Influence of pharmacokinetics/pharmacodynamics of antibacterials in their dosing regimen selection

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Date: June 2006
Publisher: Expert Reviews Ltd.
Document Type: Report
Length: 9,602 words

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Author(s): Francesco Scaglione 1 , Luca Paraboni 2


aminoglycosides; AUC/MIC ratio; azalides; [beta]-lactams; clinical efficacy; Cmax /MIC ratio; dosing regimens; fluoroquinolones; glycopeptides; ketolides; macrolides

After the introduction of penicillin for clinical use, traditionally, the choice of an initial antimicrobial dose for a clinical trial is based upon achieving serum concentrations above the minimum inhibitory concentration (MIC) of the target microorganism. Dosing intervals are often chosen roughly based on the serum elimination half-life. These procedures can be said to be based upon 'penicillin mentality' and are founded on the assumption that in vivo antimicrobial efficacy is dependent on the duration of the drug level above the MIC. Subsequent clinical dosing studies may determine the efficacy of higher or lower drug doses, however, rarely would another dosing interval be examined.

Traditional in vitro measurements such as the MIC or minimum bactericidal concentration (MBC), and serum levels of antimicrobials, are used to predict the outcome of antimicrobial therapy. While the measurements of MIC/MBC are a good indication of the potency of an antimicrobial, they do not provide the type of information necessary to determine the optimal drug dose or dosing interval. The MIC test provides information about a drug concentration at a single time point. This provides us with no information about the effect of varying drug concentrations over time or whether there may be microbiological effects that persist after drug exposure.

Recently, the kill rate, maximal kill, 50% effective concentration (EC 50 ), the Hill coefficient and concentrations and times needed to obtain a 3 log 10 decrease in the initial number of viable counts have been studied [1] . In general, these five parameters mirror an antibiotic's bactericidal or bacteriostatic activity as a function of time and/or concentration; in contrast, MICs are only static end points.

On the other side the time course of drug concentrations in the body cannot in itself predict the time course or magnitude of effect. Therefore, it would be more conclusive to correlate a parameter quantifying the kinetics of the antibacterial's in vitro activity with the pharmacokinetics (PKs) of the drug.

Rational antimicrobial therapy is strongly dependent on a basic understanding of the influence of the patient upon to the antibiotic (PK) and the patient's response to the specific drug effects (pharmacodynamics [PDs]).

In recent years, great progress has been made by linking PKs and PDs to allow for a prediction of the dose-concentration relationship and the concentration-effect relationship. In Figure 1 the inter-relationship between drug input (dose), PKs, PDs and clinical effects is schematically conceptualized.

Pharmacodynamic measures of antimicrobial effects

PK/PD relationships are vital in facilitating the translation of microbiological activity into clinical situations and to ensuring that antibiotics achieve a successful outcome. Before analyzing in detail the PK/PD properties of the major class' of antibiotics, it is necessary to remember that only the free or unbound fraction of drug is available for antimicrobial activity [2,3] . Thus, serum protein binding is one of the PK factors that can markedly impact upon antimicrobial efficacy, slowing the elimination...

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Gale Document Number: GALE|A223961047