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Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1994 May;38(5):1090–1095. doi: 10.1128/aac.38.5.1090

Pulmonary retention of free and liposome-encapsulated tobramycin after intratracheal administration in uninfected rats and rats infected with Pseudomonas aeruginosa.

A Omri 1, C Beaulac 1, M Bouhajib 1, S Montplaisir 1, M Sharkawi 1, J Lagacé 1
PMCID: PMC188155  PMID: 8067743

Abstract

The pulmonary residence time of free and liposome-encapsulated tobramycin was studied with uninfected rats and rats infected with Pseudomonas aeruginosa. Chronic infection in lungs was established by intratracheal administration of 10(8) CFU of P. aeruginosa PA 508 prepared in agar beads. After 3 days, a single dose (300 micrograms) of free or liposome-encapsulated tobramycin was given intratracheally to both infected and uninfected rats. At various time intervals (0.25 to 16 h) after drug instillations, the remaining tobramycin was evaluated in blood, lungs, and kidneys by a microbiological assay. Intratracheal instillation of liposome-encapsulated tobramycin resulted in high and sustained levels of tobramycin in lungs of uninfected and infected rats over the 16-h period studied; however, the tobramycin levels were two times higher in uninfected rats. There was no tobramycin detected in the blood or kidneys from these animals. In contrast, the intratracheally instilled free tobramycin was cleared within 3 and 1 h from the lungs of uninfected and infected animals, respectively. These data suggest that the encapsulation of tobramycin in liposomes can result in a significant increase of its residence time within lungs. This study also shows that pulmonary infection was associated with a lowering of tobramycin levels in lungs.

