of these compunds should be carefully monitored since most bacterial strains shows cross-resitance.
Cordon, S M; Elborn, J. S.; Rayner, R J; Hiller, E. J.; Shale, D. J.
The relationship between IgG antibodies to Pseudomonas aeruginosa and its isolation from sputum was determined in 100 patients with cystic fibrosis observed at intervals of two months for a median period of one year. Only one patient had a raised antibody titre (greater than 22.9 ELISA units) before isolation of P aeruginosa. Initially 65 patients were antibody negative, of whom 48 were also culture negative. Of 24 patients with positive sputum culture and negative antibodies, seven became an...
Aitken, Samuel L; Kontoyiannis, Dimitrios P; DePombo, April M; Bhatti, Micah M; Tverdek, Frank P; Gettys, Suzanne C; Nicolau, David P; Nunez, Cesar A
Multidrug-resistant Pseudomonas aeruginosa is of increasing concern in pediatric patients. Ceftolozane/tazobactam is a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant Pseudomonas; however, no data exist on its use in children. This report summarizes the treatment of a multidrug-resistant P. aeruginosa bloodstream infection in a pediatric leukemia patient with ceftolozane/tazobactam and provides the first description of its pharmacokinetics in pediatrics. PMID:27254038
Thomann, Andreas; de Mello Martins, Antonio G G; Brengel, Christian; Empting, Martin; Hartmann, Rolf W
Pseudomonas aeruginosa quorum-sensing (QS) is a sophisticated network of genome-wide regulation triggered in response to population density. A major component is the self-inducing pseudomonas quinolone signal (PQS) QS system that regulates the production of several nonvital virulence- and biofilm-related determinants. Hence, QS circuitry is an attractive target for antivirulence agents with lowered resistance development potential and a good model to study the concept of polypharmacology in autoloop-regulated systems per se. Based on the finding that a combination of PqsR antagonist and PqsD inhibitor synergistically lowers pyocyanin, we have developed a dual-inhibitor compound of low molecular weight and high solubility that targets PQS transcriptional regulator (PqsR) and PqsD, a key enzyme in the biosynthesis of PQS-QS signal molecules (HHQ and PQS). In vitro, this compound markedly reduced virulence factor production and biofilm formation accompanied by a diminished content of extracellular DNA (eDNA). Additionally, coadministration with ciprofloxacin increased susceptibility of PA14 to antibiotic treatment under biofilm conditions. Finally, disruption of pathogenicity mechanisms was also assessed in vivo, with significantly increased survival of challenged larvae in a Galleria mellonella infection model. Favorable physicochemical properties and effects on virulence/biofilm establish a promising starting point for further optimization. In particular, the ability to address two targets of the PQS autoinduction cycle at the same time with a single compound holds great promise in achieving enhanced synergistic cellular effects while potentially lowering rates of resistance development. PMID:26882081
Olejnickova, Katerina; Hola, Veronika; Ruzicka, Filip
The nosocomial pathogen Pseudomonas aeruginosa is equipped with a large arsenal of cell-associated and secreted virulence factors which enhance its invasive potential. The complex relationships among virulence determinants have hitherto not been fully elucidated. In the present study, 175 catheter-related isolates were observed for the presence of selected virulence factors, namely extracellular enzymes and siderophore production, biofilm formation, resistance to antibiotics, and motility. A high percentage of the strains produced most of the tested virulence factors. A positive correlation was identified between the production of several exoproducts, and also between the formation of both types of biofilm. An opposite trend was observed between the two types of biofilm and the production of siderophores. Whereas the relationship between the submerged biofilm production (i.e. the biofilm formed on the solid surface below the water level) and the siderophore secretion was negative, the production of air-liquid interface (A-L) biofilm (i.e. the biofilm floating on the surface of the cultivation medium) and the siderophore secretion were positively correlated. All correlations were statistically significant at the level P = 0.05 with the correlation coefficient γ ≥ 0.50. Our results suggest that: (1) the co-production of the lytic enzymes and siderophores can play an important role in the pathogenesis of the catheter-related infections and should be taken into account when the virulence potential is assessed; (2) biofilm-positive strains are capable of forming both submerged and non-attached A-L biofilms; and (3) the different micro-environment in the submerged biofilm and A-L biofilm layers have opposite consequences for the production of other virulence factors. PMID:24842562
