Anti-virulence Bispecific Monoclonal Antibody Mediated Protection Against Pseudomonas aeruginosa Ventilator-Associated Pneumonia in a Rabbit Model

2021 ◽  
Author(s):  
Fábio Aguiar-Alves ◽  
Hoan N. Le ◽  
Vuvi G. Tran ◽  
Emmanuelle Gras ◽  
Trang Vu ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Rabbit Model ◽  
Arterial Oxygen ◽  
Rank Test ◽  
Ventilator Associated Pneumonia ◽  
Exact Test ◽  
Cytokines And Chemokines ◽  
Potential Clinical Utility ◽  
Human Igg1 ◽  
Type 3

Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa . We characterized the correlates of protection of MEDI3902, a bispecific human IgG1 mAb that targets the P. aeruginosa type-3-secretion PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal volume mechanical ventilation. Rabbits infused with MEDI3902 prophylactically were protected, whereas those pretreated with irrelevant isotype-control IgG (c-IgG) succumbed between 12 and 44 hours post infection [100% (8/8) vs. 0% (8/8) survival, P <0.01 by log-rank test]. Lungs from rabbits pretreated with c-IgG, but not those with MEDI3902, had bilateral, multifocal areas of marked necrosis, hemorrhage, neutrophilic inflammatory infiltrate, diffuse fibrinous edema in alveolar spaces. All rabbits pretreated with c-IgG developed worsening bacteremia that peaked at the time of death, whereas only 38% (3/8) rabbits pretreated with MEDI3902 developed such high-grade bacteremia (two-sided Fisher’s exact test, P =0.026). Biomarkers associated with acute respiratory distress syndrome were evaluated longitudinally in blood samples collected every 2-4 hours to assess systemic pathophysiological changes in rabbits pretreated with MEDI3902 or c-IgG. Biomarkers were sharply increased or decreased in rabbits pretreated with c-IgG, but not those pretreated with MEDI3902, including ratio of arterial oxygen partial pressure to fractional inspired oxygen PaO 2 /FiO 2 <300, hypercapnia or hypocapnia, severe lactic acidosis, leukopenia and neutropenia. Cytokines and chemokines associated with ARDS were significantly downregulated in lungs from rabbits pretreated with MEDI3902 compared with c-IgG. These results suggest that MEDI3902 prophylaxis could have potential clinical utility for decreasing severity of P. aeruginosa ventilator-associated pneumonia.

scholarly journals Pseudomonas aeruginosa Ventilator-Associated Pneumonia Rabbit Model for Preclinical Drug Development

2021 ◽  
Author(s):  
Nhu T.Q. Nguyen ◽  
Emmanuelle Gras ◽  
Nguyen D. Tran ◽  
Nhi N.Y. Nguyen ◽  
Hanh H. Lam ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Supportive Care ◽  
Rabbit Model ◽  
Fluid Challenge ◽  
Arterial Oxygen ◽  
Large Animal ◽  
Ventilator Associated Pneumonia ◽  
Dosing Regimen ◽  
Large Animal Models ◽  
Severe Hypotension

Development and validation of large animal models of Pseudomonas aeruginosa ventilator-associated pneumonia is needed for testing new drug candidates in a manner mimicking how they will be used clinically. We have developed a new model in which rabbits were ventilated with low-tidal volume and challenged with P. aeruginosa to recapitulate hallmark clinical features of acute respiratory distress syndrome (ARDS): acute lung injury and inflammation, progressive decrease in arterial oxygen partial pressure to fractional inspired oxygen PaO2:FiO2, leukopenia, neutropenia, thrombocytopenia, hyperlactatemia, severe hypotension, bacterial dissemination from lung to other organs, multiorgan dysfunction, and ultimately death. We evaluated the predictive power of this rabbit model for antibiotic efficacy testing by determining whether a humanized dosing regimen of meropenem, a potent antipseudomonal β-lactam antibiotic, when administered with or without intensive care unit (ICU)-supportive care (fluid challenge and norepinephrine), could halt or reverse natural disease progression. Our humanized meropenem dosing regimen produced plasma concentration-time profile in the rabbit model similar to those reported in patients with ventilator-associated bacterial pneumonia. In this rabbit model, treatment with humanized meropenem and ICU-supportive care achieved the highest level of survival, halted the worsening of ARDS biomarkers and reversed lethal hypotension, although treatment with humanized meropenem alone also conferred some protection when compared to treatment with placebo (saline) alone or placebo plus ICU-supportive care. In conclusion, this rabbit model could help predict whether an antibiotic will be efficacious for the treatment of human ventilator-associated pneumonia.

