Vol. 298, Issue 1, 369-375, July 2001

In Vivo Synergistic Interaction of Liposome-Coencapsulated Gentamicin and Ceftazidime

Raymond M. Schiffelers , Gert Storm, Marian T. ten Kate, Lorna E. T. Stearne-Cullen, Jan G. den Hollander , Henri A. Verbrugh and Irma A. J. M. Bakker-Woudenberg

Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands (R.M.S., M.T.t.K., L.E.T.S.-C., J.G.H, H.V., I.A.J.M.B.-W.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (R.M.S., G.S.); and Department of Internal Medicine, Zuiderziekenhuis, Rotterdam, The Netherlands (J.G.H.)

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.