Successful treatment of Candida parapsilosis and Pseudomonas aeruginosa infection using medical and surgical management in an injecting drug user with mitral and aortic valve endocarditis: a case report
Full Text Available Abstract Introduction Polymicrobial endocarditis is a well-recognized problem in intravenous drug users and it accounts for 1 to 3% of endocarditis cases overall and up to 9% in other series. The most common combinations of organisms include Staphylococcus aureus and Streptococcus pneumoniae followed by Staphylococcus aureus and Pseudomonas aeruginosa. Candida parapsilosis endocarditis carries a mortality rate of 45%, and each infection with Candida or Pseudomonas endocarditis per se carries a very high mortality rate approaching 85% and 80%, respectively. The combination of P. aeruginosa and C. parapsilosis has never been encountered and there have been no earlier reports of the combination of C. parapsilosis and P. aeruginosa in adult intravenous drug users as a cause of endocarditis. Case presentation We present a 49-year-old man with bivalvular endocarditis with P. aeruginosa and C. parapsilosis. He had a prior bivalvular replacement in 2005 that became infected with the above microorganisms and he was treated with intravenous antibiotics. Because of ongoing intravenous drug use, a second valve replacement was denied. A few days later, the patient presented with septic shock secondary to P. aeruginosa and C. parapsilosis recurrent endocarditis. The infection was cured with a second bivalvular replacement and extended therapy with antibiotics and antifungals. Conclusion This is the first time a patient has presented with P. aeruginosa and C. parapsilosis endocarditis. Relapsing polymicrobial endocarditis can be cured with medical and surgical therapy.
Diagnostic multiplex polymerase chain reaction assay for the identification of Pseudomonas aeruginosa from the skin biopsy specimens in burn wound infections and detection of antibiotic susceptibility
Objective was to identify Pseudomonas aeruginosa (P. aeruginosa) from the skin biopsy specimens in burn wound infections by multiplex polymerase chain reaction (M-PCR) and detection of antimicrobial susceptibility of isolates from culture. We conducted the cross-sectional study in 140 patients with wound infections who admitted to referral burn center of Motahari, Tehran, Iran, during a 12-month period from 2005-2006. Skin biopsy specimens were aseptically taken from each patient, one for PCR and one for bacterial culture. A M-PCR test based on simultaneous amplification of 2 lipoprotein genes: oprI and oprL, was used to directly detect fluorescent pseudomonades and P. aeruginosa in skin biopsy specimens. The susceptibility of P. aeruginosa isolates to 16 antibiotics was determined using the disc diffusion method. Out of 140 biopsy specimens, M-PCR detected 66 (47.2%) isolates, while culture detected 57 (40.7%) isolates as P. aeruginosa. Positive results for both genes which observed only for P. aeruginosa, while only one gene, oprI, was amplified from other fluorescent pseudomonades (n=12) and all other bacterial tested (n=62) were negative by the amplification test. The most effective antibiotics against isolate of P. aeruginosa were cefepime (79%), azetreonam (76%), ticarcillin-clavulanic acid (68%), tobramycin (62%) and amikacin (61%). Multiplex PCR assay appears promising for the rapid and sensitive detection of P. aeruginosa from the burned skin biopsy specimens. Simultaneous amplification of 2 lipoprotein genes: oprI and oprL could detect P. aeruginosa and oprI gene only for other fluorescent pseudomonades. (author)
Jakobsen, Tim Holm; Bjarnsholt, Thomas; Jensen, Peter Østrup;
Bacterial resistance to conventional antibiotics combined with an increasing acknowledgement of the role of biofilms in chronic infections has led to a growing interest in new antimicrobial strategies that target the biofilm mode of growth. In the aggregated biofilm mode, cell-to-cell communication...... alternative antibacterial strategies. Here, we review state of the art research of quorum sensing inhibitors against the opportunistic human pathogen Pseudomonas aeruginosa, which is found in a number of biofilm-associated infections and identified as the predominant organism infecting the lungs of cystic...
