Enhanced activity of liposomal polymyxin B against Pseudomonas aeruginosa in a rat model of lung infection.
The bactericidal effectiveness of liposomal polymyxin B against Pseudomonas aeruginosa was investigated in an animal model of pulmonary infection. Polymyxin B was incorporated into liposomes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol (Chol) (2:1). Lung infection was induced in rats following intratracheal instillation of 10(7) colony-forming units (CFU) of P. aeruginosa (ATCC 27853) embedded in agar beads. Starting on day 3 post-infection, animals were treated daily, for 3 consecutive days, with saline, empty liposomes, free polymyxin B, or liposomal polymyxin B (2mg polymyxin B/kg body weight) by intratracheal instillation; animals were killed 24hr after the third drug instillation. Treatment of infected animals with liposomal polymyxin B significantly reduced the pulmonary bacterial counts (3.7+/-0.4log CFU/paired lungs) as compared with that of free polymyxin B (5.1+/-0.2log CFU/paired lungs). Treatment of infected animals with empty liposomes gave pulmonary bacterial counts similar to those obtained from the saline-treated group. Pulmonary infection with P. aeruginosa also resulted in lung injury as evidenced by increases in wet lung weight and decreases in angiotensin converting enzyme activity as well as increases in myeloperoxidase activity, an index of the inflammatory response. Treatment with free polymyxin B ameliorated the lung injuries induced by the microorganism, a protective effect that was more pronounced in the liposomal polymyxin B-treated group. The levels of polymyxin B in the lungs of the infected animals treated with the liposomal suspension were significantly higher (42.8+/-6.2 microg/paired lungs) compared with those treated with the free drug (8.2+/-0.4 microg/paired lungs). These data suggest that direct delivery of liposomal polymyxin B to the lung can be effective in the treatment of pulmonary infection with P. aeruginosa by enhancing retention of the antibiotic in the lung.
Omri
Abdelwahab
A
Department of Chemistry and Biochemistry, Laurentian University, Ont., P3E 2C6, Sudbury, Canada.
Suntres
Zacharias E
ZE
Shek
Pang N
PN
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D007668:Kidney / Q000378:metabolism; D008081:Liposomes; D008171:Lung Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008826:Microbial Sensitivity Tests; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D011112:Polymyxin B / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D008081:Liposomes; D009195:Peroxidase; D010741:Phospholipases A; D007703:Peptidyl-Dipeptidase A; D011112:Polymyxin B