Overview of Antifungal Drugs in ICU

1. Overview of Antifungal Drugs in ICU ICM seminar 22-06-07 Esther Davis

2. Background - Fungi 3 main groups Moulds � reproduce by spores, which may produce mycotoxins Yeasts � grow by budding, ferment sugars Dimorphic fungi � capable of changing growth

3. Background - fungi May be pathogenic in all exposed patients (eg histoplasma capsulatum, coccidioides immitis) opportunists (eg candida, aspergillus) or cause illness via mycotoxins or allergic reaction after inhalation of spores

4. Fungal infections Superficial mycoses � hair, skin, mucous membranes eg dermatophytosis (ringworm), candida (thrush, intertrigo) and malassezia furfur (pityriasis versicolor) Subcutaneous mycoses � dermis, subcut and adjacent bones eg mycetoma, chromoblastomycosis, sporotrichosis Systemic mycoses � Inhalation =>pulmonary infection=>disseminated (eg histoplasmosis, coccidioidomycosis, blastomycosis) Opportunist � aspergillus, candida, crytococcus. Patients compromised by disease, drugs

5. Fungal infections Risks: Exposure (living conditions, occupation and leisure activities), animal contact, warm climates, geography AIDS Immunosupression (transplant) Broad spectrum antibiotics

6. ICU fungal infections Colonisation Superficial infection Systemic infections BC +ve in 50% invasive candidiasis BAL/brushings +ve <50% pulm aspergillosis Diff distinguishing colonisation and infection

7. Candida infections ICU admission is risk factor Candida albicans or Non-candida albicans sp Risk factors peritonitis abdominal surgery broad spectrum antibiotics TPN multiple lumen catheters prior candida colonisation RRT mechanical ventilation

8. Candida infections Outcome predictors NCA ICU stay renal failure thrombocytopenia haematology malignancy need for ventilation/inotropes APACHE II >20 at time of candidaemia Early antifungal Tx and removal of cvl =>?mortality

9. Antifungal drugs Relatively few (cf antibiotics) Amphotericin B Flucytosine Imidazoles Triazoles Echinocandins

10. Amphotericin B A polyene (derived from streptomyces) effective against yeasts and other fungi by interference with cell membrane function (Nystatin is also a polyene) Not signif absorption po � though can treat GI candidiasis; also top preps for superficial infections Generalised candidiasis, cryptococcal meningitis, aspergillosis � given IV Monitor renal function, K+, Hb Side effects: phlebitis, pyrexia, n+v, anaemia, hypoK+, renal impairment (reversible)

11. Amphotericin B - cont Other formulations: Amphotericin B colloidal dispersion (Amphocil) � ABCD Liposomal (AmBisome) Lipid complex (Abelcet) - ABLC

12. Flucytosine Synthetic pyrimidine derivative active against some yeasts (candida, cryptococcus) Interferes with nucleic acid synthesis Resistance can develop Well absorbed orally, t� 4 hrs, excreted in urine. Good distrib incl csf. Used in combination with amphotericin B for systemic fungal inf (generalised candidiasis, cryptococcal meningitis) after sensitivity testing Side effects: n+v, neutropenia, thrombocytopenia Monitor levels esp with renal impairment

13. Imidazoles Broad spectrum antifungal activity � though probably not for use in serious fungal inf. Miconazole: top, iv (poorly absorbed po). No csf diffusion, metabolised liver Ketoconazole: top, po. Absoprtion with antacids, cimetidine. Altered liver function->fatal hepatotoxicity Itraconazole

14. Triazoles Fluconazole: Chemically similar to imidazole Particularly active vs candida though some species (c krusei, c glabrata) inherently resistance Well absorbed orally. Distrib widely Excreted urine Side effects: nausea, abdominal discomfort, diarrhoea, rash, angio-oedema, anaphylaxis, Stevens-Johnson syn

15. Triazoles - cont Voriconazole: 2nd gen triazole � iv and po Useful flucon resistant invas candida, as well as inv aspergillus (drug of choice vs amphot) No dose adjustment in renal dysfunction � metabolised extensively in liver, so adjust in liver dysfunction Drug interactions with rifampicin, warfarin, tacrolimus, cyclosporin Side effects: photopsia, rash 8%, Stevens-Johnson syn. Altered LFT (?dose-related hepatotoxicity)

16. Echinocandins Caspofungin, micafungin Interfere with �-glucan synthesis in fungal cell wall =>cell lysis. Cidal for candida, static for asperg Poorly absorbed po so given iv Poor cns penetration Side effects: flushing, fever, chills (infusion related), rash, headache, phlebitis. Altered LFT Dose 70 mg daily (50mg daily from day2 if <80kg); or 35mg daily from day 2 if mod liver dysfunction

17. Summary 10% of ICU acquired inf are candida 4% of critically ill deaths find unexpected fungal inf at post-mortem Significant mortality in critically ill