Browsing by Subject "Pseudomonas aeruginosa"
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Item Open Access Bacterial etiology of community-acquired pneumonia in immunocompetent hospitalized patients and appropriateness of empirical treatment recommendations: an international point-prevalence study.(European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2020-08) Carugati, Manuela; Aliberti, S; Sotgiu, G; Blasi, F; Gori, A; Menendez, R; Encheva, M; Gallego, M; Leuschner, P; Ruiz-Buitrago, S; Battaglia, S; Fantini, R; Pascual-Guardia, S; Marin-Corral, J; Restrepo, MI; GLIMP CollaboratorsAn accurate knowledge of the epidemiology of community-acquired pneumonia (CAP) is key for selecting appropriate antimicrobial treatments. Very few etiological studies assessed the appropriateness of empiric guideline recommendations at a multinational level. This study aims at the following: (i) describing the bacterial etiologic distribution of CAP and (ii) assessing the appropriateness of the empirical treatment recommendations by clinical practice guidelines (CPGs) for CAP in light of the bacterial pathogens diagnosed as causative agents of CAP. Secondary analysis of the GLIMP, a point-prevalence international study which enrolled adults hospitalized with CAP in 2015. The analysis was limited to immunocompetent patients tested for bacterial CAP agents within 24 h of admission. The CAP CPGs evaluated included the following: the 2007 and 2019 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA), the European Respiratory Society (ERS), and selected country-specific CPGs. Among 2564 patients enrolled, 35.3% had an identifiable pathogen. Streptococcus pneumoniae (8.2%) was the most frequently identified pathogen, followed by Pseudomonas aeruginosa (4.1%) and Klebsiella pneumoniae (3.4%). CPGs appropriately recommend covering more than 90% of all the potential pathogens causing CAP, with the exception of patients enrolled from Germany, Pakistan, and Croatia. The 2019 ATS/IDSA CPGs appropriately recommend covering 93.6% of the cases compared with 90.3% of the ERS CPGs (p < 0.01). S. pneumoniae remains the most common pathogen in patients hospitalized with CAP. Multinational CPG recommendations for patients with CAP seem to appropriately cover the most common pathogens and should be strongly encouraged for the management of CAP patients.Item Open Access Bloodstream infections in community hospitals in the 21st century: a multicenter cohort study.(PLoS One, 2014) Anderson, Deverick J; Moehring, Rebekah W; Sloane, Richard; Schmader, Kenneth E; Weber, David J; Fowler, Vance G; Smathers, Emily; Sexton, Daniel JBACKGROUND: While the majority of healthcare in the US is provided in community hospitals, the epidemiology and treatment of bloodstream infections in this setting is unknown. METHODS AND FINDINGS: We undertook this multicenter, retrospective cohort study to 1) describe the epidemiology of bloodstream infections (BSI) in a network of community hospitals and 2) determine risk factors for inappropriate therapy for bloodstream infections in community hospitals. 1,470 patients were identified as having a BSI in 9 community hospitals in the southeastern US from 2003 through 2006. The majority of BSIs were community-onset, healthcare associated (n = 823, 56%); 432 (29%) patients had community-acquired BSI, and 215 (15%) had hospital-onset, healthcare-associated BSI. BSIs due to multidrug-resistant pathogens occurred in 340 patients (23%). Overall, the three most common pathogens were S. aureus (n = 428, 28%), E. coli (n = 359, 24%), coagulase-negative Staphylococci (n = 148, 10%), though type of infecting organism varied by location of acquisition (e.g., community-acquired). Inappropriate empiric antimicrobial therapy was given to 542 (38%) patients. Proportions of inappropriate therapy varied by hospital (median = 33%, range 21-71%). Multivariate logistic regression identified the following factors independently associated with failure to receive appropriate empiric antimicrobial therapy: hospital where the patient received care (p<0.001), assistance with ≥3 ADLs (p = 0.005), Charlson score (p = 0.05), community-onset, healthcare-associated infection (p = 0.01), and hospital-onset, healthcare-associated infection (p = 0.02). Important interaction was observed between Charlson score and location of acquisition. CONCLUSIONS: Our large, multicenter study provides the most complete picture of BSIs in community hospitals in the US to date. The epidemiology of BSIs in community hospitals has changed: community-onset, healthcare-associated BSI is most common, S. aureus is the most common cause, and 1 of 3 patients with a BSI receives inappropriate empiric antimicrobial therapy. Our data suggest that appropriateness of empiric antimicrobial therapy is an important and needed performance metric for physicians and hospital stewardship programs in community hospitals.Item Open Access Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia: a multinational point prevalence study of hospitalised patients.