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Selected References

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  1. Abramowsky C. R., Swinehart G. L. The nephropathy of cystic fibrosis: a human model of chronic nephrotoxicity. Hum Pathol. 1982 Oct;13(10):934–939. doi: 10.1016/s0046-8177(82)80056-7. [DOI] [PubMed] [Google Scholar]
  2. Alexander M. R., Berglund E. M., Kasik J. E., Fox A., Chinn W. M. The concentration of tobramycin in bronchial secretions. Chest. 1979 Jun;75(6):675–678. doi: 10.1378/chest.75.6.675. [DOI] [PubMed] [Google Scholar]
  3. Allen T. M., Austin G. A., Chonn A., Lin L., Lee K. C. Uptake of liposomes by cultured mouse bone marrow macrophages: influence of liposome composition and size. Biochim Biophys Acta. 1991 Jan 9;1061(1):56–64. doi: 10.1016/0005-2736(91)90268-d. [DOI] [PubMed] [Google Scholar]
  4. Angus B. L., Carey A. M., Caron D. A., Kropinski A. M., Hancock R. E. Outer membrane permeability in Pseudomonas aeruginosa: comparison of a wild-type with an antibiotic-supersusceptible mutant. Antimicrob Agents Chemother. 1982 Feb;21(2):299–309. doi: 10.1128/aac.21.2.299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barends D. M., Zwaan C. L., Hulshoff A. Improved microdetermination of gentamicin and sisomicin in serum by high-performance liquid chromatography with ultraviolet detection. J Chromatogr. 1981 Feb 13;222(2):316–323. doi: 10.1016/s0378-4347(00)81068-3. [DOI] [PubMed] [Google Scholar]
  6. Barends D. M., Zwaan C. L., Hulshoff A. Micro-determination of tobramycin in serum by high-performance liquid chromatography with ultraviolet detection. J Chromatogr. 1981 Oct 9;225(2):417–426. doi: 10.1016/s0378-4347(00)80289-3. [DOI] [PubMed] [Google Scholar]
  7. Barends D. M., van der Sandt J. S., Hulshoff A. Micro determination of gentamicin in serum by high-performance liquid chromatography with ultraviolet detection. J Chromatogr. 1980 May 9;182(2):201–210. doi: 10.1016/s0378-4347(00)81624-2. [DOI] [PubMed] [Google Scholar]
  8. Beaudry P. H., Marks M. I., McDougall D., Desmond K., Rangel R. Is anti-Pseudomonas therapy warranted in acute respiratory exacerbations in children with cystic fibrosis? J Pediatr. 1980 Jul;97(1):144–147. doi: 10.1016/s0022-3476(80)80155-7. [DOI] [PubMed] [Google Scholar]
  9. Bergeron M. G. Tissue penetration of antibiotics. Clin Biochem. 1986 Apr;19(2):90–100. doi: 10.1016/s0009-9120(86)80054-6. [DOI] [PubMed] [Google Scholar]
  10. Bodem C. R., Lampton L. M., Miller D. P., Tarka E. F., Everett E. D. Endobronchial pH. Relevance of aminoglycoside activity in gram-negative bacillary pneumonia. Am Rev Respir Dis. 1983 Jan;127(1):39–41. doi: 10.1164/arrd.1983.127.1.39. [DOI] [PubMed] [Google Scholar]
  11. Brown R. B., Kruse J. A., Counts G. W., Russell J. A., Christou N. V., Sands M. L. Double-blind study of endotracheal tobramycin in the treatment of gram-negative bacterial pneumonia. The Endotracheal Tobramycin Study Group. Antimicrob Agents Chemother. 1990 Feb;34(2):269–272. doi: 10.1128/aac.34.2.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Brummett R. E. Drug-induced ototoxicity. Drugs. 1980 Jun;19(6):412–428. doi: 10.2165/00003495-198019060-00002. [DOI] [PubMed] [Google Scholar]
  13. Cash H. A., Woods D. E., McCullough B., Johanson W. G., Jr, Bass J. A. A rat model of chronic respiratory infection with Pseudomonas aeruginosa. Am Rev Respir Dis. 1979 Mar;119(3):453–459. doi: 10.1164/arrd.1979.119.3.453. [DOI] [PubMed] [Google Scholar]
  14. Demaeyer P., Akodad E. M., Gravet E., Schietecat P., Van Vooren J. P., Drowart A., Yernault J. C., Legros F. J. Disposition of liposomal gentamicin following intrabronchial administration in rabbits. J Microencapsul. 1993 Jan-Mar;10(1):77–88. doi: 10.3109/02652049309015314. [DOI] [PubMed] [Google Scholar]
  15. Di Rocco P. H., Nacucchio M. C., Sordelli D. O., Mancuso F., Hooke A. M. The effect of liposomal cefoperazone against Pseudomonas aeruginosa in a granulocytopenic mouse model of acute lung infection. Infection. 1992 Nov-Dec;20(6):360–364. doi: 10.1007/BF01710685. [DOI] [PubMed] [Google Scholar]
  16. Govan J. R., Harris G. S. Pseudomonas aeruginosa and cystic fibrosis: unusual bacterial adaptation and pathogenesis. Microbiol Sci. 1986 Oct;3(10):302–308. [PubMed] [Google Scholar]
  17. Govan J. R., Nelson J. W. Microbiology of cystic fibrosis lung infections: themes and issues. J R Soc Med. 1993;86 (Suppl 20):11–18. [PMC free article] [PubMed] [Google Scholar]
  18. Hoiby N. Pseudomonas aeruginosa infection in cystic fibrosis. Diagnostic and prognostic significance of pseudomonas aeruginosa precipitins determined by means of crossed immunoelectrophoresis. A survey. Acta Pathol Microbiol Scand Suppl. 1977;(262):1–96. [PubMed] [Google Scholar]
  19. Hutabarat R. M., Unadkat J. D., Kushmerick P., Aitken M. L., Slattery J. T., Smith A. L. Disposition of drugs in cystic fibrosis. III. Acetaminophen. Clin Pharmacol Ther. 1991 Dec;50(6):695–701. doi: 10.1038/clpt.1991.209. [DOI] [PubMed] [Google Scholar]
  20. Juliano R. L., McCullough H. N. Controlled delivery of an antitumor drug: localized action of liposome encapsulated cytosine arabinoside administered via the respiratory system. J Pharmacol Exp Ther. 1980 Aug;214(2):381–387. [PubMed] [Google Scholar]
