In vivo efficacy of biapenem with ME1071, a novel metallo-β-lactamase (MBL) inhibitor, in a murine model mimicking ventilator-associated pneumonia caused by MBL-producing Pseudomonas aeruginosa

2013 ◽  
Vol 42 (3) ◽  
pp. 238-243 ◽  
Author(s):  
Koichi Yamada ◽  
Katsunori Yanagihara ◽  
Norihito Kaku ◽  
Yosuke Harada ◽  
Yohei Migiyama ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Murine Model ◽  
Ventilator Associated Pneumonia ◽  
In Vivo Efficacy

In vivo efficacy and pharmacokinetics of biapenem in a murine model of ventilator-associated pneumonia with Pseudomonas aeruginosa

2012 ◽  
Vol 18 (4) ◽  
pp. 472-478 ◽  
Author(s):  
Koichi Yamada ◽  
Katsunori Yanagihara ◽  
Yosuke Harada ◽  
Yoshitomo Morinaga ◽  
Nobuko Araki ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Murine Model ◽  
Ventilator Associated Pneumonia ◽  
In Vivo Efficacy

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 Saturability of Granulocyte Kill of Pseudomonas aeruginosa in a Murine Model of Pneumonia

2011 ◽  
Vol 55 (6) ◽  
pp. 2693-2695 ◽  
Author(s):  
G. L. Drusano ◽  
B. VanScoy ◽  
W. Liu ◽  
S. Fikes ◽  
D. Brown ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Immune System ◽  
Murine Model ◽  
Antimicrobial Chemotherapy ◽  
Ventilator Associated Pneumonia ◽  
Bacterial Burden ◽  
Content Type ◽  
The Impact ◽  
Over Time

ABSTRACTOutcomes for patients with dense bacterial burdens, such as ventilator-associated pneumonia (VAP) patients, are often critically influenced by the adequacy of antimicrobial chemotherapy and by the response of the immune system, particularly the granulocytes. Little information is available about the quantitation of kill of organisms over time by granulocytes. In this investigation, we examined the impact of the baseline bacterial burden on the ability of granulocytes alone (without chemotherapy) to keep the number of organisms in check or to kill them over a 24-h period.Pseudomonas aeruginosaATCC 27853 was the study organism, and we employed a murine pneumonia model (granulocyte replete) for the study. We found that the ability of the immune system to killP. aeruginosawas saturable. The burden at which the system was half saturated was 2.15 × 106± 2.66 × 106CFU/g. Burdens greater than 107CFU/g demonstrated net growth over 24 h. These findings suggest the need for aggressive chemotherapy early in the treatment of VAP to keep the burden from saturating the granulocytes. This should optimize the outcome for these seriously infected patients.

scholarly journals 1066. In Vitro and in Vivo Antimicrobial Activity of Cefiderocol and Comparators against Achromobacter spp

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S625-S626
Author(s):  
Ryuichiro Nakai ◽  
Ayaka makino ◽  
Hitomi Hama ◽  
Toriko Yoshitomi ◽  
Rio Nakamura ◽  
...  
Keyword(s):  
Rat Model ◽  
Murine Model ◽  
Lung Infection ◽  
Vitro Activity ◽  
Infection Model ◽  
In Vitro Activity ◽  
Independent Contractor ◽  
In Vivo Efficacy