scholarly journals Complete Genome Sequence of Pseudomonas aeruginosa CMC-115, a Clinical Strain from an Acute Ventilator-Associated Pneumonia Patient

2020 ◽  
Vol 9 (30) ◽  
Author(s):  
Adenike Adenikinju ◽  
Roderick V. Jensen ◽  
Thomas M. Kerkering ◽  
Dorothy C. Garner ◽  
Jayasimha Rao
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Complete Genome ◽  
Secretion System ◽  
Clinical Strain ◽  
Ventilator Associated Pneumonia ◽  
Circular Chromosome ◽  
Content Type ◽  
Pneumonia Patient ◽  
Type 3 Secretion System ◽  
Type 3

ABSTRACT We report the complete genome of clinical strain Pseudomonas aeruginosa CMC-115, which was isolated from an acute ventilator-associated pneumonia patient. Illumina sequencing reads were assembled using Geneious to yield a 6,375,262-bp circular chromosome that exhibited an unusual ferrichrome receptor in the pyoverdine synthesis locus and the absence of type 3 secretion system genes.

scholarly journals Rapid genetic and phenotypic changes in Pseudomonas aeruginosa clinical strains during ventilator-associated pneumonia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elise Persyn ◽  
Mohamed Sassi ◽  
Marc Aubry ◽  
Martin Broly ◽  
Sandie Delanou ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Ventilator Associated Pneumonia ◽  
Clinical Strains ◽  
Phenotypic Changes

scholarly journals Complete Sequence of pOZ176, a 500-Kilobase IncP-2 Plasmid Encoding IMP-9-Mediated Carbapenem Resistance, from Outbreak Isolate Pseudomonas aeruginosa 96

2013 ◽  
Vol 57 (8) ◽  
pp. 3775-3782 ◽  
Author(s):  
Jianhui Xiong ◽  
David C. Alexander ◽  
Jennifer H. Ma ◽  
Maxime Déraspe ◽  
Donald E. Low ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Carbapenem Resistance ◽  
Complete Sequence ◽  
Open Reading Frames ◽  
Content Type ◽  
Conserved Sequence ◽  
Carbapenem Resistant ◽  
Class 1 ◽  
Usage Analysis ◽  
Type 3

ABSTRACTPseudomonas aeruginosa96 (PA96) was isolated during a multicenter surveillance study in Guangzhou, China, in 2000. Whole-genome sequencing of this outbreak strain facilitated analysis of its IncP-2 carbapenem-resistant plasmid, pOZ176. The plasmid had a length of 500,839 bp and an average percent G+C content of 57%. Of the 618 predicted open reading frames, 65% encode hypothetical proteins. The pOZ176 backbone is not closely related to any plasmids thus far sequenced, but some similarity to pQBR103 ofPseudomonas fluorescensSBW25 was observed. Two multiresistant class 1 integrons and several insertion sequences were identified. TheblaIMP-9-carrying integron containedaacA4→blaIMP-9→aacA4, flanked upstream by Tn21 tnpMRAand downstream by a completetnioperon of Tn402and amermodule, named Tn6016. The second integron carriedaacA4→catB8a→blaOXA-10and was flanked by Tn1403-liketnpRAand asul1-type 3′ conserved sequence (3′-CS), named Tn6217. Other features include three resistance genes similar to those of Tn5, a tellurite resistance operon, and twopiloperons. The replication and maintenance systems exhibit similarity to a genomic island ofRalstonia solanacearumGM1000. Codon usage analysis suggests the recent acquisition ofblaIMP-9. The origins of the integrons on pOZ176 indicated separate horizontal gene transfer events driven by antibiotic selection. The novel mosaic structure of pOZ176 suggests that it is derived from environmental bacteria.

scholarly journals Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Vien T. M. Le ◽  
Hoan N. Le ◽  
Marcos Gabriel Pinheiro ◽  
Kenneth J. Hahn ◽  
Mary L. Dinh ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Production ◽  
Protective Efficacy ◽  
Survival Rates ◽  
Rabbit Model ◽  
Rank Test ◽  
Necrotizing Pneumonia ◽  
Time Curve ◽  
Content Type

