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JAC Advance Access originally published online on September 10, 2007
Journal of Antimicrobial Chemotherapy 2007 60(5):1064-1073; doi:10.1093/jac/dkm341
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Targeted drug delivery to enhance efficacy and shorten treatment duration in disseminated Mycobacterium avium infection in mice

Jurriaan E. M. de Steenwinkel1,*, Wim van Vianen1, Marian T. ten Kate1, Henri A. Verbrugh1, Michiel A. van Agtmael2, Raymond M. Schiffelers3 and Irma A. J. M. Bakker-Woudenberg1

1 Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands 2 Department of General Internal Medicine, VU University Medical Center Amsterdam, PO Box 7057, 1007 MB Amsterdam, The Netherlands 3 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80.082, 3508 TB Utrecht, The Netherlands

Received 26 April 2007; returned 15 June 2007; revised 17 July 2007; accepted 10 August 2007

* Corresponding author. Tel: +31-10-4632174; Fax: +31-10-4633875; E-mail: j.desteenwinkel{at}erasmusmc.nl

Objectives: Improvement of the efficacy of drug treatment in mycobacterial infection by the development and application of targeted drug delivery.

Methods: In disseminated Mycobacterium avium infection in mice, the relative efficacy of the antimycobacterial agents that are currently used in combination therapy was investigated. Next, the effect of the addition of targeted delivery of amikacin to the infected tissues in the initial phase of treatment was studied. Amikacin was chosen because of its unique rapid and high mycobacterial killing capacity. As drug delivery tool, long-circulating sterically stabilized liposomes were used.

Results: Treatment with clarithromycin alone daily (6 days a week) slowly killed most of the mycobacteria in the lung, liver, spleen, inguinal and mesenterial lymph nodes. However, after 24 weeks of treatment, persistence of substantial numbers of mycobacteria in the infected organs was observed. The addition of ethambutol to the clarithromycin regimen did not significantly enhance the efficacy of treatment, neither did rifampicin as a third agent. In contrast, the addition of liposomal amikacin in the initial phase of therapy resulted in rapid and complete elimination of the mycobacteria in all infected organs within 12 weeks of treatment without relapse of infection. As a result, total treatment duration could be significantly reduced to 12 weeks.

Conclusions: In M. avium infection in mice, the approach of targeted drug delivery was successful. The rapid decrease in the mycobacterial load followed by complete killing, including the persistent mycobacteria considered responsible for relapse of infection, allows a significant reduction of the total treatment duration.

Keywords: liposome , carrier , mycobacterial infection , drug targeting


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