Pharmacokinetics and efficacy of liposomal polymyxin B in a murine pneumonia model
Jie He1, Kamilia Abdelraouf, Kimberly R Ledesma
1Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX, USA.
Abstract:
Polymyxin B (PB) is increasingly used as the last treatment for multidrug-resistant (MDR) Gram-negative bacterial infections. In this study, serum and epithelial lining fluid (ELF) pharmacokinetics and the efficacy of a PB liposomal formulation were investigated. Two groups of 24 Swiss Webster mice were intravenously administered PB liposomes or PB aqueous solution at ca. 3 mg/kg. Serum and ELF samples were collected for up to 6 h to quantify major PB components. Three groups of neutropenic mice (n = 6/group) were infected with a clinical MDR Pseudomonas aeruginosa strain followed by intravenous administration of PB liposomes or PB aqueous solution at 3 mg/kg every 6 h or sham (drug-free) liposomes every 6 h. Bacterial burden in animal lung tissues was quantified after 24 h of therapy and was compared using one-way ANOVA. Survival of infected animals over time (n = 10/group) was evaluated by Kaplan-Meier analysis and log-rank test. In the pharmacokinetic study, the AUC ratio in ELF between liposome and aqueous solution groups ranged from 4.6 to 11.1 for various major PB components. In the efficacy study, for strain PA 9019 a significantly lower bacterial burden was seen in the liposomal group (3.8 ± 0.7 vs. 7.9 ± 0.8 log(10)CFU/g in the aqueous solution group), which subsequently prolonged survival of infected animals. In this study, treatment with a PB liposomal formulation yielded higher drug penetration into pulmonary ELF, which resulted in superior efficacy. However, further investigations on the clinical utility of the PB liposomal formulation are warranted.
Insights
A novel liposomal formulation of Polymyxin B (PB) enhances drug delivery to lung fluids, improving treatment of multidrug-resistant Gram-negative infections and prolonging survival in mice.
Area of Science:
- Pharmacology and Pharmaceutical Sciences
- Infectious Diseases
- Drug Delivery Systems
Background:
- Polymyxin B (PB) is a critical last-resort antibiotic for multidrug-resistant (MDR) Gram-negative bacterial infections.
- Optimizing PB delivery to infection sites, such as lung tissues, is crucial for enhancing therapeutic efficacy.
- Liposomal formulations offer a potential strategy to improve drug pharmacokinetics and target site concentration.
Purpose of the Study:
- To evaluate the pharmacokinetics and efficacy of a novel liposomal Polymyxin B (PB) formulation.
- To compare the drug concentration in serum and epithelial lining fluid (ELF) between liposomal and aqueous PB.
- To assess the impact of the liposomal formulation on the treatment of MDR Pseudomonas aeruginosa infection in a murine model.
Main Methods:
- Pharmacokinetic analysis of PB in serum and ELF following intravenous administration of liposomal or aqueous PB in mice.
- Efficacy study in neutropenic mice infected with MDR Pseudomonas aeruginosa, comparing bacterial burden in lung tissue after treatment.
- Survival analysis using Kaplan-Meier and log-rank tests to evaluate the impact of PB formulations on animal survival.
Main Results:
- The liposomal PB formulation demonstrated significantly higher drug concentrations in ELF compared to the aqueous solution (AUC ratio 4.6–11.1).
- Treatment with liposomal PB resulted in a substantially lower bacterial burden in lung tissues compared to aqueous PB.
- Liposomal PB treatment led to prolonged survival of infected mice compared to the aqueous solution.
Conclusions:
- The liposomal Polymyxin B formulation enhances drug penetration into pulmonary epithelial lining fluid, leading to superior antimicrobial efficacy.
- This liposomal formulation shows promise for improving the treatment of severe Gram-negative bacterial infections.
- Further research is warranted to explore the clinical applicability of this advanced PB drug delivery system.
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