Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: a proof-of-concept study

Lin, Yu Wei; Chang, Yoon Kyung; Rao, Gauri G.; Jermain, Brian; Han, Mei; Zhao, Jinxin; Chen, K.; Wang, J.P.; Barr, Jeremy J.; Schooley, Robert T.; Kutter, Elizabeth; Chan, Hak Kim; Li, J.

doi:10.1016/j.cmi.2020.04.039

Cited by 44 publications

(35 citation statements)

References 23 publications

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“…To address this, we integrated our experimental data ( Fig. 5) with an established PK model for phage administration in a rats (38).…”

Section: Phage Inactivation and Internalisation Influences Pharmacokimentioning

confidence: 99%

“…The model was established from a single-dose PK study performed in healthy rats, following an intravenous bolus of phages. The phage disposition in blood was well characterised using a standard three-compartment PK model (38). In order to evaluate the impact of phage inactivation and internalisation by eukaryotic cells on phage distribution, a fourth-compartment was added to the existing model, representing the epi-and endothelial cell layers (Fig.…”

Section: Phage Inactivation and Internalisation Influences Pharmacokimentioning

confidence: 99%

“…First, natural barriers such as cell layers and mucus can decrease accessibility of phages to sites of infection, thereby necessitating the administration of higher doses to achieve a favourable therapeutic effect. Second, phage clearance has been reported to occur rapidly; sometimes within just minutes to hours following parenteral administration in animal models and patients (14,(34)(35)(36)(37)(38)(39)(40). Phage clearance within the body is thought to be mediated by three main components: 1) Phagocytic cells (41), 2) The Mononuclear Phagocytic System (MPS;…”

Section: Introductionmentioning

confidence: 99%

“…During therapy, large quantities of phage monocultures or cocktails are administered to patients in order to maintain a killing titre to combat a bacterial infection. Once within the body, these phages can have very short half-lives and are actively removed or inactivated by the body (38)(39)(40)44). Following administration during phage therapy, epithelial and endothelial cell layers are amongst the first and most abundant phageeukaryote interactions.…”

Section: Introductionmentioning

confidence: 99%

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Bacteriophage uptake by Eukaryotic cell layers represents a major sink for phages during therapy

Bichet

Chin

Richards

et al. 2020

Preprint

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For over 100 years, bacteriophages have been known as viruses that infect bacteria. Yet it is becoming increasingly apparent that bacteriophages, or phages for short, have tropisms outside their bacterial hosts. During phage therapy, high doses of phages are directly administered and disseminated throughout the body, facilitating broad interactions with eukaryotic cells. Using live cell imaging across a range of cell lines we demonstrate that cell type plays a major role in phage internalisation and that smaller phages (< 100 nm) are internalised at higher rates. Uptake rates were validated under physiological shear stress conditions using a microfluidic device that mimics the shear stress to which endothelial cells are exposed to in the human body. Phages were found to rapidly adhere to eukaryotic cell layers, with adherent phages being subsequently internalised by macropinocytosis and functional phages accumulating and stably persisting intracellularly. Finally, we incorporate these results into an established pharmacokinetic model demonstrating the potential impact of phage accumulation by these cell layers, which represents a major sink for circulating phages in the body. Understanding these interactions will have important implications on innate immune responses, phage pharmacokinetics, and the efficacy of phage therapy.

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“…To address this, we integrated our experimental data ( Fig. 5) with an established PK model for phage administration in a rats (38).…”

Section: Phage Inactivation and Internalisation Influences Pharmacokimentioning

confidence: 99%

Section: Phage Inactivation and Internalisation Influences Pharmacokimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Bacteriophage uptake by Eukaryotic cell layers represents a major sink for phages during therapy

Bichet

Chin

Richards

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Phage therapy has distinct advantages over conventional antibiotic treatment in that phages are (i) a naturally occurring antibacterial, (ii) self-replicating, (iii) self-limiting upon resolution of infection, (iv) effective against both MDR or antibiotic sensitive bacteria, (v) highly specific with low inherent toxicity, (vi) able to co-evolve with bacteria, and (vii) able to penetrate biofilms (5). The potential use of phages as antibacterial agents has been demonstrated in in vitro (6,7), preclinical (8)(9)(10)(11) and in compassionate single case studies (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of inhaled antipseudomonal bacteriophage therapy in mice

Chow

Chang

et al. 2020

Preprint

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Inhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR) Pseudomonas aeruginosa infections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different to antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study was to investigate the in vivo PK and PD profiles of antipseudomonal phage PEV31 delivered by pulmonary route in mice. BALB/c mice were administered phage PEV31 at doses of 107 and 109 PFU by the intratracheal route. Mice (n = 4) were sacrificed at 0, 1, 2, 4, 8 and 24 h post-treatment and various tissues (lungs, kidney, spleen and liver), bronchoalveolar lavage and blood were collected for phage quantification. In a separate study, mice (n = 4) were treated with PEV31 (109 PFU) or PBS at 2 h post-inoculation with MDR P. aeruginosa. Infective PEV31 and bacteria were enumerated from the lungs. In the phage only study, PEV31 titer gradually decreased in the lungs over 24 hours with a half-life of approximately 8 h for both doses. In the presence of bacteria, PEV31 titer increased by almost 2-log10 in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Some phage-resistant colonies were observed from the lung homogenates sampled at 24 h post-phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.

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Pharmacokinetics and Biodistribution of Phages and their Current Applications in Antimicrobial Therapy

Kang,

Bagchi,

Chen

2023

Advanced Therapeutics

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Antimicrobial resistance remains a critical global health concern, necessitating the investigation of alternative therapeutic approaches. With the diminished efficacy of conventional small molecule drugs due to the emergence of highly resilient bacterial strains, there is growing interest in the potential for alternative therapeutic modalities. As naturally occurring viruses of bacteria, bacteriophage (or phage) are being re‐envisioned as a platform to engineer properties that can be tailored to target specific bacterial strains and employ diverse antibacterial mechanisms. However, limited understanding of key pharmacological properties of phage is a major challenge to translating its use from preclinical to clinical settings. Here, this work reviews modern advancements in phage‐based antimicrobial therapy and discusses the in vivo pharmacokinetics and biodistribution of phage, addressing critical challenges in their application that must be overcome for successful clinical implementation.

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Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: a proof-of-concept study

Cited by 44 publications

References 23 publications

Bacteriophage uptake by Eukaryotic cell layers represents a major sink for phages during therapy

Bacteriophage uptake by Eukaryotic cell layers represents a major sink for phages during therapy

Pharmacokinetics and pharmacodynamics of inhaled antipseudomonal bacteriophage therapy in mice

Pharmacokinetics and Biodistribution of Phages and their Current Applications in Antimicrobial Therapy

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