Podcast
Questions and Answers
What is the primary mechanism of action of voriconazole?
Which of the following drugs would likely interact with voriconazole due to its role as a CYP450 substrate?
What is the recommended loading dose for voriconazole when treating invasive disease?
Which adverse effect is specifically noted to occur at high concentrations of voriconazole?
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What classification of antifungal drug does voriconazole belong to?
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What is the primary mechanism of action of posaconazole?
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How does inflammation affect voriconazole concentrations in patients?
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Which statement is true regarding posaconazole dosing regimens for invasive infections?
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Which of the following factors can significantly reduce drug clearance in patients?
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What class of drugs does posaconazole belong to?
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Which statement about drug-drug interactions with posaconazole is correct?
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What is the expected effect on metabolic rate at higher levels of C-reactive protein?
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How does reduced liver function primarily impact drug metabolism?
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What is a significant characteristic of posaconazole that affects its absorption?
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Which of the following is true regarding echinocandins?
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What reduces drug exposure when using rifamycins?
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What is the primary treatment regimen step for invasive Candida infections?
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What diagnosis method is primarily used to confirm azole drug resistance?
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What is a potential adverse effect of posaconazole?
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What complicating factor related to COVID-19 can increase the risk of fungal infections?
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What does TDM stand for in the context of posaconazole administration?
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Study Notes
WHO Fungal Priority Pathogens List
- Purpose: Guide research, development and public health action regarding fungal infections
- Actions driven:
- Direct research towards priority pathogens
- Facilitate international coordination for research and development
- Monitor and track antifungal development
- Define R&D priorities
- Promote knowledge on fungal infections and resistance
- Inform policymakers on antifungal resistance issues
Types of Fungal Infections
- Mold: Multicellular filaments (hyphae). Causes pulmonary infections. Examples: Aspergillus
- Yeast: Single oval cells reproducing by budding. Often found on moist surfaces like skin, mouth, gut . Examples: Candida
Inhalation of Spores
- Spores easily grow into the brain after landing in sinuses.
- Aspergillus fumigatus is an example of a fungus that spreads this way.
Types of Fungal Infections (Examples)
- Candida
- Aspergillus
- Cryptococcus
- Pneumocystis
Risk Factors for Fungal Infections
- Risk factors and Mechanisms
- Acute leukemia: Increased proliferation of leukemia cells decreased production of normal neutrophils
- Neutropenia: Decreased production of normal neutrophils
- Immunosuppression: Impaired immune response
- Glucocorticoids: Impaired immune response
- Mucositis: Impaired immune response
- Central venous catheters: Impaired immune response, port of entry (Candida)
- Broad spectrum antibiotic use: Increased colonization with Candida
- Genetic factors: Impaired immune response
- HIV/AIDS CD4<200: Impaired immune response
Diagnosis of Invasive Fungal Infections
- Imaging: High resolution CT scan, PET-CT scan, MRI
- Microbiological diagnostics: Microscopy, Culture, Molecular tests
- Clinical signs and symptoms: Fever, chills, cough, blood in cough, shortness of breath, chest/joint pain, headaches, eye symptoms, skin lesions
Diagnosis and Techniques (Timeline)
- Time frame for different diagnoses (e.g. PCR, Antigen detection, HRCT scans, X-rays, Culture/Histology)
Diagnosis of Fungal Infections Difficulty
- Diagnosis Difficulty with varying levels of certainty. Possible, Probable, Proven
Drugs and Mechanism of Action
- Describes the way antifungal drugs work at a cellular level- Targets on fungal cells
- Mechanisms of action of various drugs (Azoles, Echinocandin, 5-FC)
Treatment of Aspergillus Infections
- First choice: Voriconazole- Loading dose IV and PO maintenance dose.