(The European respiratory journal, 2018-08) Restrepo, Marcos I; Babu, Bettina L; Reyes, Luis F; Chalmers, James D; Soni, Nilam J; Sibila, Oriol; Faverio, Paola; Cilloniz, Catia; Rodriguez-Cintron, William; Aliberti, Stefano; GLIMPPseudomonas aeruginosa is a challenging bacterium to treat due to its intrinsic resistance to the antibiotics used most frequently in patients with community-acquired pneumonia (CAP). Data about the global burden and risk factors associated with P. aeruginosa-CAP are limited. We assessed the multinational burden and specific risk factors associated with P. aeruginosa-CAP.We enrolled 3193 patients in 54 countries with confirmed diagnosis of CAP who underwent microbiological testing at admission. Prevalence was calculated according to the identification of P. aeruginosa Logistic regression analysis was used to identify risk factors for antibiotic-susceptible and antibiotic-resistant P. aeruginosa-CAP.The prevalence of P. aeruginosa and antibiotic-resistant P. aeruginosa-CAP was 4.2% and 2.0%, respectively. The rate of P. aeruginosa CAP in patients with prior infection/colonisation due to P. aeruginosa and at least one of the three independently associated chronic lung diseases (i.e. tracheostomy, bronchiectasis and/or very severe chronic obstructive pulmonary disease) was 67%. In contrast, the rate of P. aeruginosa-CAP was 2% in patients without prior P. aeruginosa infection/colonisation and none of the selected chronic lung diseases.The multinational prevalence of P. aeruginosa-CAP is low. The risk factors identified in this study may guide healthcare professionals in deciding empirical antibiotic coverage for CAP patients.Item Open Access Characterizing Stress-Induced Outer Membrane Vesicle Production in Pseudomonas aeruginosa(2013) MacDonald, Ian AlexanderAs an opportunistic Gram-negative pathogen, Pseudomonas aeruginosa must be able to adapt to changes and survive stressors in its environment during the course of infection. To aid survival in the hostile host environment, P. aeruginosa has evolved a myriad of virulence factors including the production of an exopolysaccharide capsule, as well as secretion of degradative proteases and lipases that also function as defense mechanisms. Outer membrane vesicles (OMVs) acts as a secretion system to disseminate virulence factors and function as a general bacterial stress response to remove accumulated periplasmic waste. Despite the growing insights of the field into the potential functions of OMVs, the mechanism for formation remains to be fully elucidated. The three proposed mechanisms for OMV formation in P. aeruginosa are mediated by the Pseudomonas quinolone signal PQS, the AlgU envelope stress response pathway, and the periplasmic chaperone MucD. This report investigates how P. aeruginosa responds to sublethal physiological stressors with regards to OMV production levels and whether the proposed mechanisms for OMV formation are required for stress-induced OMV formation. We concluded that exposure to cell wall directed stressors increased OMV production and activity of the sigma factor that controls MucD expression, AlgU. AlgU was shown to be sufficient to induced OMV production upon overexpression; however, stress-induced OMV production was not dependent on activation of AlgU as vesiculation could be induced in strains lacking AlgU. Furthermore, MucD levels were not inversely proportional to OMV production under acute stress, and the ability to produce PQS was not required for OMV production. Finally, an investigation of the response of P. aeruginosa to oxidative stress revealed that hydrogen peroxide-induced OMV production requires the presence of B-band but not A-band lipopolysaccharide. We also demonstrated that the ability for P. aeruginosa to sense oxidative stress via OxyR, was important for hydrogen peroxide-induced OMV production, by a yet to be determined method. Together these results demonstrate that current proposed mechanisms for OMV formation do not universally apply under all stress conditions, and that additional mechanisms for OMV formation are still to be identified and fully elucidated during acute stress in P. aeruginosa.
