The most important PK/PD parameter for clinical outcome in CF patients was C(max)/MIC. Outcome prediction of AUC(24)/MIC was dependent on the regimen. The increase of P. aeruginosa resistance after once-daily administration is linked to a long dosing interval. More and larger studies are needed to optimize the dosing regimen for maximum clinical outcome with minimum resistance development.

For an adequate dose adjustment of highly protein-bound drugs like ertapenem, knowledge of actual albumin concentrations is necessary. A shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function.

In contrast to patients undergoing regular IHD, in which a dose reduction is required, our data suggest that in patients treated with EDD a standard dose of ertapenem (1 g/day), i.e. dose for patients without renal failure, is required to maintain adequate plasma drug levels.

Traditionally, plasma or serum drug concentrations have been used for the assessment of bioavailability and bioequivalence. Since in the majority of cases the site of drug action is in the tissue rather than the blood, the use of corresponding free, unbound concentrations in the tissue is a much more meaningful approach. This can become especially important for topical drug administrations, where locally active drug concentrations can significantly exceed free concentrations in plasma. The ability to measure these free concentrations at the site of drug action over time makes microdialysis a very valuable tool for the assessment of bioavailability and bioequivalence. This has been recognized by industry and regulatory authorities, resulting in a recommendation of the microdialysis technique as a tool for bioequivalence determination of topical dermatologic products. The aim of this article is to provide an updated review of the microdialysis technique, its applications in skin and soft tissues, and the resulting impact on clinical drug development.

We previously identified Candida albicans Irs4p as an epidermal growth factor substrate 15 homology (EH) domain-containing protein that is reactive with antibodies in the sera of patients with candidiasis and contributes to cell wall integrity, hyphal formation and virulence. In this study, we use a yeast two-hybrid method and co-immunoprecipitation to show that Irs4p physically interacts with the phosphatase Inp51p. Disruption of the Inp51p Asn-Pro-Phe (NPF) motif eliminates the interaction, suggesting that this motif is targeted by Irs4p. Both inp51 and irs4 null mutants exhibit significantly increased levels of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ] without changes in levels of other phosphoinositides. Like the irs4 mutant, the inp51 mutant demonstrates increased susceptibility to cell wall-active agents, impaired hyphal formation and abnormal chitin distribution along hyphal walls during growth within solid agar. Moreover, the inp51 and irs4 mutants overactivate the cell wall integrity pathway as measured by Mkc1p phosphorylation. As anticipated, mortality due to disseminated candidiasis is significantly attenuated among mice infected with the inp51 mutant, and tissue burdens and inflammation within the kidneys are reduced. Hyphal formation and chitin distribution in vivo are also impaired, consistent with observations of embedded growth in vitro. All phenotypes exhibited by the inp51 and irs4 mutants are rescued by complementation with the respective genes. In conclusion, our findings suggest that Irs4p binds and activates Inp51p to negatively regulate PI(4,5)P 2 levels and the cell integrity pathway, and that PI(4,5)P 2 homeostasis is important for coordinating cell wall integrity, hyphal growth and virulence under conditions of cell wall stress.

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The selection of appropriate doses and dosing regimens is extremely important in antimicrobial therapy in order to increase the chances of clinical success and decrease the likelihood of toxic side effects and the development of resistance. Therefore, empirical treatment of bacterial infections is not reliable enough and more rational approaches are needed. Pharmacokinetic/pharmacodynamic (PK/PD) modeling provides a powerful tool to systematically link PK and PD properties in order to predict antimicrobial efficacy. However, commonly used minimum inhibitory concentration (MIC) based PK/PD indices, although easy to obtain, have a number of limitations. Thus, more reliable PK/PD indices need to be developed. The following article provides an overview of the present PK/PD approaches used in anti-infective therapy and discusses their role in improving drug therapy.

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