ABSTRACT The protective efficacy of tedizolid phosphate, a novel oxazolidinone that potently inhibits bacterial protein synthesis, was compared to those of linezolid, vancomycin, and saline in a rabbit model of Staphylococcus aureus necrotizing pneumonia. Tedizolid phosphate was administered to rabbits at 6 mg/kg of body weight intravenously twice daily, which yielded values of the 24-h area under the concentration-time curve approximating those found in humans. The overall survival rate was 83% for rabbits treated with 6 mg/kg tedizolid phosphate twice daily and 83% for those treated with 50 mg/kg linezolid thrice daily (P = 0.66 by the log-rank test versus the results obtained with tedizolid phosphate). These survival rates were significantly greater than the survival rates of 17% for rabbits treated with 30 mg/kg vancomycin twice daily (P = 0.003) and 17% for rabbits treated with saline (P = 0.002). The bacterial count in the lungs of rabbits treated with tedizolid phosphate was significantly decreased compared to that in the lungs of rabbits treated with saline, although it was not significantly different from that in the lungs of rabbits treated with vancomycin or linezolid. The in vivo bacterial production of alpha-toxin and Panton-Valentine leukocidin, two key S. aureus-secreted toxins that play critical roles in the pathogenesis of necrotizing pneumonia, in the lungs of rabbits treated with tedizolid phosphate and linezolid was significantly inhibited compared to that in the lungs of rabbits treated with vancomycin or saline. Taken together, these results indicate that tedizolid phosphate is superior to vancomycin for the treatment of S. aureus necrotizing pneumonia because it inhibits the bacterial production of lung-damaging toxins at the site of infection.

scholarly journals Phenotypic Characterization of Juvenile Idiopathic Arthritis in African American Children

2016 ◽  
Vol 43 (4) ◽  
pp. 799-803 ◽  
Author(s):  
Lauren Fitzpatrick ◽  
K. Alaine Broadaway ◽  
Lori Ponder ◽  
Sheila T. Angeles-Han ◽  
Kirsten Jenkins ◽  
...  
Keyword(s):  
African American ◽  
Juvenile Idiopathic Arthritis ◽  
Early Onset ◽  
Disease Onset ◽  
Phenotypic Characterization ◽  
Rank Test ◽  
Chi Square ◽  
Phenotypic Data ◽  
Exact Test ◽  
American Children

Objective.Juvenile idiopathic arthritis (JIA) affects children of all races. Prior studies suggest that phenotypic features of JIA in African American (AA) children differ from those of non-Hispanic white (NHW) children. We evaluated the phenotypic differences at presentation between AA and NHW children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and replicated the findings in a JIA cohort from a large center in the southeastern United States.Methods.Children with JIA enrolled in the multicenter CARRA Registry and from Emory University formed the study and replication cohorts. Phenotypic data on non-Hispanic AA children were compared with NHW children with JIA using the chi-square test, Fisher’s exact test, and the Wilcoxon signed-rank test.Results.In all, 4177 NHW and 292 AA JIA cases from the CARRA Registry and 212 NHW and 71 AA cases from Emory were analyzed. AA subjects more often had rheumatoid factor (RF)-positive polyarthritis in both the CARRA (13.4% vs 4.7%, p = 5.3 × 10−7) and the Emory (26.8% vs 6.1%, p = 1.1 × 10−5) cohorts. AA children had positive tests for RF and cyclic citrullinated peptide antibodies (CCP) more frequently, but oligoarticular or early onset antinuclear antibody (ANA)-positive JIA less frequently in both cohorts. AA children were older at onset in both cohorts and this difference persisted after excluding RF-positive polyarthritis in the CARRA Registry (median age 8.5 vs 5.0 yrs, p = 1.4 × 10−8).Conclusion.Compared with NHW children, AA children with JIA are more likely to have RF/CCP-positive polyarthritis, are older at disease onset, and less likely to have oligoarticular or ANA-positive, early-onset JIA, suggesting that the JIA phenotype is different in AA children.

scholarly journals The rapid in vivo evolution of Pseudomonas aeruginosa in ventilator-associated pneumonia patients leads to attenuated virulence

Open Biology ◽  
2017 ◽  
Vol 7 (9) ◽  
pp. 170029 ◽  
Author(s):  
Ke Wang ◽  
Yi-qiang Chen ◽  
May M. Salido ◽  
Gurjeet S. Kohli ◽  
Jin-liang Kong ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Opportunistic Pathogen ◽  
Ventilator Associated Pneumonia ◽  
Loss Of Function ◽  
Short Term ◽  
Airway Infections ◽  
Evolutionary Trajectories ◽  
Human Airways ◽  
Late Stages

