In Vivo Synergistic Interaction of Liposome-Coencapsulated Gentamicin and Ceftazidime

Antimicrobial agents may interact synergistically. But to ensure synergy in vivo, the drugs should both be present at the site of infection at sufficiently high concentrations for an adequate period of time. Coencapsulation of the drugs in a drug carrier may ensure parallel tissue distributions. Sin...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2001-07, Vol.298 (1), p.369-375
Main Authors: Schiffelers, Raymond M., Storm, Gert, ten Kate, Marian T., Stearne-Cullen, Lorna E.T., den Hollander, Jan G., Verbrugh, Henri A., Bakker-Woudenberg, Irma A.J.M.
Format: Article
Language:English
Subjects:
Animals
Capsules
Ceftazidime - administration & dosage
Ceftazidime - pharmacology
Drug Resistance, Microbial
Drug Synergism
Drug Therapy, Combination - administration & dosage
Drug Therapy, Combination - pharmacology
Female
Gentamicins - administration & dosage
Gentamicins - pharmacology
Klebsiella Infections - drug therapy
Klebsiella Infections - mortality
Klebsiella pneumoniae - drug effects
Liposomes
Rats
Survival Rate
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Summary:Antimicrobial agents may interact synergistically. But to ensure synergy in vivo, the drugs should both be present at the site of infection at sufficiently high concentrations for an adequate period of time. Coencapsulation of the drugs in a drug carrier may ensure parallel tissue distributions. Since liposomes localize preferentially at sites of infection, this mode of drug delivery could, in addition, increase drug concentrations at the focus of infection. The therapeutic efficacy of gentamicin and ceftazidime coencapsulated into liposomes was examined by monitoring survival in a rat model of an acute unilateral pneumonia caused by antibiotic-susceptible and antibiotic-resistant Klebsiella pneumoniae strains. It is shown that administration of gentamicin in combination with ceftazidime in the free form either as single dose or as 5-day treatment resulted in an additive effect on rat survival in both models. In contrast, targeted delivery of liposome-coencapsulated gentamicin and ceftazidime resulted in a synergistic interaction of the antibiotics in both models. Consequently, liposome coencapsulation of gentamicin and ceftazidime allowed both a shorter course of treatment at lower cumulative doses compared with administration of the antibiotics in the free form to obtain complete survival of rats. Liposomal coencapsulation of synergistic antibiotics may open new perspectives in the treatment of severe infections.
ISSN:0022-3565
1521-0103
DOI:10.1016/S0022-3565(24)29390-3