Mathematical modelling of Pseudomonas aeruginosa biofilm growth and treatment in the cystic fibrosis lung

Miller, Judy Z.; Brantner, Justin S.; Clemons, C. B.; Kreider, K. L.; Milsted, Amy; Wilber, Pat; Yun, Yang; Youngs, Wiley J.; Young, G. W.; Badawy, Hope T.; Wagers, Patrick O.

doi:10.1093/imammb/dqt003

Cited by 13 publications

(13 citation statements)

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“…One would anticipate that with leaky boundary conditions, as considered in [26], a higher amount of antimicrobial would need to be administered.…”

Section: Resultsmentioning

confidence: 99%

“…We note that these conditions at the top and bottom of the biofilm describe a ‘best case’ scenario for the treatment strategy, because all aqueous antimicrobial or antimicrobial released within the biofilm from the nanoparticles remains in the biofilm. In [26] we examine a variety of potential dosing strategies combining each form of delivery and considering ‘completely leaky’ boundaries. In addition that work considers a two-dimensional continuum model for a biofilm with a spatially varying thickness, H ( x, t ), of the biofilm.…”

Section: Governing Equationsmentioning

confidence: 99%

“…In this model we have chosen to simulate antimicrobial activity linked to the metabolic rate of the bacteria. In [26] antimicrobial activity in the absence of nutrient is also included. The term bB represents the natural death of the bacteria, where b is the natural death rate.…”

Section: Governing Equationsmentioning

confidence: 99%

“…A comprehensive mathematical model of a drug delivery system based on nebulization of SCC should describe (i) the transport of SCC, nebulized either in aqueous solution or in nanoparticles, through the lung airways, (ii) the penetration of nanoparticles into the biofilm, (iii) the erosion of nanoparticles and the subsequent release of agents, (iv) the reactive-diffusive transport of SCC within the biofilm, and (v) the growth or decay of the biofilm in response to antimicrobial treatment. We note that the modeling presented later in this paper and in our other work [26] is an initial effort to address only items (iii)–(v) in an idealized flow cell setting, rather than a biofilm embedded in mucus. We have partially addressed items (i) and (ii) in the context of biofilms grown in a flow cell setup in [27].…”

Section: Introductionmentioning

confidence: 99%

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Modeling the response of a biofilm to silver-based antimicrobial

Stine

Nassar

Miller

et al. 2013

Mathematical Biosciences

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Biofilms are found within the lungs of patients with chronic pulmonary infections, in particular patients with cystic fibrosis, and are the major cause of morbidity and mortality for these patients. The work presented here is part of a large interdisciplinary effort to develop an effective drug delivery system and treatment strategy to kill biofilms growing in the lung. The treatment strategy exploits silver-based antimicrobials, in particular, silver carbene complexes (SCC). This manuscript presents a mathematical model describing the growth of a biofilm and predicts the response of a biofilm to several basic treatment strategies. The continuum model is composed of a set of reaction-diffusion equations for the transport of soluble components (nutrient and antimicrobial), coupled to a set of reaction-advection equations for the particulate components (living, inert, and persister bacteria, extracellular polymeric substance, and void). We explore the efficacy of delivering SCC both in an aqueous solution and in biodegradable polymer nanoparticles. Minimum bactericidal concentration (MBC) levels of antimicrobial in both free and nanoparticle-encapsulated forms are estimated. Antimicrobial treatment demonstrates a biphasic killing phenomenon, where the active bacterial population is killed quickly followed by a slower killing rate, which indicates the presence of a persister population. Finally, our results suggest that a biofilm with a ready supply of nutrient throughout its depth has fewer persister bacteria and hence may be easier to treat than one with less nutrient.

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“…One would anticipate that with leaky boundary conditions, as considered in [26], a higher amount of antimicrobial would need to be administered.…”

Section: Resultsmentioning

confidence: 99%

Section: Governing Equationsmentioning

confidence: 99%

Section: Governing Equationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modeling the response of a biofilm to silver-based antimicrobial

Stine

Nassar

Miller

et al. 2013

Mathematical Biosciences

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“…For example, P. aeruginosa has been shown to grow in sessile biofilm matrices both in vivo and in artificial sputum medium mimicking the CF lung habitat (8)(9)(10)(11)(12)(13)(14). In contrast, Bcc biofilm-like structures have not yet been identified within the intraluminal CF mucus inhabited by P. aeruginosa.…”

