What Preclinical Data Are Needed to Justify Once‐Daily Therapy?

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Abstract
Before applying in clinical practice once‐daily dosing of antimicrobials, one must take into consideration several factors that may influence the pharmacodynamic interaction between antimicrobials and microbes at the site of infection. The ideal agent should demonstrate rapid concentration‐dependent killing activity and a postantibiotic effect that could allow for a clinically significant delay with levels below the minimal inhibitory concentration before regrowth of the microorganism. The pharmacokinetic properties of the antibiotic should allow for a good therapeutic ratio (concentration/MIC) at the site of infection. To evaluate the importance of dosage schedule on outcome, investigators have to use animal models where peak levels, half‐life, area under the curve, time above MIC in interstitial fluid or infected tissues, and other pharmacodynamic properties can be evaluated simultaneously. The pharmacodynamics of several antibiotics administered at different dosing interval is compared using an animal model of infected fibrin clots. In this model, once‐daily therapy resulted in better killing than other modes of administration. Aminoglycosides and quinolones may be better suited for once‐daily therapy than β‐lactams unless these latter agents have a long half‐life.