Module 13 Fungal Infections

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.