Projects per year
Abstract
Objectives: Pan-drug-resistant (PDR) Pseudomonas aeruginosa is one of the three top-priority pathogens identified by the WHO, and bacteriophages have been investigated as an alternative therapy. However, knowledge on the pharmacokinetics/pharmacodynamics (PK/PD) of phage therapy is sparse, limiting its clinical applications. This study aimed to evaluate the PK/PD of the antipseudomonal phage øPEV20 in vivo following intravenous administration. Methods: Healthy Sprague-Dawley rats were given øPEV20 as a single intravenous bolus of ~6, 9 and 11-log10PFU/rat. Arterial blood was sampled over 72 h. At 72 h, the animals were killed and multiple tissues were harvested for biodistribution studies. A PK model was developed using the importance sampling algorithm and deterministic simulations with a PD model were performed. Results: A three-compartment model with non-linear clearance described the exposure of øPEV20 in blood. Model evaluation indicated that the model was robust and parameter estimates were accurate. The median (standard error) values of model-predicted PK parameters for VC, VP1, VP2, Q1, Q2, Vm and Km were 111 mL/rat (8.5%), 128 mL/rat (4.97%), 180 mL/rat (4.59%), 30.4 mL/h/rat (19.2%), 538 mL/h/rat (4.97%), 4.39 × 1010 PFU/h/rat (10.2%) and 1.64 × 107 PFU/mL/rat (3.6%), respectively. The distribution of øPEV20 was not homogeneous; there was preferential accumulation in the liver and spleen. Deterministic simulations with a PD model confirmed the importance of the host immune system in facilitating phage-mediated bacterial elimination. Conclusions: We developed a robust PK model to describe the disposition of phages in healthy rats. This model may have significant potential in facilitating future preclinical and clinical PK/PD investigations.
Original language | English |
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Pages (from-to) | 1229-1235 |
Number of pages | 7 |
Journal | Clinical Microbiology and Infection |
Volume | 26 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sept 2020 |
Keywords
- Antibiotic resistance
- Gram-negative bacteria
- Phage therapy
- Pharmacokinetics/Pharmacodynamics
- Pseudomonas aeruginosa
Projects
- 3 Finished
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Bacteriophage therapy increases antibiotic sensitivities in multiply antibiotic resistant Acinetobacter baumannii
Barr, J. (Primary Chief Investigator (PCI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/19 → 31/12/21
Project: Research
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A systems approach to combat the significant antibiotic resistance challenge: Novel therapeutic strategies, mechanistic discoveries, and drug development
Li, J. (Primary Chief Investigator (PCI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/19 → 31/12/23
Project: Research
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Mucus Control – Applying concepts from bacteriophage-mucus interactions.
Barr, J. (Primary Chief Investigator (PCI))
1/01/17 → 31/12/19
Project: Research