Impact of pharmacokinetics on the postantibiotic effect exhibited by Pseudomonas aeruginosa following tobramycin exposure: application of an in-vitro model.
The postantibiotic effect (PAE) exhibited by Pseudomonas aeruginosa after exposure to single doses of tobramycin was investigated under various pharmacokinetic conditions using an established in-vitro kinetic model. At equal doses of the antibiotic stimulating an intravenous bolus condition, the effects of varying elimination half-life on PAE were assessed. The PAE was longer when the rate of antibiotic elimination was lower. However, after correcting for the different degrees of antibiotic exposure using the area under the concentration-time curve above the MIC (AUC > MIC), a coherent PAE versus antibiotic exposure profile was obtained. The effects of increasing tobramycin dose and exposure time on PAE were investigated in another series of experiments; PAE was assessed during antibiotic exposure when the exponentially decreasing concentrations were above the MIC, at the MIC and below the MIC. A longer PAE was achieved at higher doses and changes were dependent on both the degree and time of exposure. For all the doses tested, the PAE was longest when the decreasing antibiotic concentrations were near or at the MIC. Shorter PAEs were detected at sub-MIC concentrations and diminished rapidly as antibiotic concentrations continued to decline. Such a decrease in PAE was counteracted by the longer exposure time, so that the total time for which the organism was under the influence of the antimicrobial effects, i.e. the sum of exposure time and PAE, remained steady at sub-MIC concentrations. Under these simulated pharmacokinetic conditions, present data support a substantial impact of pharmacokinetics on PAE. Along with MIC, AUC > MIC can be a useful pharmacokinetic parameter for PAE assessments. Should PAE be a relevant factor in antibiotic chemotherapy, both time and degree of antibiotic exposure would have to be considered.
Department of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Shatin.
Z Y
ZY
Zhu
R C
RC
Li
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014031:Tobramycin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D014031:Tobramycin