Podcast
Questions and Answers
What is the primary mechanism of action of voriconazole?
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?
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?
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?
Which adverse effect is specifically noted to occur at high concentrations of voriconazole?
Signup and view all the answers
What classification of antifungal drug does voriconazole belong to?
What classification of antifungal drug does voriconazole belong to?
Signup and view all the answers
What is the primary mechanism of action of posaconazole?
What is the primary mechanism of action of posaconazole?
Signup and view all the answers
How does inflammation affect voriconazole concentrations in patients?
How does inflammation affect voriconazole concentrations in patients?
Signup and view all the answers
Which statement is true regarding posaconazole dosing regimens for invasive infections?
Which statement is true regarding posaconazole dosing regimens for invasive infections?
Signup and view all the answers
Which of the following factors can significantly reduce drug clearance in patients?
Which of the following factors can significantly reduce drug clearance in patients?
Signup and view all the answers
What class of drugs does posaconazole belong to?
What class of drugs does posaconazole belong to?
Signup and view all the answers
Which statement about drug-drug interactions with posaconazole is correct?
Which statement about drug-drug interactions with posaconazole is correct?
Signup and view all the answers
What is the expected effect on metabolic rate at higher levels of C-reactive protein?
What is the expected effect on metabolic rate at higher levels of C-reactive protein?
Signup and view all the answers
How does reduced liver function primarily impact drug metabolism?
How does reduced liver function primarily impact drug metabolism?
Signup and view all the answers
What is a significant characteristic of posaconazole that affects its absorption?
What is a significant characteristic of posaconazole that affects its absorption?
Signup and view all the answers
Which of the following is true regarding echinocandins?
Which of the following is true regarding echinocandins?
Signup and view all the answers
What reduces drug exposure when using rifamycins?
What reduces drug exposure when using rifamycins?
Signup and view all the answers
What is the primary treatment regimen step for invasive Candida infections?
What is the primary treatment regimen step for invasive Candida infections?
Signup and view all the answers
What diagnosis method is primarily used to confirm azole drug resistance?
What diagnosis method is primarily used to confirm azole drug resistance?
Signup and view all the answers
What is a potential adverse effect of posaconazole?
What is a potential adverse effect of posaconazole?
Signup and view all the answers
What complicating factor related to COVID-19 can increase the risk of fungal infections?
What complicating factor related to COVID-19 can increase the risk of fungal infections?
Signup and view all the answers
What does TDM stand for in the context of posaconazole administration?
What does TDM stand for in the context of posaconazole administration?
Signup and view all the answers
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.
Studying That Suits You
Use AI to generate personalized quizzes and flashcards to suit your learning preferences.
Related Documents
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.
