Exogenous rh-urokinase modifies inflammation and Pseudomonas aeruginosa infection in a rat chronic pulmonary infection model

1993 ◽  
Vol 39 (12) ◽  
pp. 1127-1134 ◽  
Author(s):  
David A. Hart ◽  
Francis Green ◽  
Paul Whidden ◽  
Jack Henkin ◽  
Donald E. Woods
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pulmonary Infection ◽  
Pulmonary Inflammation ◽  
Infection Model ◽  
Sprague Dawley ◽  
Short Term ◽  
Intratracheal Administration ◽  
Pseudomonas Aeruginosa Infection ◽  
Vitro Analysis

The effect of recombinant human urokinase (rh-UK) in a rat model of chronic Pseudomonas aeruginosa pulmonary infection was studied. Efficacy was assessed by lung histology and quantitative bacteriology. Male Sprague–Dawley rats received 1 × 104 or 1 × 105P. aeruginosa encapsulated in agar beads via the intratracheal route on day 1. Intratracheal administration of up to 12 500 units of rh-UK on day 21 led to a dose-dependent disappearance of viable organisms from the lungs by day 24 in rats receiving 104 organisms. In slightly longer term infections (30 days), rh-UK was still effective in facilitating the disappearance of the organisms from the lungs of most of the treated animals. rh-UK was effective in eliminating organisms when animals were infected with 104, but not 105 bacteria. In vitro analysis revealed that rh-UK was not directly toxic for the organisms. Histologically, lungs from short-term infected control animals exhibited acute inflammation, inflammatory cell infiltrates, and fibrin deposition. Histology of lungs from UK-treated, short-term infected rats revealed decreased airway inflammation and cellular infiltration compared with infected controls. Lungs from infected animals treated with 12 500 units of rh-UK were histologically indistinguishable from the lungs of uninfected control animals, except for the foreign body reaction. These results indicate that exogenous rh-UK may be efficacious in the treatment of pulmonary inflammation accompanying exposure to Gram-negative bacteria such as P. aeruginosa.Key words: chronic pulmonary infection, Pseudomonas aeruginosa infection, fibrinolysis, urokinase.

scholarly journals The Combination of Meropenem and Levofloxacin Is Synergistic with Respect to both Pseudomonas aeruginosa Kill Rate and Resistance Suppression

2010 ◽  
Vol 54 (6) ◽  
pp. 2646-2654 ◽  
Author(s):  
Arnold Louie ◽  
Caroline Grasso ◽  
Nadzeya Bahniuk ◽  
Brian Van Scoy ◽  
David L. Brown ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Combination Therapy ◽  
Infection Model ◽  
Combination Regimen ◽  
Time Data ◽  
Kaplan Meier ◽  
Drug Concentrations ◽  
Cell Kill ◽  
The Impact

ABSTRACT New approaches are needed for the treatment of Pseudomonas aeruginosa infections. All available single agents are suboptimal, especially for resistance suppression. Classical β-lactam/aminoglycoside combinations are not used often enough at least in part because of concern for nephrotoxicity. We evaluated the combination of meropenem and levofloxacin against the P. aeruginosa PAO1 wild type and its isogenic MexAB pump-overexpressed mutant. The drugs were studied using an in vitro hollow-fiber pharmacodynamic infection model. There were 16 different regimens evaluated for both isolates. Both total population and resistant subpopulations were quantified. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The impact of monotherapy versus that of combination therapy for attainment of a 3-log cell kill and for resistance suppression was examined using Kaplan-Meier analysis. Drug exposures were calculated by fitting the concentration-time data using the ADAPT II package of programs. For both isolates, monotherapy allowed resistance emergence with all but the largest exposure or with all exposures. In contrast, there was no resistance emergence with any combination regimen. Kaplan-Meier analysis showed significant differences in time to attainment of a 3-log cell kill as well as time to resistance emergence for monotherapy and combination therapy for both isolates, in favor of the combination regimens. Determination of the pharmacodynamic indices associated with resistance suppression demonstrated a 2- to 3-fold reduction with the use of combinations. Combination therapy with meropenem and levofloxacin provides a significantly faster time to attain a 3-log cell kill and significantly better resistance suppression than does either monotherapy. This combination should be evaluated in a clinical trial.

In vitro analysis of green fabricated silver nanoparticles (AgNPs) against Pseudomonas aeruginosa PA14 biofilm formation, their application on urinary catheter

2021 ◽  
Vol 151 ◽  
pp. 106058
Author(s):  
Felix LewisOscar ◽  
Chari Nithya ◽  
Sasikumar Vismaya ◽  
Manivel Arunkumar ◽  
Arivalagan Pugazhendhi ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Silver Nanoparticles ◽  
Biofilm Formation ◽  
Urinary Catheter ◽  
Vitro Analysis ◽  
In Vitro Analysis

scholarly journals 707. QPX9003: Pharmacology of a Novel Polymyxin in Mice and Rats

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S319-S319
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
Jonathan Parkinson ◽  
Kade Roberts ◽  
Philip Thompson ◽  
...  
Keyword(s):  
Post Infection ◽  
Lethal Dose ◽  
Lung Infection ◽  
Infection Model ◽  
Rat Lung ◽  
Sprague Dawley ◽  
Bacterial Killing ◽  
Swiss Mice ◽  
Infection Models

Abstract Background Currently available polymyxins are limited by toxicity and poor efficacy at tolerated doses. We have developed a new series of polymyxin derivatives with improved safety profiles and in vitro potency against major MDR bacteria. The following describes studies on the in vivo antimicrobial activity and toxicity of QPX9003 in mice and rats. Methods Mouse studies. The minimum lethal dose (MLD by IV bolus) and nephrotoxicity (6 IP doses administered 2 hours apart) of QPX9003 and polymyxin B (PMB) were determined in Swiss mice. For the neutropenic mouse thigh infection using A. baumannii, Swiss mice were infected with ~106 CFU/thigh. Doses were administered IP at various intervals starting 2-hour post-infection and continued over 24 hours. Rat studies. For the rat lung infection model, Sprague-Dawley rats were infected with ~107 CFU/lung. QPX9003 and PMB were administered IV every 4 hours starting 2 hours post-infection and continued over 24 hours. Bacteria. For both infection models, animals were infected with A. baumannii AB1016 (QPX9003 MIC of 0.5 mg/L and PMB MIC of 1.0 mg/L). Untreated control groups were sacrificed at the start of treatment and both untreated and treated groups were sacrificed 24 hours after the start of treatment, infected tissues harvested, homogenized, and plated to determine colony counts. Results QPX9003 had reduced acute toxicity and nephrotoxicity compared with PMB in mice. QPX9003 showed better bacterial killing of A. baumannii than PMB at similar plasma exposures in both the mouse thigh model (−0.41 vs. +0.83 log CFU/thigh) and rat lung infection model (−1.10 vs. +1.44 log CFU/lung). Conclusion QPX9003 was less acutely toxic, less nephrotoxic, and was more efficacious in mouse and rat infection models compared with PMB. QPX9003 is a promising new polymyxin. (This work was supported in part by federal funds from the National Institutes of Allergy and Infectious Diseases [R01AI098771], and the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under OTA number HHSO100201600026C). Disclosures All authors: No reported disclosures.

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