Antifungals for GIT Infections

Antifungals for GIT Infections

• Antifungals are used to treat fungal infections in the gastrointestinal tract.
• Learning outcomes include identifying antifungal drugs, describing their mechanisms of action, pharmacokinetic considerations, and adverse effects/contraindications for azoles, amphotericin B, and echinocandins.
• Introduction: Antifungal classes like amphotericin B, azoles (fluconazole, voriconazole, miconazole, clotrimazole), and echinocandins (anidulafungin, caspofungin, micafungin) are discussed.

Learning Outcomes

• Identify antifungal drugs used in treating gastrointestinal tract infections.
• Describe the mechanism of action for azoles, amphotericin B, nystatin, and echinocandins.
• Explain pharmacokinetic considerations for azoles, amphotericin B, and echinocandins.
• Describe adverse effects and contraindications for azoles, amphotericin B, and echinocandins.

Introduction to Antifungal Classes

• Amphotercin B: A crucial antifungal.
• Azoles: Fluconazole, voriconazole, miconazole (oral gel), clotrimazole (topical) are examples.
• Echinocandins: Anidulafungin, caspofungin, micafungin

Indications and First/Alternative Choices

• Aspergillosis: Voriconazole is the first choice, with amphotericin B, caspofungin, itraconazole, and posaconazole as alternatives. Use of prophylactic antifungals can affect treatment choices.
• Candidiasis (oropharyngeal/oesophageal): Fluconazole is the first choice, with echinocandins (anidulafungin, caspofungin, micafungin), itraconazole, posaconazole, voriconazole, and amphotericin B as alternatives.
• Candidiasis (systemic): Echinocandins and fluconazole, along with voriconazole and amphotericin B are options.

Mechanism of Action

• Antifungals target fungal cell walls and membranes as well as other fungal components, leading to fungal death.
• Azoles: Inhibit ergosterol synthesis.
• Amphotericin B and Nystatin: Bind to ergosterol, changing membrane permeability.
• Echinocandins: Inhibit synthesis of 1,3-β-D-glucan.

Pharmacokinetic Considerations – Amphotericin B

• Two formulations: amphotericin B deoxycholate (available via intravenous route only) and liposomal amphotericin B (AmBisome), often preferable for better tolerability and reduced toxicity.
• Poor oral bioavailability, hence intravenous route.
• IV administration, lozenges for oral candidiasis.
• High protein binding (up to 99%).
• No dose adjustments needed for renal or hepatic impairment.

Pharmacokinetic Considerations – Azoles

• Fluconazole has the highest oral bioavailability.
• Loading dose followed by a maintenance dose is common.
• Long half-lives, which can influence the time it takes for concentrations to reach steady state.

Pharmacokinetic Considerations – Echinocandins

• Administered intravenously.
• Variable half-lives.
• Variable metabolism properties.
• Poor CYP450 substrates..
• High protein binding (up to 99%).
• Dose reduction possible in moderate hepatic impairment. Avoidance of dose reduction normally for renal impairment.

Adverse Effects & Contraindications – Amphotericin B

• Infusion-related reactions: Fever, chills, muscle spasms, vomiting, headache, and hypotension are possible.
• Slowing infusion rate or pre-treatment with antihistamines and paracetamol is crucial.
• Renal toxicity: Decreased perfusion and tubular injury may occur. Serum creatinine should be monitored.

Adverse Effects & Contraindications – Azoles

• Mild gastrointestinal disturbance, liver enzyme abnormalities, prolonged QT interval, which can lead to arrhythmia.
• Visual side effects and photosensitivity are also potential issues.
• Fluconazole use in pregnancy is classified as Category D.
• Drug-drug interactions due to cytochrome P450 enzyme (CYP) inhibition or induction.

Adverse Effects & Contraindications – Echinocandins

• Generally well-tolerated, with similar adverse effects (AEs) across all echinocandins.
• Mild gastrointestinal upset, liver abnormalities are common.
• Infusion reactions are rare.

Resources

• Australian Medicines Handbook, MIMS Online, UpToDate
• Clinical Pharmacology texts (Brown et al (2019), Rang et al (2020), Katzung (2015))