Johansen, H K; Cryz, S J; Hougen, H P;
The ongoing lung tissue damage in chronically Pseudomonas aeruginosa infected cystic fibrosis (CF) patients has been shown to be caused by elastase liberated from polymorphonuclear leukocytes (PMN), which dominate the chronic inflammation in these patients. Most CF patients, however, contract the...... of the macroscopic lung inflammation compared to the other vaccination groups (p = 0.009). The same effect could be obtained by IFN-gamma treatment (p = 0.004). The chronic P. aeruginosa lung infection was established in two inbred mice strains C3H/HeN, known as TH1 responders, and Balb/c, known as...
Wilson, R; Cohen, J.M.; Jose, R J; Vogel, C; Baxendale, H.; Brown, J. S.
Streptococcus pneumoniae is a common cause of pneumonia and infective exacerbations of chronic lung disease, yet there are few data on how adaptive immunity can specifically prevent S. pneumoniae lung infection. We have used a murine model of nasopharyngeal colonization by the serotype 19F S. pneumoniae strain EF3030 followed by lung infection to investigate whether colonization protects against subsequent lung infection and the mechanisms involved. EF3030 colonization induced systemic and lo...
Artsiom V. Tsyrkunou
Full Text Available We report a case of pulmonary Rhizopus microsporus infection in a patient with untreated diabetes following brush clearing. The patient was successfully treated with a combined medical and surgical approach with complete resolution of the lung lesions and remains asymptomatic at 11-month follow-up.
Haas, Michelle K; Daley, Charles L
Mycobacterial infections have caused enormous morbidity and mortality in people living with human immunodeficiency virus (HIV) infection. Of these, the most devastating has been tuberculosis (TB), the leading cause of death among HIV-positive persons globally. TB has killed more people living with HIV than any other infection. Diagnosis of latent TB infection (LTBI) is critical as treatment can prevent emergence of TB disease. Bacteriologic confirmation of TB disease should be sought whenever possible as well as drug susceptibility testing. When detected early, drug susceptible TB is curable. Similar to TB, nontuberculous mycobacteria (NTM) can also produce pulmonary and extrapulmonary infections including disseminated disease that can be fatal. Diagnosis through accurate identification of the pathogenic organism will greatly inform treatment. Depending on the NTM identified, treatment may not be curable. Ultimately, preventive strategies such as initiation of antiretroviral drugs and treatment of LTBI are interventions expected to have significant impacts on control of TB and NTM in the setting of HIV. This chapter will review the impact of pulmonary mycobacterial infections on HIV-positive individuals. PMID:26974300
Krylov, Victor; Shaburova, Olga; Krylov, Sergey; Pleteneva, Elena
Pseudomonas aeruginosa is a frequent participant in wound infections. Emergence of multiple antibiotic resistant strains has created significant problems in the treatment of infected wounds. Phage therapy (PT) has been proposed as a possible alternative approach. Infected wounds are the perfect place for PT applications, since the basic condition for PT is ensured; namely, the direct contact of bacteria and their viruses. Plenty of virulent ("lytic") and temperate ("lysogenic") bacteriophages are known in P. aeruginosa. However, the number of virulent phage species acceptable for PT and their mutability are limited. Besides, there are different deviations in the behavior of virulent (and temperate) phages from their expected canonical models of development. We consider some examples of non-canonical phage-bacterium interactions and the possibility of their use in PT. In addition, some optimal approaches to the development of phage therapy will be discussed from the point of view of a biologist, considering the danger of phage-assisted horizontal gene transfer (HGT), and from the point of view of a surgeon who has accepted the Hippocrates Oath to cure patients by all possible means. It is also time now to discuss the possible approaches in international cooperation for the development of PT. We think it would be advantageous to make phage therapy a kind of personalized medicine. PMID:23344559
Full Text Available Pseudomonas aeruginosa is a frequent participant in wound infections. Emergence of multiple antibiotic resistant strains has created significant problems in the treatment of infected wounds. Phage therapy (PT has been proposed as a possible alternative approach. Infected wounds are the perfect place for PT applications, since the basic condition for PT is ensured; namely, the direct contact of bacteria and their viruses. Plenty of virulent (“lytic” and temperate (“lysogenic” bacteriophages are known in P. aeruginosa. However, the number of virulent phage species acceptable for PT and their mutability are limited. Besides, there are different deviations in the behavior of virulent (and temperate phages from their expected canonical models of development. We consider some examples of non-canonical phage-bacterium interactions and the possibility of their use in PT. In addition, some optimal approaches to the development of phage therapy will be discussed from the point of view of a biologist, considering the danger of phage-assisted horizontal gene transfer (HGT, and from the point of view of a surgeon who has accepted the Hippocrates Oath to cure patients by all possible means. It is also time now to discuss the possible approaches in international cooperation for the development of PT. We think it would be advantageous to make phage therapy a kind of personalized medicine.
