DOSAGE REGIMENS OF ANTIBACTERIALS - IMPLICATIONS OF A PHARMACOKINETIC-PHARMACODYNAMIC MODEL

A prominent trend in optimising anti-infective therapy is to prescribe time-dependent antibacterials (e.g. beta-lactams, glycopeptides) usin g short dosing intervals, but to prescribe concentration-dependent ant ibacterials (e.g. aminoglycosides, quinolones) using widely spaced int ervals - even once daily. However, the currently prevailing notion tha t the clinical efficacy of concentration-dependent antibacterials can be improved by lengthening the dosing interval has not been well estab lished. 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 l-compartment pharmacokinetic model with i ntravenous administration, according to the ratio between the dosing i nterval and the half-life of the drug, for a given daily dose. Simulat ions 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-depend ent nature of the antibacterial agent and the susceptibility of the pa thogen, steady-state efficacy will decrease as the dosing interval inc reases, and therefore all antibacterials should ideally be administere d at relatively short dosing intervals compared with their half-life, so that concentrations are below the minimum inhibitory concentration (MIG) as little as possible. Some arguments support the use of a large loading dose for concentration-dependent antibacterials, to rapidly r each steady-state at the infection site (this is also valid for time-d ependent antibacterials), and to avoid the emergence of resistant muta nts. Aminoglycosides are a special case within the class of concentrat ion-dependent antibacterials, because of the possibility of adaptive r esistance in terms of efficacy and of saturable target-organ uptake in terms of toxicity, both of which may support the concept of a long ad ministration interval for these agents. Widely spaced administration o f large doses of antibacterials with little dose-dependent toxicity ma y remain a valuable option, for reasons of cost and convenience, in th e case of high susceptibility of the pathogen. However, in difficult s ituations (e.g. short drug half-life, high MIC of the pathogen, compro mised 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, et c.) to achieve and maintain specific peak and trough concentrations se lected according to the infecting organism and its susceptibility to t he drug.