JAC Advance Access published online on July 1, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg317
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Faculty of Pharmacy, University
of Montreal, Montreal, QC; MDS
Pharma Services, 2350 Cohen Street,
St-Laurent (Montreal), QC, Canada
* Corresponding author. E-mail: Murray.Ducharme{at}mdsps.com.
Received 4 October 2002
; revised 9 April 2003
; accepted 6 May 2003
Objective: To determine the pharmacokinetics
and efficacy of tobramycin against pulmonary infections of Pseudomonas
aeruginosa in rats after intratracheal administration of conventional
and liposomal formulations. Methods: Male Sprague-Dawley rats were
inoculated with 106 cfu of a mucoid variant of P.
aeruginosa (MIC of tobramycin for PA 508 = 1
mg/L) and tobramycin (conventional or liposomal formulations) was administered
in single (490 µg) and multiple dose
(490 µg during 4 days) experiments.
Rats were killed at multiple time points to determine
the residual cfu of P. aeruginosa and tobramycin
amounts in lungs. Pharmacokinetic parameters were calculated using
a two-compartment model with NONMEM. Results: Mean (±S.D.) elimination half-life (t1/2 Conclusion: The liposomal formulation of tobramycin
promoted drug retention in lungs and improved its efficacy after
multiple treatments.
Keywords: pharmacokinetics, efficacy, liposomal tobramycin, P. aeruginosa
Liposomal tobramycin against pulmonary infections
of
Pseudomonas aeruginosa: a pharmacokinetic and efficacy study following
single and multiple intratracheal administrations in rats
2 Faculty of Pharmacy, University
of Montreal, Montreal, QC
3 MDS
Pharma Services, 2350 Cohen Street,
St-Laurent (Montreal), QC, Canada
) and pulmonary exposure (AUC)
of the conventional formulation were 14.0 ±4.0
h and 663 ±89 µgxh/lungs,
respectively. The pharmacokinetic profile of liposomal tobramycin
was markedly different, with a longer t1/2 (34.4 ±5
h, P < 0.05), resulting in an increased
AUC (3890 ±560 µgxh/lungs, P < 0.05). 
2 analyses
were carried out on cfu data distributed in the following categories:
below 103, 103-105, and
above 105 cfu. In the single dose experiments, approximately
90% of the observations were above 105 cfu for
both formulations. Significant differences in cfu distribution were observed
after multiple treatments, with approximately 10% of the
observations falling below 103 cfu of P. aeruginosa for the conventional formulation
versus 30% for the liposomal formulation.
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