Item Open Access Drug design from the cryptic inhibitor envelope.(Nat Commun, 2016-02-25) Lee, Chul-Jin; Liang, Xiaofei; Wu, Qinglin; Najeeb, Javaria; Zhao, Jinshi; Gopalaswamy, Ramesh; Titecat, Marie; Sebbane, Florent; Lemaitre, Nadine; Toone, Eric J; Zhou, PeiConformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.Item Open Access Interactions of a secreted Pseudomonas aeruginosa aminopeptidase with bacterial outer membrane molecules: characterization and implications for bacterial pathogenic phenotypes.(2017-05-08) Campbell, TimothyThe protein Pseudomonas aeruginosa aminopeptidase (PaAP) is secreted by the opportunistic, Gram-negative bacterial pathogen Pseudomonas aeruginosa. PaAP expression appears to be upregulated in clinical isolates of P. aeruginosa, especially in strains found in the lungs of cystic fibrosis patients, likely indicating that it serves a role in the development of pathogenic phenotypes. However, the function(s) that PaAP serves in pathogenic contexts are as yet unknown, as are the mechanisms by which PaAP accomplishes them. This work seeks to identify molecules of the Gram negative outer membrane with which PaAP interacts in order to understand the role that PaAP plays in the establishment and maintenance of P. aeruginosa infections. Particular attention is given to determining whether PaAP interacts with lipopolysaccharide (LPS), which is the major constituent of the Gram negative outer membrane and a potent toxin and immune system agonist. To accomplish this goal, a range of biochemical analyses are used, particularly immunochemistry techniques. While results from these assays are preliminary, our findings suggest that PaAP does not interact with P. aeruginosa LPS, suggesting that proteins or non-LPS saccharides are the primary interaction partners of PaAP in the outer membrane.Item Open Access Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial.(Critical care (London, England), 2022-11) Chastre, Jean; François, Bruno; Bourgeois, Marc; Komnos, Apostolos; Ferrer, Ricard; Rahav, Galia; De Schryver, Nicolas; Lepape, Alain; Koksal, Iftihar; Luyt, Charles-Edouard; Sánchez-García, Miguel; Torres, Antoni; Eggimann, Philippe; Koulenti, Despoina; Holland, Thomas L; Ali, Omar; Shoemaker, Kathryn; Ren, Pin; Sauser, Julien; Ruzin, Alexey; Tabor, David E; Akhgar, Ahmad; Wu, Yuling; Jiang, Yu; DiGiandomenico, Antonio; Colbert, Susan; Vandamme, Drieke; Coenjaerts, Frank; Malhotra-Kumar, Surbhi; Timbermont, Leen; Oliver, Antonio; Barraud, Olivier; Bellamy, Terramika; Bonten, Marc; Goossens, Herman; Reisner, Colin; Esser, Mark T; Jafri, Hasan S; COMBACTE-MAGNET EVADE Study GroupBackground
Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects.Methods
EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee.Results
Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% (n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% (n = 15/83) of placebo recipients (relative risk reduction [RRR]: - 23.7%; 80% confidence interval [CI] - 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) μg/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 μg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups.Conclusions
The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov ( NCT02696902 ) on 11th February 2016 and on EudraCT ( 2015-001706-34 ) on 7th March 2016.Item Open Access Stress-induced outer membrane vesicle production by Pseudomonas aeruginosa.(J Bacteriol, 2013-07) Macdonald, Ian A; Kuehn, Meta JAs an opportunistic Gram-negative pathogen, Pseudomonas aeruginosa must be able to adapt and survive changes and stressors in its environment during the course of infection. To aid survival in the hostile host environment, P. aeruginosa has evolved defense mechanisms, including the production of an exopolysaccharide capsule and the secretion of a myriad of degradative proteases and lipases. The production of outer membrane-derived vesicles (OMVs) serves as a secretion mechanism for virulence factors as well as a general bacterial response to envelope-acting stressors. This study investigated the effect of sublethal physiological stressors on OMV production by P. aeruginosa and whether the Pseudomonas quinolone signal (PQS) and the MucD periplasmic protease are critical mechanistic factors in this response. Exposure to some environmental stressors was determined to increase the level of OMV production as well as the activity of AlgU, the sigma factor that controls MucD expression. Overexpression of AlgU was shown to be sufficient to induce OMV production; however, stress-induced OMV production was not dependent on activation of AlgU, since stress caused increased vesiculation in strains lacking algU. We further determined that MucD levels were not an indicator of OMV production under acute stress, and PQS was not required for OMV production under stress or unstressed conditions. Finally, an investigation of the response of P. aeruginosa to oxidative stress revealed that peroxide-induced OMV production requires the presence of B-band but not A-band lipopolysaccharide. Together, these results demonstrate that distinct mechanisms exist for stress-induced OMV production in P. aeruginosa.Item Open Access SulA inhibits assembly of FtsZ by a simple sequestration mechanism.(Biochemistry, 2012-04) Chen, Yaodong; Milam, Sara L; Erickson, Harold PWe have investigated the inhibition by SulA of the assembly of Escherichia coli FtsZ. Using quantitative GTPase and fluorescence assays, we found that SulA inhibition resulted in an increase in the apparent critical concentration for FtsZ assembly. The increase in apparent critical concentration was always less than the total amount of SulA added, suggesting that the association of SulA and FtsZ was of modest affinity. Isothermal titration calorimetry gave a value of 0.78 μM for the dissociation constant of the FtsZ-SulA complex, similar in magnitude to the 0.72 μM critical concentration of FtsZ protofilament assembly at steady state. We modeled the reaction as an equilibrium competition between (a) FtsZ subunits assembling onto protofilaments or (b) binding SulA. When FtsZ was assembled in GMPCPP or in EDTA, the inhibition by SulA was reduced. The reduced inhibition could be explained by a 3- and 10-fold weaker binding of SulA to FtsZ. The mutant D212G, which has no GTPase activity and therefore minimal subunit cycling, was shown here to assemble one-stranded protofilaments, and the assembly was blocked by SulA. We also assayed the SulA and FtsZ proteins from Pseudomonas. The SulA inhibition was stronger than with the E. coli proteins, and the model indicated a 5-fold higher affinity of Pseudomonas SulA for FtsZ.