Pseudomonas aeruginosa is an opportunistic pathogen that causes severe airway infections in humans. These infections are usually difficult to treat and associated with high mortality rates. While colonizing the human airways, P. aeruginosa could accumulate genetic mutations that often lead to its better adaptability to the host environment. Understanding these evolutionary traits may provide important clues for the development of effective therapies to treat P. aeruginosa infections. In this study, 25 P. aeruginosa isolates were longitudinally sampled from the airways of four ventilator-associated pneumonia (VAP) patients. Pacbio and Illumina sequencing were used to analyse the in vivo evolutionary trajectories of these isolates. Our analysis showed that positive selection dominantly shaped P. aeruginosa genomes during VAP infections and led to three convergent evolution events, including loss-of-function mutations of lasR and mpl , and a pyoverdine-deficient phenotype. Specifically, lasR encodes one of the major transcriptional regulators in quorum sensing, whereas mpl encodes an enzyme responsible for recycling cell wall peptidoglycan. We also found that P. aeruginosa isolated at late stages of VAP infections produce less elastase and are less virulent in vivo than their earlier isolated counterparts, suggesting the short-term in vivo evolution of P. aeruginosa leads to attenuated virulence.

scholarly journals MODERN APPROACHES TO TREATMENT OF PSEUDOMONAS AERUGINOSA VENTILATOR-ASSOCIATED PNEUMONIA (LITERATURE REVIEW)

2019 ◽  
Vol 72 (5) ◽  
pp. 892-896
Author(s):  
Olha A. Poda ◽  
Tetyana O. Kryuchko ◽  
Inna N. Nesina ◽  
Olha Ya. Tkachenko ◽  
Nataliia V. Kuzmenko
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Causative Agent ◽  
Optimal Dose ◽  
Correct Choice ◽  
Antibacterial Drug ◽  
Controversial Issues ◽  
Ventilator Associated Pneumonia ◽  
Scientific Investigations ◽  
Multiresistant Strains ◽  
Hospital Acquired

Introduction: Nowadays anti-microbial therapy of ventilator-associated pneumonia caused by is one of the most topical issue as a consequence of widespread multiresistant strains of causative agent and their biological peculiarity of actively formation of resistance to new antibacterial drugs. The aim is to describe modern approaches to therapy of ventilator-associated pneumonia causative agent of which is presented by Pseudomonas aureginosa . Materials and methods: An analysis and summing up of results of scientific investigations described in medical publications concerning the issues of therapy of ventilatorassociated pneumonia caused by Pseudomonas aureginosa was done. Conclusions: Despite the development of modern approaches to anti-microbial therapy of ventilator-associated pneumonia caused by Pseudomonas aeruginosa, which are also concerned with such controversial issues as correct choice of antibacterial drug, its optimal dose, and duration of this therapy, the problem of treatment of hospital-acquired infections of respiratory airways caused by Pseudomonas aeruginosa has been discussable yet and requires the further study.

scholarly journals Association of Increased Circulating Acetic Acid With Poor Survival in Pseudomonas aeruginosa Ventilator-Associated Pneumonia Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoling Qi ◽  
Li Zhang ◽  
Jing Xu ◽  
Zheying Tao ◽  
Xiaoli Wang ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acetic Acid ◽  
Short Chain Fatty Acids ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
Ventilator Associated Pneumonia ◽  
Fermentation Products ◽  
Spectrometry Analysis ◽  
Beneficial Effects ◽  
Microbial Dysbiosis

BackgroundWe previously found that microbial disruption in Pseudomonas aeruginosa ventilator-associated pneumonia (PA-VAP) patients are long-lasting. Long-term microbial dysbiosis may lead to changes in metabolites. Short-chain fatty acids (SCFAs) are microbial fermentation products and show beneficial effects in patients with pneumonia. In this study, we aimed to explore the association between circulating SCFA levels and clinical outcomes in patients with PA-VAP.MethodsIn this study, we analyzed SCFAs in the serum of 49 patients with PA-VAP by gas chromatography-mass spectrometry analysis. Twenty of these patients died, and 29 survived. The correlation between serum SCFAs and patient survival and immune parameters was analyzed.ResultsWe developed a partial least squares discriminant analysis (PLS-DA) model to examine differential SCFAs in 49 patients with PA-VAP. Among the seven SCFAs, only acetic acid was increased in non-survivors (P = 0.031, VIP &gt; 1). Furthermore, high levels of acetic acid (&gt;1.96ug/ml) showed increased 90-day mortality compared to low levels of acetic acid (&lt;1.96ug/ml) in Kaplan-Meier survival analyses (P = 0.027). Increased acetic acid also correlated with reduced circulating lymphocyte and monocyte counts.ConclusionOur study showed that increased circulating acetic acid is associated with 90-day mortality in PA-VAP patients. The decrease in lymphocytes and monocytes might be affected by acetic acid and involved in the poor prognosis.

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