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confidence: 99%

Localization of Burkholderia cepacia Complex Bacteria in Cystic Fibrosis Lungs and Interactions with Pseudomonas aeruginosa in Hypoxic Mucus

et al. 2014

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eThe localization of Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) lungs, alone or during coinfection with Pseudomonas aeruginosa, is poorly understood. We performed immunohistochemistry for Bcc and P. aeruginosa bacteria on 21 coinfected or singly infected CF lungs obtained at transplantation or autopsy. Parallel in vitro experiments examined the growth of two Bcc species, Burkholderia cenocepacia and Burkholderia multivorans, in environments similar to those occupied by P. aeruginosa in the CF lung. Bcc bacteria were predominantly identified in the CF lung as single cells or small clusters within phagocytes and mucus but not as "biofilm-like structures." In contrast, P. aeruginosa was identified in biofilm-like masses, but densities appeared to be reduced during coinfection with Bcc bacteria. Based on chemical analyses of CF and non-CF respiratory secretions, a test medium was defined to study Bcc growth and interactions with P. aeruginosa in an environment mimicking the CF lung. When test medium was supplemented with alternative electron acceptors under anaerobic conditions, B. cenocepacia and B. multivorans used fermentation rather than anaerobic respiration to gain energy, consistent with the identification of fermentation products by high-performance liquid chromatography (HPLC). Both Bcc species also expressed mucinases that produced carbon sources from mucins for growth. In the presence of P. aeruginosa in vitro, both Bcc species grew anaerobically but not aerobically. We propose that Bcc bacteria (i) invade a P. aeruginosa-infected CF lung when the airway lumen is anaerobic, (ii) inhibit P. aeruginosa biofilm-like growth, and (iii) expand the host bacterial niche from mucus to also include macrophages.

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Mathematical models of cystic fibrosis as a systemic disease

Olivença

Davis

Kumbale

et al. 2023

WIREs Mechanisms of Disease

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Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal dysfunction first. CF ultimately impairs not only the pancreas and intestine but also the lungs, gonads, liver, kidneys, bones, and the cardiovascular system. It is caused by one of several mutations in the gene of the epithelial ion channel protein CFTR. Intense research and improved antimicrobial treatments during the past eight decades have steadily increased the predicted life expectancy of a person with CF (pwCF) from a few weeks to over 50 years. Moreover, several drugs ameliorating the sequelae of the disease have become available in recent years, and notable treatments of the root cause of the disease have recently generated substantial improvements in health for some but not all pwCF. Yet, numerous fundamental questions remain unanswered. Complicating CF, for instance in the lung, is the fact that the associated insufficient chloride secretion typically perturbs the electrochemical balance across epithelia and, in the airways, leads to the accumulation of thick, viscous mucus and mucus plaques that cannot be cleared effectively and provide a rich breeding ground for a spectrum of bacterial and fungal communities. The subsequent infections often become chronic and respond poorly to antibiotic treatments, with outcomes sometimes only weakly correlated with the drug susceptibility of the target pathogen. Furthermore, in contrast to rapidly resolved acute infections with a single target pathogen, chronic infections commonly involve multi‐species bacterial communities, called “infection microbiomes,” that develop their own ecological and evolutionary dynamics. It is presently impossible to devise mathematical models of CF in its entirety, but it is feasible to design models for many of the distinct drivers of the disease. Building upon these growing yet isolated modeling efforts, we discuss in the following the feasibility of a multi‐scale modeling framework, known as template‐and‐anchor modeling, that allows the gradual integration of refined sub‐models with different granularity. The article first reviews the most important biomedical aspects of CF and subsequently describes mathematical modeling approaches that already exist or have the potential to deepen our understanding of the multitude aspects of the disease and their interrelationships. The conceptual ideas behind the approaches proposed here do not only pertain to CF but are translatable to other systemic diseases.This article is categorized under: Congenital Diseases > Computational Models

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Mathematical modelling of Pseudomonas aeruginosa biofilm growth and treatment in the cystic fibrosis lung

Cited by 13 publications

References 144 publications

Modeling the response of a biofilm to silver-based antimicrobial

Modeling the response of a biofilm to silver-based antimicrobial

Localization of Burkholderia cepacia Complex Bacteria in Cystic Fibrosis Lungs and Interactions with Pseudomonas aeruginosa in Hypoxic Mucus

Mathematical models of cystic fibrosis as a systemic disease

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