Sandrina von Winckelmann

Therapeutic Drug Monitoring of Phenytoin in Critically Ill Patients

Therapeutic drug monitoring of phenytoin is necessary to ensure therapeutic and nontoxic levels. Hypoalbuminemia, renal failure, and interactions with other highly protein‐bound drugs (e.g., valproic acid) alter protein binding of phenytoin. When these conditions are present, free serum concentrations, which represent the pharmacologically active entity, cannot be predicted from total serum concentrations. Besides general alterations in drug distribution and elimination, protein binding is often altered in critically ill patients. Case reports describe phenytoin toxicity secondary to inappropriate dosage adjustments based solely on total serum concentrations in patients with hypoalbuminemia. Free drug measurements and theoretical equations to facilitate the interpretation of total phenytoin serum levels have been introduced. However, they are not widely implemented in clinical practice because evidence of improvements in patient outcomes is limited. Knowledge of the pharmacokinetic properties of phenytoin is indispensable for correct interpretation of total serum concentrations when protein binding is altered. Free serum concentrations should be measured, or theoretically calculated if measurements are unavailable, to avoid misinterpretation of total serum levels and consequent inappropriate adjustments in the dosage of phenytoin in critically ill patients.

Mini-series: II. Clinical aspects. Clinically relevant CYP450-mediated drug interactions in the ICU

BackgroundIn the critically ill, multiple drug therapies for acute and chronic conditions are often used at the same time and adverse drug events occur frequently. Many pharmacological and disease-related factors, e.g. altered renal and hepatic function, catecholamine-related circulatory changes, altered drug volume of distribution, enteral versus parenteral feeding and morbid obesity, along with concomitant multiple drug regimens may account for the wide inter-individual variability in drug exposure and response in critically ill patients and for the high risk for drug–drug interactions to occur. The practicing intensivist must remain aware of the major mechanisms for drug–drug interactions, among which the drug-metabolizing enzyme inhibitory or induction potential of associated chemical entities are paramount. Metabolism-based drug–drug interactions are largely due to changes in levels of drug-metabolizing enzymes caused by one drug, leading to changes in the systemic exposure clearance of another. Among the numerous drug-metabolizing enzymes identified to date, the activity of cytochrome P450s (CYP450) is a critical determinant of drug clearance and appears to be involved in the mechanism of numerous clinically relevant drug–drug interactions observed in critically ill patients.DiscussionThis manuscript will cover a practical overview of clinically relevant CYP450-mediated drug–drug interactions. Medications frequently used in the intensive care unit such as benzodiazepines, immunosuppressive agents, opioid analgesics, certain anticonvulsants, the azoles and macrolides have the potential to interact with CYP450-mediated metabolism and may lead to toxicity or therapeutic failure.

OPAT: proof of concept in a peripheral Belgian hospital after review of the literature

ABSTRACT Since its introduction in the 1970s in the United States, outpatient parenteral antibiotic/antimicrobial therapy (OPAT) has been adopted internationally for long-term intravenous (IV) treatment of stable infectious diseases. The aim is to provide a safe and successful completion of IV antimicrobial treatment at the ambulatory care center or at home without complications and costs associated with hospitalization. OPAT implementation has been accelerated by progress in vascular access devices, newly available antibiotics, the emphasis on cost-savings, as well as an improved patient comfort and a reduced incidence of health care associated infections with a similar outcome. OPAT utilization is supported by an extensive published experience and guidelines of the British Society of Antimicrobial Chemotherapy and the Infectious Diseases Society of America for adults as well as for children. Despite these recommendations and its widespread adoption, in Belgium OPAT is only fully reimbursed and established for cystic fibrosis patients. Possible explanations for this unpopularity include physician unfamiliarity and a lack of uniform funding arrangements with higher costs for the patient. This article aims to briefly review benefits, risks, indications, financial impact for supporting OPAT in a non-university hospital as standard of care. Our experience with OPAT at the ambulatory care center of our hospital and its subsequent recent introduction in the home setting is discussed.