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Antimicrobial Agents and Chemotherapy, February 2001, p. 464-470, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.464-470.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Therapeutic Efficacy of Liposome-Encapsulated Gentamicin in Rat Klebsiella pneumoniae Pneumonia in Relation to Impaired Host Defense and Low Bacterial Susceptibility to Gentamicin

Raymond M. Schiffelers,1,2 Gert Storm,2 Marian T. ten Kate,1 and Irma A. J. M. Bakker-Woudenberg1,*

Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, Rotterdam,1 and Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht,2 The Netherlands

Received 5 June 2000/Returned for modification 28 August 2000/Accepted 27 October 2000

Long-circulating liposomes (LCL) may be used as targeted antimicrobial drug carriers as they localize at sites of infection. As a result, LCL-encapsulated gentamicin (LE-GEN) has demonstrated superior antibacterial activity over the free drug in a single-dose study of immunocompetent rats with Klebsiella pneumoniae pneumonia. In the present study, the therapeutic efficacy of LE-GEN was evaluated by monitoring rat survival and bacterial counts in blood and lung tissue in clinically relevant models, addressing the issue of impaired host defense and low bacterial antibiotic susceptibility. The results show that in immunocompetent rats infected with the high-GEN-susceptibility K. pneumoniae strain, a single dose of LE-GEN is clearly superior to an equivalent dose of free GEN. Yet complete survival can also be obtained with multiple doses of free GEN. In leukopenic rats infected with the high-GEN-susceptible K. pneumoniae strain, free GEN at the maximum tolerated dose (MTD) was needed to obtain survival. However, with the addition of a single dose of LE-GEN to free-GEN treatment, complete survival can be obtained using a sevenfold-lower cumulative amount of GEN than with free-GEN treatment alone. In leukopenic rats infected with low-GEN-susceptible K. pneumoniae cells, free GEN at the MTD did not result in survival. The use of LE-GEN is needed for therapeutic success. Increasing LE-GEN bilayer fluidity resulted in an increased GEN release from the liposomes and hence improved rat survival, thus showing the importance of the liposome lipid composition for therapeutic efficacy. These results warrant further clinical studies of liposomal formulations of aminoglycosides in immunocompromised patients with severe infections.

* Corresponding author. Mailing address: Ee1751, Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31 10 4087666. Fax: 31 10 4089454. E-mail: bakker{at}kmic.fgg.eur.nl.

Antimicrobial Agents and Chemotherapy, February 2001, p. 464-470, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.464-470.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • de Steenwinkel, J. E. M., van Vianen, W., ten Kate, M. T., Verbrugh, H. A., van Agtmael, M. A., Schiffelers, R. M., Bakker-Woudenberg, I. A. J. M. (2007). Targeted drug delivery to enhance efficacy and shorten treatment duration in disseminated Mycobacterium avium infection in mice. J Antimicrob Chemother 60: 1064-1073 [Abstract] [Full Text]  
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