Targeted drug delivery to enhance efficacy and shorten treatment duration in disseminated Mycobacterium avium infection in mice.
OBJECTIVE
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.
de Steenwinkel
Jurriaan E M
JE
Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. j.desteenwinkel@erasmusmc.nl
van Vianen
Wim
W
Ten Kate
Marian T
MT
Verbrugh
Henri A
HA
van Agtmael
Michiel A
MA
Schiffelers
Raymond M
RM
Bakker-Woudenberg
Irma A J M
IA
D000583:Amikacin / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D017291:Clarithromycin / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D004977:Ethambutol / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D009162:Mycobacterium avium / Q000187:drug effects*; D012293:Rifampin / Q000008:administration & dosage / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
D000995:Antitubercular Agents; D008081:Liposomes; D000583:Amikacin; D004977:Ethambutol; D017291:Clarithromycin; D012293:Rifampin