Dosage Regimens of Antibacterials

Summary

A prominent trend in optimising anti-infective therapy is to prescribe time-dependent antibacterials (e.g. β-lactams, glycopeptides) using short dosing intervals, but to prescribe concentration-dependent antibacterials (e.g. aminoglycosides, quinolones) using widely spaced intervals — even once daily. However, the currently prevailing notion that the clinical efficacy of concentration-dependent antibacterials can be improved by lengthening the dosing interval has not been well established. We integrated the differential equations of a pharmacokinetic/pharmacodynamic model describing the fate of a bacterial population in the presence of an antibacterial agent. We studied the variations of predicted efficacy, using a 1-compartment pharmacokinetic model with intravenous administration, according to the ratio between the dosing interval and the half-life of the drug, for a given daily dose. Simulations were performed using the published in vitro killing curve data of Pseudomonas aeruginosa obtained with tobramycin and ticarcillin. The results suggest that, independent of the time- or concentration-dependent nature of the antibacterial agent and the susceptibility of the pathogen, steady-state efficacy will decrease as the dosing interval increases, and therefore all antibacterials should ideally be administered at relatively short dosing intervals compared with their half-life, so that concentrations are below the minimum inhibitory concentration (MIC) as little as possible. Some arguments support the use of a large loading dose for concentration-dependent antibacterials, to rapidly reach steady-state at the infection site (this is also valid for time-dependent antibacterials), and to avoid the emergence of resistant mutants. Aminoglycosides are a special case within the class of concentration-dependent antibacterials, because of the possibility of adaptive resistance in terms of efficacy and of saturable target-organ uptake in terms of toxicity, both of which may support the concept of a long administration interval for these agents. Widely spaced administration of large doses of antibacterials with little dose-dependent toxicity may remain a valuable option, for reasons of cost and convenience, in the case of high susceptibility of the pathogen. However, in difficult situations (e.g. short drug half-life, high MIC of the pathogen, compromised host defences), optimising therapy using short dosing intervals should be most beneficial, especially when both the dose and the dose interval are adjusted for each patient (bodyweight, renal function, etc.) to achieve and maintain specific peak and trough concentrations selected according to the infecting organism and its susceptibility to the drug.