WINTER, JB; GROEN, M; VANDERLOGT, K; WILDEVUUR, CRH; PROP, J
Lung transplant recipients suffer from a high number of viral infections. It has been suggested that the defense against viral infections is impaired in lung transplants, Therefore, we investigated in rat lung transplants whether antibody responses against an intrapulmonary viral infection were impa
Full Text Available Purpose: Damage caused by an organism during infection is attributed to production of virulence factors. Different virulence factors produced by the organism contribute to its pathogenicity, individually. During infectious conditions, role of virulence factors produced by the pathogen is different, depending upon the site of involvement. Pseudomonas aeruginosa is an opportunistic nosocomial pathogen known to cause infections of the respiratory tract, burn wound, urinary tract and eye. Importance of virulence factors produced by P. Aeruginosa during infections such as keratitis, burn wound and respiratory tract is known. The present study was designed to understand the importance of different virulence factors of P. aeruginosa in urinary tract infection in vivo. Materials and methods: An ascending urinary tract infection model was established in mice using standard parent strain PAO1 and its isogenic mutant, JP2. Mice were sacrificed at different time intervals and renal tissue homogenates were used for estimation of renal bacterial load and virulence factors. Results: Both parent and mutant strains were able to reach the renal tissue. PAO 1 PAO1was isolated from renal tissue till day 5 post-infection. However, the mutant strain was unable to colonise the renal tissue. Failure of mutant strain to colonise was attributed to its inability to produce protease, elastase and rhamnolipid. Conclusion: This study suggests that protease, elastase and rhamnolipid contribute to pathogenesis and survival of P. aeruginosa during urinary tract infection.
Ciofu, Oana; Jensen, Tim; Pressler, Tacjana;
OBJECTIVE: To assess the efficacy and safety of meropenem, administered on a compassionate basis to 62 cystic fibrosis (CF) patients (age: 24plus minus6 years) with hypersensitivity reactions to beta-lactam antibiotics and/or infection by bacteria resistant to other antibiotics. METHODS: Fifty......-seven patients were chronically infected with Pseudomonas aeruginosa and 5 with Burkholderia cepacia. In total, 124 courses (1 to 6/patient) of meropenem, 2 g three times a day by intravenous infusion (10 to 15 min) for 14 days, were administered. RESULTS: During treatment for P. aeruginosa the mean increase in...... chronic infection with B. cepacia the post treatment FEV1 and FVC values were higher than the pre-treatment values, and all the inflammatory parameters decreased. The geometric means of minimal inhibitory concentration (MICs) (microg/mL) for P. aeruginosa (B. cepacia) were: tobramycin 6 (59...
Full Text Available Background: A majority of the studies done on the western population have shown that Pseudomonas aeruginosa causes many severe infections in patients with bronchiectasis as compared to other pathogens. There is scarcity of similar data from the Asian population. Materials and Methods: A prospective study was undertaken to identify the various pathogens isolated from the respiratory samples of 117 patients with bronchiectasis from south India and to compare the clinicomicrobiological profile of infections caused by P. aeruginosa and other respiratory pathogens. Results: The respiratory pathogens were isolated from 63 (53.8% patients. P. aeruginosa was the most common isolate (46.0% followed by Klebsiella pneumoniae (14.3% and other pathogenic bacteria. Patients included in the P. aeruginosa group had a higher number of exacerbations (p: 0.008, greater number of hospital admissions (p: 0.007, a prolonged hospital stay (p: 0.03, and poor lung function, compared to the patients infected with the non-Pseudomonas group. Conclusion: It is necessary to investigate the etiology of respiratory tract infections among bronchiectasis patients followed by the prompt management of cases diagnosed with P. aeruginosa infections, so as to lower the morbidity and have a better prognosis.
