Clinical Pharmacology of Antimycotic Agents for Systemic Fungal Infections

In the present “Kumulativen Habilitationsschrift”, studies on clinical pharmacology of antifungal drugs for treatment of systemic mycoses are consolidated. All these clinical studies were performed in high-risk patients with specific co-morbidities aiming for optimisation of dosing strategies or treatment selection for the respective special patient population. The first part of the “Habilitationsschrift” (paper 1-2) reports on plasma pharmacokinetics of antifungal drugs in Special populations. The second part (paper 3-6) describes target-site penetration and drug distribution of antimycotics in these critically-ill patients. Clinical Importance of Pharmacokinetics of Antifungals The optimal drug for invasive fungal infections would display an adequate spectrum of activity against fungal pathogens, low potential for drug interactions and toxicity, a known pharmacokinetic profile and a good target-site penetration of the drug [45]. The variety of the drugs and the drug classes show advantages and disadvantages in different clinical situations. In the present “Habilitationsschrift” the human plasma and target-site pharmacokinetics of amphotericin B preparations, voriconazole and caspofungin are enlightened in specific clinical situations. In contrast to other drugs for certain diseases, anti-infectives cannot be monitored by the clinical course due to a lagtime in response [46-51]. In fungal infections, timely and appropriate therapy is mandatory for success. Underdosing may result in therapeutic failure. Substance removal is critical in organ replacement therapy such as continuous hemofiltration, hemodialysis or liver support [52-54]. Extracorporeal devices can exert hardly predictable effects on drug disposition [55-59]. Optimizing antibiotic dosage in critically ill patients receiving organ replacement therapies is challenging. Several factors must be considered in antimycotic prescription under organ replacment therapies such as pharmacokinetics, causative microorganism and their minimal inhibitory concentrations, mode of organ replacement therapy, properties and surface area of the membrane applied [60]. Therefore, we studied the pharmacokinetics of caspofungin in patients on renal replacement therapy (paper 1). On the other hand the therapeutic window is narrow for most antifungals. Hence, an increased dose leads to toxicity, such as kidney injury by polyenes [62-68]. Vulnerable populations for drug accumulation are patients with impairment of elimination organs such as renal or liver failure. We evaluated the clinical pharmacokinetics of amphotericin B colloidal dispersion in patients with cholestatic liver failure (paper 2). For these patient populations dose recommendations were not available prior to these two studies (table 2). Drug Penetration to the Site of Infection Fungal infections can affect almost every compartment of the human body. Fungi are either endogenous (e.g. Candida in the gastro-intestinal tract) or exogenous (e.g. Aspergillus or Mucor by inhalation) pathogens. Fungi can spread via blood circulation (e.g. Candidemia) or by local Infiltration (e.g. Zygomyoces). The time course of an antifungal drug as well as its absolute concentrations at the site of infection may differ from those observed in the bloodstream [69]. Sufficient antifungal concentrations at the site of the pathogen are considered to be substantial for therapeutic response [69-71]. The minimal inhibitory concentration of the pathogen for antimicrobial agents gives an indication for the adequate levels which should be reached. Disposition patterns and distribution of antifungal drugs depend on substance factors like protein binding, molecular weight, lipophilicity and charge. Patient characteristics like blood flow, compartment barriers or transporters also play an important role in drug penetration. Therefore, the tissue distribution was studied for amphotericin B preparations (paper 3) and voriconazole (paper 4). The penetration into pleural effusion was assessed for different amphotericin B preparations (paper 5). Pharmacokinetic and pharmacodynamic aspects of amphotericin B lipid formulations were determined in bile fluid of liver transplant patients (paper 6).