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

Abstract

The influence of half-life on the postantibiotic effect (PAE) of tobramycin against Pseudomonas aeruginosa and Staphylococcus aureus was investigated during one dosing interval. Tobramycin half-lives of 0.5 to 2.5 h were simulated in an in vitro model, and the PAE was determined by an enzymatic inactivation method at different time points, i.e., when the tobramycin concentrations were 20×, 5×, and 1× the MIC. At the time point during therapy when the tobramycin concentrations had declined to 1× the MIC, at a tobramycin half-life of 0.5 h, the times of the PAEs were approximately 0.7 and 1.7 h for P. aeruginosa and S. aureus, respectively, and the PAE disappeared completely at half-lives corresponding to those found in humans (i.e., 2 to 2.5 h). The PAE itself cannot be fully explained by the presence of free intrabacterial tobramycin or the emergence of resistant subpopulations. The explanation for the disappearance of the PAE during the dosing interval may therefore be explained by the repair of sublethal damage. Since the standard method of determining the PAE in animal models is somewhat different from the method used for measurement of the PAE in vitro, the conditions under which the PAE is measured in vivo were also simulated in the in vitro model. This resulted in PAEs longer than those found by the standard method of obtaining in vitro PAE measurements. We conclude that the PAE of tobramycin, as determined by conventional in vitro methods, has virtually no clinical importance. PAEs determined in vivo may have some clinical relevance, but they are probably primarily caused by sub-MIC effects