title: Pharmacokinetics and efficacy of liposomal polymyxin B in a murine pneumonia model.
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.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.forename: Kamilia
authors.initials: K
authors.lastname: Abdelraouf
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Ledesma
authors.forename: Diana S-L
authors.initials: DS
authors.lastname: Chow
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D058491:Bacterial Load; D004195:Disease Models, Animal; D005260:Female; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008168:Lung / Q000382:microbiology; D051379:Mice; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D011112:Polymyxin B / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D020545:Respiratory Mucosa / Q000737:chemistry; D044967:Serum / Q000737:chemistry; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D008081:Liposomes; D011112:Polymyxin B
keywords: Epithelial lining fluid; Multidrug resistance; Pseudomonas aeruginosa; Pulmonary
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