Alteration of postantibiotic effect during one dosing interval of tobramycin, simulated in an in vitro pharmacokinetic model

Abstract

The kinetics of the postantibiotic effect (PAE) during one dosing interval of tobramycin against Staphylococcus aureus and Pseudomonas aeruginosa was investigated. We determined the PAE at different time points during this dosing interval of 12 h in an in vitro pharmacokinetic model simulating human pharmacokinetics in which the half-life of tobramycin was adjusted to 2.4 +/- 0.2 h. Using an enzymatic method to inactivate tobramycin, we determined PAEs in samples extracted from the model at 1, 5, 8, and 12 h, corresponding with tobramycin concentrations of 20, 5, 2, and 1 times the MIC for the test organism. The PAE decreased significantly from 2.5 h at 1 h to 0 h at 12 h. No change in MIC was observed for the strains during the experiments. We conclude that the PAE decreases with decreasing tobramycin concentrations during a 12-h dosing interval and completely disappears after the concentration has reached the MIC for the test organism. On the basis of these observations, the emphasis that is placed on the PAE in discussions about the optimal dosing interval in aminoglycoside therapy is questionable.

Duration and Clinical Relevance of Postantibiotic Effect in Relation to the Dosing Interval

“…Recently, we showed that the PAE completely disappeared during one interval of dosing with tobramycin simulated in an in vitro pharmacokinetic model (5). The PAE determined at the peak concentration (20ϫ the MIC) correlated well with the PAE measured under standard conditions, but it declined to zero at the end of a dosing interval.…”

“…Another explanation might be a growth retardation due to free tobramycin which remains inside the bacteria and which is not removed during the washout phase of the PAE experiment. On the other hand, the disappearance of the PAE, which was observed during one interval of dosing with tobramycin (5), may be a result of the outgrowth of resistant subpopulations of bacteria. Alternatively, the phenomenon may be due to slow diffusion of tobramycin out of the bacteria or may be a result of a fast repair process in the bacteria.…”

Aminoglycoside therapy against Pseudomonas aeruginosa in cystic fibrosis: A review

“…The pharmacokinetics of aminoglycosides in patients with CF has been evaluated extensively [33][34][35][36][37][38][39][40][41][42][43][44]. The volume of distribution per kg body weight is often increased, and the elimination half-life is decreased [40].…”

“…An adjustment of dosing to achieve high serum levels has a significant effect on pulmonary function [39]. If aminoglycosides are given at higher doses, the dosing frequency may be reduced due to the sub-inhibitory MIC effect, the bactericidal concentration-dependent killing and adaptive resistance [41]. Indeed, high aminoglycoside doses given at once-daily intervals have been shown to be less toxic and equally effective when data from four studies comparing once-and three-times-daily aminoglycoside regimens were analysed [37].…”

Novel Approaches to Drug Delivery in Critical Care

“…In vitro data suggests that the PAE decreases with decreasing tobramycin concentrations during a 12hour dosing interval. 39 The optimal empiric dosage of SDD aminoglycoside therapy (3 to 7 mg/kg/day) is also controversial. If SDD aminoglycoside regimens are used, serum concentration monitoring should be used to tailor therapy, especially for patients with fluctuating pharmacokinetic parameters or renal function.…”