Abstract Background Achromobacter spp. is intrinsically resistant to multiple antibiotics, and the treatment options are limited. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active against a wide variety of aerobic Gram-negative bacteria, including carbapenem-resistant strains. In this study, in vitro and in vivo antibacterial activity of CFDC against Achromobacter spp. was evaluated. Methods A total of 334 global isolates collected by IHMA from 39 countries in 2015-2019 were used. Minimum inhibitory concentrations (MICs) of CFDC and comparators were determined by broth microdilution method using iron-depleted CAMHB or CAMHB, respectively, as recommended by CLSI guidelines. In vivo efficacy of CFDC was compared with meropenem (MEM), piperacillin-tazobactam (PIP/TAZ), ceftazidime (CAZ), and ciprofloxacin (CIP) in a neutropenic murine lung infection model (n=5), and compared with MEM in a immunocompetent rat lung infection model (n=3-7) caused by 2 A. xylosoxydans. In the murine model, treatment was given 2, 5, and 8 hours post-infection, and the numbers of viable cfu in lungs were determined 24 hours post-infection. In the rat model, the humanized PK in plasma resulting from CFDC 2 g every 8 h (3-h infusion) or meropenem 1 g every 8 h (0.5-h infusion) were recreated via continuous intravenous infusion for 4 days, following which cfu in lungs were determined. Results CFDC showed in vitro activity with MIC50/90 of 0.06/0.5 µg/mL against 334 Achromobacter spp. Only 7 isolates (2.1%) had MICs > 4 µg/mL. These were the lowest values among all compound tested (Table). In the murine model, CFDC caused > 1.5 log10 decrease of viable cfu in lungs at 100 mg/kg dose (%fT >MIC: < 50%) from baseline control against both of strains (CFDC MIC: 0.5 and 2 µg/mL) (P< 0.05). No decrease of cfu in lungs was observed for the comparators at 100 mg/kg (MEM, PIP/TAZ, CAZ, and CIP MICs were >16, >64, >32, and >8 µg/mL, respectively). In the rat model, humanized CFDC dosing reduced the viable cfu by >1 log10 CFU/lung compared with baseline controls (P< 0.05). MEM showed no significant activity. In vitro activity of CFDC and comparator agents against Achromobacter spp. 334 Achromobacter spp. isolates collected from 2015 and 2019. The majority of isolates tested were A. xylosoxidans (312/334; 93.4%), followed by A. insolitus (11/334; 3.3%), Achromobacter sp. (8/334; 2.4%), A. denitrificans (2/334; 0.6%), and A. piechaudii (1/334; 0.3%). Conclusion CFDC showed potent in vivo efficacy reflecting in vitro activity against A. xylosoxidans. The results suggested that CFDC has the potential to be an effective therapeutic option for Achromobacter spp. infections. Disclosures Ryuichiro Nakai, MSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Ayaka makino, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Yoshinori Yamano, PhD, Shionogi (Employee)

scholarly journals In vivo efficacy of KRP-109, a novel elastase inhibitor, in a murine model of severe pneumococcal pneumonia

2011 ◽  
Vol 24 (6) ◽  
pp. 660-665 ◽  
Author(s):  
Koichi Yamada ◽  
Katsunori Yanagihara ◽  
Nobuko Araki ◽  
Yosuke Harada ◽  
Yoshitomo Morinaga ◽  
...  
Keyword(s):  
Murine Model ◽  
Pneumococcal Pneumonia ◽  
Elastase Inhibitor ◽  
In Vivo Efficacy

scholarly journals In Vivo Efficacy of a Synthetic Coumarin Derivative in a Murine Model of Aspergillosis

PLoS ONE ◽  
2014 ◽  
Vol 9 (8) ◽  
pp. e103039 ◽  
Author(s):  
Seema Singh ◽  
Rajesh Dabur ◽  
Madhumanjiri M. Gatne ◽  
Bharat Singh ◽  
Shilpi Gupta ◽  
...  
Keyword(s):  
Murine Model ◽  
Coumarin Derivative ◽  
In Vivo Efficacy

scholarly journals In vivo efficacy of sitafloxacin in a new murine model of non-typeable Haemophilus influenzae pneumonia by sterile intratracheal tube

2009 ◽  
Vol 34 (3) ◽  
pp. 210-214 ◽  
Author(s):  
Shigeki Nakamura ◽  
Katsunori Yanagihara ◽  
Nobuko Araki ◽  
Yoshitomo Morinaga ◽  
Koichi Izumikawa ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Murine Model ◽  
In Vivo Efficacy

scholarly journals Inhaled bacteriophage therapy in a porcine model of ventilator-associated pneumonia caused by pseudomonas aeruginosa.

2021 ◽  
Author(s):  
Antoine Guillon ◽  
Jeoffrey Pardessus ◽  
Guillaume L’Hostis ◽  
Cindy Fevre ◽  
Celine Barc ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Pseudomonas Aeruginosa ◽  
Phage Therapy ◽  
Antimicrobial Efficacy ◽  
Resistant Bacteria ◽  
Ventilator Associated Pneumonia ◽  
Bacteriophage Therapy ◽  
Log Reduction

Background and Purpose. Pseudomonas aeruginosa is a main cause of ventilator-associated pneumonia (VAP) with drug-resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of VAP caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized-phage therapy. Experimental Approach. (i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled-phage therapy was evaluated in pigs, which were anesthetized, mechanically ventilated and infected with P. aeruginosa. Key Results. By selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5 Log reduction, p<0.001). No phage was detected in the sera and urines throughout the experiment. Conclusion and Implications. Our findings demonstrated: (i) the feasibility of delivering large amounts of active phages by nebulization during mechanical ventilation, (ii) rapid control of in situ infection by inhaled bacteriophage in an experimental model of VAP with high translational value.

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