  21. Jurima-Romet M., Shek P. N. Lung uptake of liposome-entrapped glutathione after intratracheal administration. J Pharm Pharmacol. 1991 Jan;43(1):6–10. doi: 10.1111/j.2042-7158.1991.tb05438.x. [DOI] [PubMed] [Google Scholar]
  22. Lagacé J., Dubreuil M., Montplaisir S. Liposome-encapsulated antibiotics: preparation, drug release and antimicrobial activity against Pseudomonas aeruginosa. J Microencapsul. 1991 Jan-Mar;8(1):53–61. doi: 10.3109/02652049109021857. [DOI] [PubMed] [Google Scholar]
  23. Lam J., Chan R., Lam K., Costerton J. W. Production of mucoid microcolonies by Pseudomonas aeruginosa within infected lungs in cystic fibrosis. Infect Immun. 1980 May;28(2):546–556. doi: 10.1128/iai.28.2.546-556.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Liu F. Y., Shao Z., Kildsig D. O., Mitra A. K. Pulmonary delivery of free and liposomal insulin. Pharm Res. 1993 Feb;10(2):228–232. doi: 10.1023/a:1018934810512. [DOI] [PubMed] [Google Scholar]
  25. Luft F. C., Kleit S. A. Renal parenchymal accumulation of aminoglycoside antibiotics in rats. J Infect Dis. 1974 Dec;130(6):656–659. doi: 10.1093/infdis/130.6.656. [DOI] [PubMed] [Google Scholar]
  26. Lyon M. D., Smith K. R., Saag M. S., Cloud G. A., Cobbs C. G. In vitro activity of piperacillin, ticarcillin, and mezlocillin alone and in combination with aminoglycosides against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1986 Jul;30(1):25–30. doi: 10.1128/aac.30.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Marks M. I. The pathogenesis and treatment of pulmonary infections in patients with cystic fibrosis. J Pediatr. 1981 Feb;98(2):173–179. doi: 10.1016/s0022-3476(81)80631-2. [DOI] [PubMed] [Google Scholar]
  28. Meisner D., Pringle J., Mezei M. Liposomal pulmonary drug delivery. I. In vivo disposition of atropine base in solution and liposomal form following endotracheal instillation to the rabbit lung. J Microencapsul. 1989 Jul-Sep;6(3):379–387. doi: 10.3109/02652048909019920. [DOI] [PubMed] [Google Scholar]
  29. Nacucchio M. C., Gatto Bellora M. J., Sordelli D. O., D'Aquino M. Enhanced liposome-mediated antibacterial activity of piperacillin and gentamicin against gram-negative bacilli in vitro. J Microencapsul. 1988 Oct-Dec;5(4):303–309. doi: 10.3109/02652048809036726. [DOI] [PubMed] [Google Scholar]
  30. Padmanabhan R. V., Gudapaty R., Liener I. E., Schwartz B. A., Hoidal J. R. Protection against pulmonary oxygen toxicity in rats by the intratracheal administration of liposome-encapsulated superoxide dismutase or catalase. Am Rev Respir Dis. 1985 Jul;132(1):164–167. doi: 10.1164/arrd.1985.132.1.164. [DOI] [PubMed] [Google Scholar]
  31. Pedersen S. S., Koch C., Høiby N., Rosendal K. An epidemic spread of multiresistant Pseudomonas aeruginosa in a cystic fibrosis centre. J Antimicrob Chemother. 1986 Apr;17(4):505–516. doi: 10.1093/jac/17.4.505. [DOI] [PubMed] [Google Scholar]
  32. Pennington J. E. Penetration of antibiotics into respiratory secretions. Rev Infect Dis. 1981 Jan-Feb;3(1):67–73. doi: 10.1093/clinids/3.1.67. [DOI] [PubMed] [Google Scholar]
  33. Poste G., Papahadjopoulos D. The influence of vesicle membrane properties on the interaction of lipid vesicles with cultured cells. Ann N Y Acad Sci. 1978;308:164–184. doi: 10.1111/j.1749-6632.1978.tb22021.x. [DOI] [PubMed] [Google Scholar]
  34. Rider E. D., Ikegami M., Jobe A. H. Localization of alveolar surfactant clearance in rabbit lung cells. Am J Physiol. 1992 Aug;263(2 Pt 1):L201–L209. doi: 10.1152/ajplung.1992.263.2.L201. [DOI] [PubMed] [Google Scholar]
  35. Siegenthaler W. E., Bonetti A., Luthy R. Aminoglycoside antibiotics in infectious diseases. An overview. Am J Med. 1986 Jun 30;80(6B):2–14. doi: 10.1016/0002-9343(86)90473-0. [DOI] [PubMed] [Google Scholar]
  36. Smith B. R., LeFrock J. L. Bronchial tree penetration of antibiotics. Chest. 1983 Jun;83(6):904–908. doi: 10.1378/chest.83.6.904. [DOI] [PubMed] [Google Scholar]
  37. Szoka F., Jr, Papahadjopoulos D. Comparative properties and methods of preparation of lipid vesicles (liposomes). Annu Rev Biophys Bioeng. 1980;9:467–508. doi: 10.1146/annurev.bb.09.060180.002343. [DOI] [PubMed] [Google Scholar]
  38. Valcke Y. J., Pauwels R. A. Pharmacokinetic evaluation of tobramycin in the alveolar lining fluid of the rat after endotracheal administration. Am Rev Respir Dis. 1991 Nov;144(5):1199–1201. doi: 10.1164/ajrccm/144.5.1199. [DOI] [PubMed] [Google Scholar]
  39. Valcke Y., Pauwels R., Van der Straeten M. The penetration of aminoglycosides into the alveolar lining fluid of rats. The effect of airway inflammation. Am Rev Respir Dis. 1990 Nov;142(5):1099–1103. doi: 10.1164/ajrccm/142.5.1099. [DOI] [PubMed] [Google Scholar]
  40. Wilmott R. W., Tyson S. L., Matthew D. J. Cystic fibrosis survival rates. The influences of allergy and Pseudomonas aeruginosa. Am J Dis Child. 1985 Jul;139(7):669–671. doi: 10.1001/archpedi.1985.02140090031019. [DOI] [PubMed] [Google Scholar]
  41. Wood R. E., Boat T. F., Doershuk C. F. Cystic fibrosis. Am Rev Respir Dis. 1976 Jun;113(6):833–878. doi: 10.1164/arrd.1976.113.6.833. [DOI] [PubMed] [Google Scholar]
  42. Yoshimura F., Nikaido H. Permeability of Pseudomonas aeruginosa outer membrane to hydrophilic solutes. J Bacteriol. 1982 Nov;152(2):636–642. doi: 10.1128/jb.152.2.636-642.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]

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