- Alternative: Liposomal Amphotericin B, Isavuconazole, Posaconazole
Effect of a Loading Dose
- Achieves target concentration earlier in treatment compared to a standard dosing regimen
- More crucial for severe/invasive infections, reduces the possibility of delayed treatment.
Treatment of Candida Infections
- Candida pneumonia: Uncommon (aspiration, hematogenous spread). Requires differentiation between colonisation and infection. Treatments including Caspofungin loading dose IV. Anidulafungin loading dose IV, Micafungin intravenous.
- Alternative treatment options including Fluconazole loading dose.
Treatment of Cryptococcus Infections
- Severe pulmonary infection: Induction therapy (2 weeks) using Liposomal amphotericin B, Flucytosine, Fluconazole. Consolidation therapy (8 weeks), and maintenance therapy (12 months) with Fluconazole.
- Mild infection: Fluconazole once daily, for 6-12 months
Treatment of Pneumocystis Infections
- Prophylaxis: Trimethoprim-sulfamethoxazole
- Treatment: Trimethoprim-sulfamethoxazole (preferably IV), for 14 days.
- Alternatives: Dapsone, trimethoprim, clindamycin, primaquine, atovaquone, pentamidine.
Table Antifungal Drugs
- Summary table of various antifungal drugs, their dosing, administraton routes, mechanisms (Renal, Hepatic)
Antifungal Stewardship: Stepdown Therapy
- Starts with broad spectrum treatment
- Collects microbiological cultures
- Switches to narrow spectrum antifungal when results from tests are available
- Transitions from intravenous to oral drugs when possible
Fluconazole
- Drug class: Triazole
- Mechanism of action: Inhibits ergosterol synthesis needed for cell wall production
- Use: Treatment of oral thrush, invasive Candida disease
- Drug-drug interactions: Inhibits CYP3A4, 2C19, and 2C9
- Renal function loss considerations: Adjustments needed, based on Creatinine Clearance (CrCl) levels
Voriconazole
- Drug class: Triazole
- Mechanism of action: Inhibits ergosterol synthesis required for cell wall production
- Use: Against Candida and Aspergillus infections
- Treatment of invasive disease with loading dose and maintenance dose
- Drug-drug interactions: CYP3A4, 2C19, and 2C9
- Adverse Effects: Hepatotoxicity, Visual hallucinations, rash due to photosensitivity
CYP450 Enzymes & Voriconazole
- Different forms of CYP450 enzyme have different effects on voriconazole metabolism
Voriconazole & Liver Function
- Metabolism in the liver and Liver dysfunction
- Reduced metabolism of Voriconazole, and long half life- can lead to high concentrations.
- Non-linear Pharmacokinetics (PK): Reduced metabolism at high concentrations
Inflammation and Cytochrome P450
- Inflammation and cytokines affect drug clearance
- Cytokines lead to reduced drug clearance.
Voriconazole Target Concentration
- Target for success/toxicity and corresponding blood levels
Voriconazole Level and Efficacy
- Plot of success against voriconazole plasma concentration from clinical trial data
Target for Voriconazole TDM
- FAUC/MIC ratio of 20-25, MIC90- A. fumigatus 0.5 mg/L, fAUC 10-12.5 mgh/L, AUC 25-30 mgh/L, Cmin ~ 2mg/L
Using Voriconazole - Metabolite Ratio (Voriconazole-N-oxide) to Guide TDM
- Table summarizing scenarios where voriconazole N-oxide concentrations might vary according to different clinical situations. Different scenarios based on low/high levels
Bayesian Software
- Use of Bayesian dosing strategies to achieve target concentration for voriconazole earlier, which improves the treatment outcome
Summary
- Overview of fungal infections, antifungal therapy, pharmacokinetics, drug-drug interactions, inflammation, adverse effects, and the importance of therapeutic drug monitoring.
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Description
Test your knowledge on voriconazole, an important antifungal medication. This quiz covers its mechanism of action, drug interactions, recommended dosing, adverse effects, and classification.
