Characterisation of a refined rat model of respiratory infection with Pseudomonas aeruginosa and the effect of ciprofloxacin

Growcott, Ellena; Coulthard, Alan; Amison, Richard T.; Hardaker, Elizabeth; Saxena, Vidit; Malt, Layla; Jones, Peter; Grevot, Armelle; Poll, Chris; Osborne, Colin; Banner, Katharine H.

doi:10.1016/j.jcf.2010.12.007

Cited by 20 publications

(23 citation statements)

References 20 publications

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“…The bead size and the time after inoculation (14 days) used in this study were chosen on the basis of the findings of previous studies (16,17) to be more reflective of the infection seen in CF patients.…”

Section: Resultsmentioning

confidence: 99%

“…The rat model of biofilm lung infection proposed by Johansen and Høiby (39) was used with minor modifications. The model is reported in the literature to produce a pulmonary infection that is stable for more than a month, and this chronic lung infection mimics what is found in human chronic lung infections, for example, infections in patients with cystic fibrosis (16,17,(39)(40)(41). Briefly, P. aeruginosa cells were immobilized in spherical alginate beads to mimic the biofilm matrix effect and to prevent clearance from the lung after bacterial inoculation into the animals.…”

Section: Methodsmentioning

confidence: 99%

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Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

Torres

Helfer

Bernardes

et al. 2017

Antimicrob Agents Chemother

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Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 Ϯ 12.1 g · h/ml and 13.3 Ϯ 3.5 g · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor ϭ 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CL lung ) was added to the model for these animals (CL lung ϭ 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

Torres

Helfer

Bernardes

et al. 2017

Antimicrob Agents Chemother

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“…To mimic biofilm, agar or seaweed alginate beads are used as extracellular polymeric substances which are loaded with bacteria in a process that requires mixing with mineral oil (55,75) and addition of an emulsifying agent, sorbitanmonooleate, to increase uniformity of the beads (75) (Figure 1). For sham animals, sterile beads are prepared using PBS or saline, however, instillation of sterile beads itself incites an inflammatory response resulting in increased cellular infiltrates in lungs (55,75) (Figure 2C) and increased release of inflammatory cytokines that, depending on the precise clinical endpoints utilized in the study, could obscure the potential beneficial treatment effects (75).…”

Section: Agar-bead (Chronic) Pneumonia Modelmentioning

confidence: 99%

Animal models of hospital-acquired pneumonia: current practices and future perspectives

Bielen¹,

Jongers²,

Malhotra-Kumar³

et al. 2017

Ann. Transl. Med.

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Lower respiratory tract infections are amongst the leading causes of mortality and morbidity worldwide. Especially in hospital settings and more particularly in critically ill ventilated patients, nosocomial pneumonia is one of the most serious infectious complications frequently caused by opportunistic pathogens.Pseudomonas aeruginosa is one of the most important causes of ventilator-associated pneumonia as well as the major cause of chronic pneumonia in cystic fibrosis patients. Animal models of pneumonia allow us to investigate distinct types of pneumonia at various disease stages, studies that are not possible in patients.Different animal models of pneumonia such as one-hit acute pneumonia models, ventilator-associated pneumonia models and biofilm pneumonia models associated with cystic fibrosis have been extensively studied and have considerably aided our understanding of disease pathogenesis and testing and developing new treatment strategies. The present review aims to guide investigators in choosing appropriate animal pneumonia models by describing and comparing the relevant characteristics of each model using P. aeruginosa as a model etiology for hospital-acquired pneumonia. Key to establishing and studying these animal models of infection are well-defined end-points that allow precise monitoring and characterization of disease development that could ultimately aid in translating these findings to patient populations in order to guide therapy. In this respect, and discussed here, is the development of humanized animal models of bacterial pneumonia that could offer unique advantages to study bacterial virulence factor expression and host cytokine production for translational purposes.

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“…Agar beads were prepared following a previously published protocol with minor modifications (Growcott et al, 2011). Briefly, colonies from an overnight culture of P. aeruginosa were diluted with 30 mL sterile PBS to achieve a suspension of 0.3 O.D.…”

Section: Methodsmentioning

confidence: 99%

“…In this model, bacteria are slowly released from agarose. Agarose is a linear polymer of repeating units of agarobiose that closely mimics the extracellular polymeric substances or exopolysaccharides secreted by P. aeruginosa (Cash et al, 1979; Growcott et al, 2011). Genetically modified murine models based on mutations in gene encoding for cystic fibrosis transmembrane conductance regulator (CFTR) have contributed invaluably to the current understanding of CFTR function.…”

Section: Introductionmentioning

confidence: 99%

Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa

Bielen

Jongers

Boddaert

et al. 2017

Front. Cell. Infect. Microbiol.

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Biofilm-producing strains of Pseudomonas aeruginosa are a major cause of morbidity and mortality in cystic fibrosis (CF) patients. In these patients, increased levels of IL-17 as well as of IL-5 and IL-13 along with arginase (Arg)-positive macrophages have been observed in bronchoalveolar lavage fluid. While IL-17 is a strong proinflammatory cytokine associated with host defense against bacterial and fungal infections and is also elevated in several autoimmune diseases, IL-5/IL-13 and Arg1-positive M2 macrophages are part of the anti-inflammatory type 2 (Th2) immunity. To study whether increased IL-5 and IL-13 levels are related to biofilm formation, which is frequently observed in CF patients colonized by P. aeruginosa, we utilized an agarose bead-embedded P. aeruginosa rat model commonly employed in in vivo biofilm studies. We showed that “sterile” agarose bead instillation in rat notably increased lung transcript levels of IL-5 and IL-13 at two post-instillation study-points, day 1 and day 3. Concurrently, increased infiltration of type 2 innate cells such as eosinophils and Arg1 positive M2 activated macrophages (Arg1+CD68+) was also observed both at day 1 and day 3 while the proportion of M1 activated macrophages (iNOS+CD68+) at these time-points decreased. In contrast, P. aeruginosa-loaded beads caused a drastic elevation of proinflammatory Th1 (IFNγ, TNFα, IL-12a) and antibacterial Th17 (IL-17a, IL-17f, IL-22, IL-23a) cytokines along with a high influx of neutrophils and M1 macrophages, while Th2 cytokines (IL-5 and IL-13) drastically declined at day 1 post-infection. Interestingly, at day 3 post-infection, both Th1 and Th17 cytokines sharply declined and corroborated with decreased M1 and increased M2 macrophages. These data suggest that while IL-17 is linked to episodes of acute exacerbations of infection in CF patients, the increased Th2 cytokines and M2 macrophages observed in these patients are largely due to the biofilm matrix. The data presented here has important implications for clinical management of CF patients.

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Characterisation of a refined rat model of respiratory infection with Pseudomonas aeruginosa and the effect of ciprofloxacin

Abstract: SPAN(®) 80 can control the particle size and lung distribution of agar beads and P. aeruginosa-embedded beads prepared with 0.01%v/v SPAN(®)80 can induce infection and inflammation over 7 days.

Cited by 20 publications

References 20 publications

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

Animal models of hospital-acquired pneumonia: current practices and future perspectives

Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa

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