Principles and Complexity of Antifungal Therapy
Associate Professor of Medicine, Infectious Diseases
Department of Medical and Surgical Sciences
Infectious Diseases Unit- IRCCS S. Orsola University Hospitals
Alma Mater Studiorum Università di Bologna
Bologna, Italy
Disclosures
- Research funding: Merck & Co Inc., Gilead Sciences
- Speaking: Avir, Gilead
- Consultancy: F2G, Scynexis, Gilead Sciences, Cidara Therapeutics
Objectives
- Identify common pharmacological factors that affect treatment success
- Discuss how uncertainty in antifungal drug dosing can be addressed through PK/PD principles
- Recognise common toxicity problems with antifungals and the general management approach
Antifungal timeline
Current antifungal targets
What factors drive the success of antifungal therapy?
The PK/PD index
Antifungal PK/PD targets associated with efficacy
| Antifungal | Preclinical efficacy target | Clinical efficacy target |
|---|---|---|
| Amphotericin B (AMB) | Cmax/MIC; AUC0-24/MIC | Not established |
| Liposomal AMB | AUC0-24/MIC | Not established |
| Flucytosine (5FC) | Time > MIC | >20-45% Time >MIC |
| Fluconazole | AUC0-24/MIC | fAUC0-24/MIC < 25-100; Cmin 10-15 mg/L |
| Itraconazole | AUC0-24/MIC | Cmin > 0.5 mg/L (prophylaxis); Cmin> 1 mg/L (treatment) |
| Voriconazole | AUC0-24/MIC | fAUC0-24/MIC 25-50; Cmin > 1 mg/L or Cmin/MIC 2-5 mg/L |
| Posaconazole | AUC0-24/MIC | fAUC0-24/MIC 25-50; prophylaxis Cmin > 0.5-0.7 mg/L; treatment Cmin > 1 mg/L |
| Isavuconazole | AUC0-24/MIC | fAUC0-24/MIC 25-50 |
| Echinocandins | AUC0-24/MIC | AUC/MIC > 3000 |
What factors drive the success of antifungal therapy?
What factors drive the success of antifungal therapy?
Intrinsic activity of antifungals
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Acquired antifungal resistance
Acquired resistance mechanisms and detection
Antifungal susceptibility testing- Where do we stand?
Reference methods for yeasts and moulds have been developed by:
European Committee on Antimicrobial Susceptibility Testing (EUCAST)
Clinical Laboratory Standards Institute (CLSI)
- Fungal species and drug-specific susceptibility breakpoints for Candida and Aspergillus spp.
Some commercial phenotypic and molecular tests are approved for detection of common antifungal resistance mechanisms
Need for “in house” antifungal susceptibility testing will increase with the introduction of new antifungals
Pharmacokinetic factors
Antifungal tissue distribution studies
Pharmacokinetic factors
Antifungal pharmacokinetics in the critically-ill
Pharmacokinetic complexity of voriconazole
Triazole therapeutic drug monitoring during
antifungal treatment
| Reference | Fluconazole (mg/L) |
Itraconazole (mg/L) |
Voriconazole (mg/L) |
Posaconazole (mg/L) |
Isavuconazole (mg/L) |
|---|---|---|---|---|---|
| (Gómez-López 2020) | Not routine | 1-4 (HPLC) | 1-6 | >1 | Not routine |
| (Ashbee et al. 2013) | Not routine | 0.5-1 (HPLC) | 1-6 | >1 | Not routine |
| (Scodavolpe et al. 2014) | AUC/MIC > 25; Cmin 10-15 |
>1-2 (HPLC) | 1-4 | 0.5-1.5 | Not routine |
| (M. M. Chau et al. 2014) | Not routine | 0.5-1 (HPLC) | 1-6 | >1 | Not routine |
| (Abdul-Aziz et al. 2020) | Not routine | >0.5-1 (HPLC) | 2-6 | >1 | Not routine |
| (Maggie M. Chau et al. 2021) | Not routine; Cmin >11 |
1-4 (HPLC) | 1-5.5 | >1 | Not routine |
Toxicity
Common antifungal toxicities
Antifungal toxicities: Acute vs. Chronic
Triazole drug interactions
What factors drive the success of antifungal therapy?
Summary
- Pharmacokinetic and pharmacodynamic factors need to be considered when selecting antifungal therapy
- MIC testing and therapeutic drug monitoring (TDM) are important tools used to address pharmacodynamic and pharmacokinetic variability of antifungals.
- Knowledge of PK/PD can be used to individualise patient drug selection and dosing to improve the probability of a positive microbiological/clinical outcome
- Antifungal toxicities and drug interactions are common, and should be anticipated and managed individually depending on the treatment scenario and risks (e.g., acute vs. chronic infections)
References
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