Respiratory Fungal Infections Slides 2024 PDF

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COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been copied and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968. (The Act). The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice. The University of Sydney Page 1 Respiratory fungal infections Presented by Professor Jan-Willem Alffenaar School of Pharmacy Westmead hospital Sydney Infectious Diseases Institute The University of Sydney Page 2  Learning objectives General aspects of respiratory fungal infections Aspects of antifungal therapy Therapeutic drug monitoring The University of Sydney Page 3  WHO fungal priority pathogens list to guide research, development and public health action In response to the rising threat of fungal infections, combined with existing and emerging resistance and treatability issues, WHO developed this first WHO FPPL to: – Direct and drive research efforts towards the pathogens that pose the greatest public health threat and/or have the greatest gaps in knowledge. – Facilitate international coordination and inform investment in R&D to discover new and optimize existing therapeutics and diagnostics, and to improve patient outcomes. – Monitor antifungal development pipeline to track trends and identify gaps. – Define research and development (R&D) priorities to align investments and funding with identified unmet public health needs. – Promote knowledge generation to improve global understanding of and the response to fungal infections and antifungal resistance. – Inform and enable policymakers to design and implement measures to address IFDs and antifungal resistance. The University of Sydney Page 4 https://www.who.int/publications/i/item/9789240060241  Types of fungal infections MOLD; a furry growth on the YEAST; a fungus consisting of surface of organic matter, single oval cells that reproduce caused by fungi in the form of by budding. Commonly on multicellular filaments called normal human skin, in areas of hyphae. Inhaled spores cause moisture, such as the mouth, gut pulmonary infections – e.g. Candida – e.g. Aspergillus Predominantly “non-respiratory infection” Predominantly The University of Sydney “respiratory infection” but it can still happen! Page 5  Inhalation of spores ‘Relatively easy’ to grow into the brain once the spores have landed in sinuses. The University of Sydney Page 6 Types of fungal infections Cryptococcus Candida Pneumocystis Aspergillus The University of Sydney Page 7  Risk factors for fungal infections Risk factor Mechanism Acute leukemia Increased proliferation of leukemia cells leads to decreased production of normal neutrophils Neutropenia decreased production of normal neutrophils Immunosuppression (e.g. transplantation) Impaired immune response Glucocorticoids (>0.3mg/kg/day) Impaired immune response Mucositis Impaired mucosal barrier with translocation of pathogens to the blood (Candida) Central venous catheters Port of entry (Candida) Broad spectrum antibiotic use Increased colonization with Candida Genetic factors Impaired innate and/or adaptive immune response HIV/Aids CD480kg 70mg) – Anidulafungin loading dose IV 200mg followed by 100mg once daily – Micafungin IV 100mg once daily Alternative: – Fluconazole loading dose IV/PO 800 mg (12mg/kg) followed by a maintenance dose of 400mg (6mg/kg) – Not critically ill – Not suitable for fluconazole resistant Candida spp The University of Sydney Page 15 Patterson et al CID 2016, Pappas et al CID 2016  Treatment of Cryptococcus infections Severe pulmonary infection Induction therapy – 2 weeks – Liposomal amphotericin B 10mg/kg ONE DOSE + – Flucytosine 25 mg/kg every 6 hours – Fluconazole 1200 mg once daily (if flucytosine is not available Liposomal amphotericin B 3-4 mg/kg for 14 days). Consolidation therapy – 8 weeks – Fluconazole 400-800mg daily Maintenance therapy – 12 months – Fluconazole 200mg daily Mild infection – Fluconazole 400-800 mg once daily for 6-12 months The University of Sydney Page 16 Chang et al Lancet Infec Dis 2024  Treatment of Pneumocystis infections Prophylaxis – Trimethoprim-sulfamethoxazole 960mg daily, or if not tolerated 960mg 3 times weekly/480mg daily Treatment – Trimethoprim-sulfamethoxazole 30mg/kg 3-4 times daily for 14 days, preferably IV. Alternative: – dapsone with trimethoprim, clindamycin with primaquine, atovaquone, or pentamidine. The University of Sydney Page 17  Table antifungal drugs Loading IV/PO Renal Hepatic Spectrum DDI (effect of dose other drugs on antifungal) fluconazole Y IV/PO Y N + N itraconazole Y IV/PO N Y ++ Y voriconazole Y IV/PO N Y ++ Y posaconazole Y IV/PO N N +++ Y isavuconazole Y IV/PO N N +++ Y caspofungin Y IV N Y ++ N anidulafungin Y IV N N ++ N micafungin N IV N N ++ N amphotericin B N IV Y N +++ N flucytosine N IV (PO*) Y N + N * Not in Australia The University of Sydney Page 18  Antifungal stewardship: Stepdown therapy – Empirical treatment – Microbiological cultures are collected Echinocandin IV – Treatment is started with broad spectrum – Results of microbiological tests become available – Narrow spectrum antifungal – Switch from IV to oral when feasible Fluconazole PO The University of Sydney Page 19  Fluconazole Drug class: triazole Mechanism of action: inhibits ergosterol synthesis required for cell wall Use: against Candida albicans, Cryptococcus -treatment oral thrush: oral 50-200 mg once daily -treatment of invasive Candida disease >loading dose 800mg or IV 12mg/kg once daily >maintenance dose 400mg or IV 6mg/kg once daily Drug-drug interactions: inhibits CYP3A4, 2C19 and 2C9 Renal function loss: – CrCl >50 mL/minute, once daily. – CrCl 21-50 mL/minute, 50% once daily. – CrCl 11-20 mL/minute, 25% once daily. The University of Sydney Page 20  Voriconazole Drug class: triazole Mechanism of action: inhibits ergosterol synthesis required for cell wall Use: against Candida and Aspergillus infections -treatment of invasive disease >loading dose 400mg or IV 6mg/kg twice daily >maintenance dose 200mg or IV 4mg/kg twice daily Drug-Drug interactions: inhibitor & substrate of CYP3A4, 2C19, 2C9 Adverse effects: hepatotoxicity, visual hallucination at high drug concentrations, rash due to photosensitivity The University of Sydney Page 21  CYP450 enzymes & voriconazole CYP450 enzymes: – 2C19*17 => ultra rapid – 2C19*1 => extensive metabolizer – 2C19*2/*3 => poor metabolizer UR1 EM HEM PM 10 ±1.5 The University of Sydney Page 22 1Wang et al Eur J Clin Pharmacol 2009, Lee et al J Clin Pharmacol 2011  Voriconazole & liver function Stopped due to high level Half-life is prolonged! Metabolism in the liver Mild liver dysfunction Reduced metabolism Long t½ Toxic concentrations Non-linear PK reduced metabolism at high concentrations The University of Sydney Page 23 Alffenaar et al Br J Clin Pharmacol 2009 Inflammation and cytochrome P450 and drug concentrations The University of Sydney Page 24 Morgan CLPT 2009  Patient Reduction >80% Inflammation infection cytokines P450 Within 24h Drug clearance The University of Sydney Page 25 Harvey Clin Pharmacol Ther 2014, Morgan Clin Pharmacol Ther 2009, Siewert et al Hepatology 2000 Voriconazole concentrations and inflammation With increased inflammation (higher C-reactive protein) higher voriconazole concentration at the same dose The University of Sydney Page 26 van Wanrooy AAC 2014 Metabolic ratio (how fast metabolized) is lower at higher C-reactive protein levels (measure of severity of inflammation) Study was repeated for posaconazole but CRP had no influence on the posaconazole plasma concentration (not a CYP450 substrate) The University of Sydney Page 27 Veringa et al JAC 2016 , Märtson et al IJAA 2019  Posaconazole Drug class: triazole Mechanism of action: inhibits ergosterol cell wall synthesis Use: Candida and Aspergillus + Mucorales Infection Loading dose Maintenance dose IV Invasive 300mg twice daily 300mg once daily Tablet Invasive 300mg twice daily 300mg once daily Suspension Local 200mg once daily 100mg once daily Invasive 400mg twice daily 400mg twice daily Drug-Drug interactions: -p-glycoprotein (P-gp) efflux substrate (e.g. rifamycins are inducers and reduce drug exposure by 40%) -suspension: proton pump inhibitors reduce absorption Adverse effects: hepatotoxicity The University of Sydney Page 28 Chen et al Drugs 2020, Dekkers et al Curr Fung Inf Rep 2016  Posaconazole (continued) – Formulations: Tablets, Intravenous, Suspension – Lipophilic compound makes absorption difficult – 77% is excreted in feces after intake of the suspension – suspension needs acidic environment/food to be absorbed – modified release tablets: no absorption issues at all, not influenced by food, acidity of the stomach – TDM of posaconazole: for every patient on suspension and for selected patients on tablets for whom you may suspect altered drug exposure The University of Sydney Page 29 Chen et al Drugs 2020, Dekkers et al Curr Fung Inf Rep 2016  Echinocandins – Invasive Candida infections – Few adverse effects – Hardly drug-drug interactions – Caspofungin, anidulafungin, micafungin Caspofungin (molecular structure is not an exam questions) – ONLY intravenous administration – Step down therapy to – Fluconazole (C. albicans) – Voriconazole/posaconazole (other Candida spp) The University of Sydney Page 30  What about azole drug resistance? Patient acquired Environmental resistance resistance Chronic, cavitary All types of or aspergilloma infection Previous therapy No history Multiple Single mutation mutations Abnormal Normal fitness morphology, reduced growth rate – Diagnosis (mutations) – Combination therapy (amphotericin B + azole), step down when no resistance is shown The University of Sydney Page 31 Verweij et al CID 2016  COVID-19 and fungal infections? – COVID-19 +, on ventilator – Diagnosis for aspergillosis – 30-day mortality – OR 11.6 (95%CI 3.24-41.29; p