The advantages and limitations of MRI in lung infections in children have not been well established. This article illustrates the MRI findings in children with pneumonia caused by Mycoplasma pneumoniae, Streptococcus pneumoniae, and other pathogens. Lung parenchymal, pleural, and lymph node abnormalities are well characterized by MRI. Loculation of pleural fluid is detected in children with empyema. Contrast enhancement may be useful in the differentiation of active inflammation from noninflammatory changes. MRI can be particularly useful in the follow-up of children with chronic pulmonary diseases. (orig.)
Peltola, Ville; Ruuskanen, Olli [Turku University Hospital, Department of Paediatrics, Turku (Finland); Svedstroem, Erkki [Turku University Hospital, Department of Radiology, Turku (Finland)
The advantages and limitations of MRI in lung infections in children have not been well established. This article illustrates the MRI findings in children with pneumonia caused by Mycoplasma pneumoniae, Streptococcus pneumoniae, and other pathogens. Lung parenchymal, pleural, and lymph node abnormalities are well characterized by MRI. Loculation of pleural fluid is detected in children with empyema. Contrast enhancement may be useful in the differentiation of active inflammation from noninflammatory changes. MRI can be particularly useful in the follow-up of children with chronic pulmonary diseases. (orig.)
Kolpen, Mette; Appeldorff, Cecilie F.; Brandt, Sarah; Mousavi, Nabi; Kragh, Kasper N.; Aydogan, Sevtap; Uppal, Haleema A.; Bjarnsholt, Thomas; Ciofu, Oana; Høiby, Niels; Jensen, Peter Ø.
Tolerance towards antibiotics of Pseudomonas aeruginosa biofilms is recognized as a major cause of therapeutic failure of chronic lung infection in cystic fibrosis (CF) patients. This lung infection is characterized by antibiotic-tolerant biofilms in mucus with zones of O2 depletion mainly due to polymorphonuclear leukocytic activity. In contrast to the main types of bactericidal antibiotics, it has not been possible to establish an association between the bactericidal effects of colistin and...
Lehrer Robert I
Full Text Available Abstract Background Pseudomonas aeruginosa and Burkholderia cepacia infections of cystic fibrosis patients' lungs are often resistant to conventional antibiotic therapy. Protegrins are antimicrobial peptides with potent activity against many bacteria, including P. aeruginosa. The present study evaluates the correlation between protegrin-1 (PG-1 sensitivity/resistance and protegrin binding in P. aeruginosa and B. cepacia. Methods The PG-1 sensitivity/resistance and PG-1 binding properties of P. aeruginosa and B. cepacia were assessed using radial diffusion assays, radioiodinated PG-1, and surface plasmon resonance (BiaCore. Results The six P. aeruginosa strains examined were very sensitive to PG-1, exhibiting minimal active concentrations from 0.0625–0.5 μg/ml in radial diffusion assays. In contrast, all five B. cepacia strains examined were greater than 10-fold to 100-fold more resistant, with minimal active concentrations ranging from 6–10 μg/ml. When incubated with a radioiodinated variant of PG-1, a sensitive P. aeruginosa strain bound considerably more protegrin molecules per cell than a resistant B. cepacia strain. Binding/diffusion and surface plasmon resonance assays revealed that isolated lipopolysaccharide (LPS and lipid A from the sensitive P. aeruginosa strains bound PG-1 more effectively than LPS and lipid A from resistant B. cepacia strains. Conclusion These findings support the hypothesis that the relative resistance of B. cepacia to protegrin is due to a reduced number of PG-1 binding sites on the lipid A moiety of its LPS.
The mucosal surface of the lung is the key interface between the external atmosphere and the bloodstream. Normally, this well oxygenated tissue is maintained in state of sterility by a number of innate immune processes. These include a physical and dynamic mucus barrier, the production of microbiocidal peptides and the expression of specific pattern recognition receptors on alveolar epithelial cells and resident macrophages and dendritic cells which recognise microbial structures and initiate innate immune responses which promote the clearance of potentially infectious agents. In a range of diseases, the mucosal surface of the lung experiences decreased oxygen tension leading to localised areas of prominent hypoxia which can impact upon innate immune and subsequent infectious and inflammatory processes. Under these conditions, the lung is generally more susceptible to infection and subsequent inflammation. In the current review, we will discuss recent data pertaining to the role of hypoxia in regulating both host and pathogen in the lung during pulmonary disease and how this contributes to innate immunity, infection and inflammation.