Managing uncertainty in antifungal dosing: antibiograms, therapeutic drug monitoring and drug-drug interactions

Abstract

Purpose of reviewA number of pharmacokinetic and pharmacodynamic factors in critically ill or severely immunosuppressed patients influence the effectiveness of antifungal therapy making dosing less certain. Recent position papers from infectious diseases societies and working groups have proposed methods for dosage individualization of antibiotics in critically ill patients using a combination of population pharmacokinetic models, Monte-Carlo simulation and therapeutic drug monitoring (TDM) to guide dosing. In this review, we examine the current limitations and practical issues of adapting a pharmacometrics-guided dosing approaches to dosing of antifungals in critically ill or severely immunosuppressed populations.Recent findingsWe review the current status of antifungal susceptibility testing and challenges in incorporating TDM into Bayesian dose prediction models. We also discuss issues facing pharmacometrics dosage adjustment of newer targeted chemotherapies that exhibit severe pharmacokinetic drug-drug interactions with triazole antifungals.SummaryAlthough knowledge of antifungal pharmacokinetic/pharmacodynamic is maturing, the practical application of these concepts towards point-of-care dosage individualization is still limited. User-friendly pharmacometric models are needed to improve the utility of TDM and management of a growing number of severe pharmacokinetic antifungal drug-drug interactions with targeted chemotherapies.

Management of Polypharmacy and Potential Drug–Drug Interactions in Patients with Pulmonary Aspergillosis: A 2-Year Study of a Multidisciplinary Outpatient Clinic

“…The heavy polypharmacy resulted in a high rate of overall pDDIs, which were equally distributed between antifungal therapy and co-medications. However, when analyzing the results more deeply, we found that the large majority (around 70%) of red-flag DDIs were mainly driven by voriconazole and involved its potential to (a) increase the toxicity of co-medication by inhibiting drug metabolism (PK-driven DDI) and (b) exert additive effects on QT prolongation with an increased risk of cardiotoxicity (PD-driven DDI) [12][13][14]20]. Nearly 30% of the red-flag pDDIs involved an increased risk of respiratory dysfunction, a condition mainly ascribed to a combination of non-antifungal agents (i.e., isoniazid with fentanyl, peridopril with pregabalin, and propranolol with umeclidinium/vilanterol).…”

“…Indeed, antifungal azoles, which are among the first-line treatment for this disease, are strong inhibitors of cytochrome P450 isoenzymes, resulting in many clinically relevant pharmacokinetic (PK)-driven pDDIs, especially when co-administered with narrow therapeutic index drugs; such immunosuppressants and/or targeted therapies are used for the treatment of hematological malignancies [12]. Additionally, these drugs could also cause some important pharmacodynamic (PD) interactions, such as potential additional effects of voriconazole if combined with other drugs known to cause QT prolongation [12][13][14].…”

Consensus for antifungal stewardship in China (2024 edition)

“…There are many risk factors for breakthrough IFD, mostly including the host, fungal and iatrogenic aspects, e.g., host use of immunosuppressants, resistance to antifungal drugs, inappropriate selection of antifungals or substandard blood concentrations. It is worth noting that the absorption, distribution, metabolism, and clearance of antifungals are easily affected by multiple factors such as host immune status, underlying diseases, co-administration of drugs, infection by inherently resistant fungi or acquired infections during treatment, and antifungal resistance ( 46 ), while breakthrough IFD generally has a poor prognosis. Therefore, this consensus recommends the selection of well-tolerated, broad-spectrum and potent antifungal drugs for treatment.…”

Invasive candidiasis: current clinical challenges and unmet needs in adult populations

“… 109 , 110 Finally, TDM may also be helpful in those cases of treatment failure, breakthrough infections, serious toxicity or those Candida infections caused by species with high minimum inhibitory concentration (MIC). 111 …”