Optimal adaptive control of pharmacodynamic effects with aminoglycoside antibiotics: a required approach for the future.

Many factors are considered in designing optimal drug regimens, including dose, route of administration, and the frequency and rate of administration. It is evident that the first parameter to be considered in dosage regimen determinations is the pharmacokinetics of the drug in the treated patient, or more extensively in the corresponding specific population of patients characterized by a similar pathophysiological status, e.g. neutropenics, ICU patients, subjects with renal insufficiency, children, geriatrics... Therefore, over the last two decades, pharmacokinetic principles have widely, and almost exclusively influenced the optimal adaptative control of antibiotics with a small therapeutic index. The large number of available new drugs associated with medical progress, specially in considering the increase of surviving patients with severe diseases or precarious physiopathological status (e.g., neutropenia, AIDS, ICU patients ...) have demonstrated the limits of this approach and pointed out the necessity of the determination of suitable parameters reflecting the in vivo efficacy. Thus, the search for pharmacodynamic parameters that can be accurately related to pharmacokinetic profiles in patients becomes a major tool. The progress in measurement of antibiotics and the additional dimension of the antibiotic's efficacy evaluation based on the analysis of the time course of the antibacterial effects, have provided the basis for the coupled evaluation of pharmacokinetics and pharmacodynamics of antibiotics, which has been largely assessed by in vivo animal models. In an attempt to propose a methodology that can provide information directly applicable to patients to be treated, we have developed a human in vivo/ex vivo model of analysis of the pharmacodynamics of antibiotics. This model has been applied to several drugs and particularly to aminoglycosides. It allows one to have a more rational evaluation of the dose-concentration-effect relations for antibiotics in man. The pharmacodynamics of aminoglycosides is characterized by a strong concentration dependent bactericidal activity and a significant post-antibiotic effect against Gram-negative bacilli. Experimental animal studies confirmed by investigations in man have shown that in vivo efficacy is enhanced by increasing the Cmax and the AUC of these antibiotics regardless of the possible below-MIC value of the C min. Moreover, the in vivo efficacy seems to be the same whether the total dose of aminoglycoside is given as a once a day dosing or as several doses while the toxic risk appears to be attenuated by the first dosage schedule. These data also emphasize the need for the development of models and software for optimal adaptive control including the pharmacodynamic parameters of antibiotics.