Review of our Fungal “Players” Opportunistic fungi Newly emerging fungi Antifungals and – Normal flora Fusarium Candida spp. Scedosporidium Anti-Tuberculosis Agents – Ubiquitous in our environment Trichosporin Aspergillus spp. Cryptococcus spp. Mucor spp. Endemic geographically restricted Christine Kubin, Pharm.D., BCPS Blastomyces sp. Clinical Pharmacist, Infectious Diseases Coccidioides sp. Histoplasma sp. NewYork-Presbyterian Hospital Columbia University Medical Center Risk Factors for Fungal Disease Candidiasis Aspergillosis –Antibiotics – Granulocytopenia (↓ Antifungal Agents – Indwelling catheters neutrophil numbers or – Hyperalimentation function) – Multiple abdominal – T-cell dysfunction surgeries hematologic and other malignancies – Prosthetic material organ allograft recipients – Severe burns immunosuppressive – Neoplastic therapy diseases/chemotherapy – Corticosteroids – Immunosuppressive – Chronic granulomatous therapy disease – Diabetes mellitus –AIDS – Extremes of age – Burn patients Fungi An optimal antifungal drug has... Yeasts Moulds Mucormycosis Wide spectrum of activity (rarely septate) Pneumocystis Aspergillus sp. Favorable pharmacokinetic Candida sp. jervici Dimorphic (septate) Rhizopus Rhizomucor profile Histoplasmosis Mucor HOST FUNGUS Cryptococcus Blastomycosis Absidia Adequate in vivo efficacy neoformans Coccidioidomycosis Paracoccidioidomycosis [Zygomycetes] Low rate of toxicity Sporotrichosis Chromoblastomycosis Dermatophytes Low cost Trichophyton Microsporum Miscellaneous Epidermophyton Pseudoallerscheria boydii (Scedosporium apiospermum) Scedosporium prolificans DRUG Penicillium marneffei Fusarium sp. Phaeohyphomycosis (dark walled fungi) 1 Invasive Aspergillosis Mortality Targets of Antifungal Agents Review of 1941 Patients from 50 Studies mannoproteins 100 Yeast 80 β1,3 β1,6 glucans 60 PPL bilayer beta-1,3 glucan synthase chitin Echinocandins 40 - Caspofungin Ergosterol - Micafungin • Polyene antibiotics - Anidulafungin* - Amphotericin B Case Fatality Rate (%) 20 - Lipid-AMB • Azole antifungals - Ketoconazole DNA Synthesis - Itraconazole - Fluctyosine 0 - Fluconazole Overall (1941) BMT (285) Leuk/Lymph (288) Pulm (1153) CNS/Dissem (175) - Voriconazole - Posaconazole* Lin S-J et al, Clin Infect Dis 2001; 32:358-66 * Investigational Systemic Antifungal Agents Amphotericin B By Mechanism of Action A polyene Membrane disrupting Nucleic acid inhibitor Clinical use since 1960 agents – Flucytosine Insoluble in water – Amphotericin B – Solubilized by sodium deoxycholate Glucan synthesis Most broad spectrum antifungal Ergosterol synthesis inhibitors – “gold standard” inhibitors – Echinocandins Pharmacokinetics – Extensively tissue bound –Azoles Highest concentrations in liver, spleen, bone marrow with less in kidneys and lung – Half-life Tissue ~15 days, Plasma ~5 days Amphotericin B Binds to Ergosterol The Promise of a Dynamic Era… and Generates Pores Fluconazole Ketoconazole Caspofungin Mechanism of action Amphotericin B Itraconazole Flucytosine – Binds to ergosterol and alter cell Voriconazole membrane permeability → cell death – Also binds to cholesterol → adverse effects 1950 1960 19701980 1990 2000 Micafungin Lipid amphotericin products Clin Microbiol Rev 1999; 12: 501. 2 Amphotericin B Azole Antifungals Most broad spectrum antifungal – long considered the “gold standard” Imidazoles Clinical activity Pharmacokinetics – Ketoconazole – Candida sp. – Intravenous formulation only C. lusitaniae often resistant – Distribution Triazoles – Cryptococcus neoformans Extensively tissue bound – Itraconazole – Blastomycosis – Half-life – Fluconazole – Histoplasmosis Tissue ~15 days – Voriconazole Plasma ~5 days Voriconazole – Aspergillus sp. N N N CH3 F Mechanism of action OH – Zygomycetes Toxicities – Inhibit ergosterol synthesis through inhibition of F NN Rhizopus sp., Mucor sp., etc. – Nephrotoxicity CYP450-dependent lanosterol 14-α-demethylase F Little to no activity – Infusion Related Reactions Depletion of ergosterol on fungal cell membrane – Aspergillus terreus, (IRRs) Aspergillus nidulans, – Electrolyte Abnormalities Resistance Aspergillus flavus, Fusarium – Thrombophlebitis – ERG 11 mutations (gene encoding 14-α sterol sp., Pseudoallescheria boydii, – Anemia demethylase) leading to overexpression Scedosporium prolificans, – ↑ azole efflux Trichosporon beigelii – ↑ production or alteration 14-α-demethylase Available Lipid-Based Understanding the Candida species Amphotericin B Agents Product Chemical Structure Fluconazole Itraconazole Voriconazole Flucytosine Ampho B Echinocandins Flattened, ribbon-like complex. C. albicans S S S S S S Lipid Complex Molecular ratio (drug:lipid) = 3:7 ABLC; Abelcet® Particle size = 1,600 – 11,000 nm. C. tropicalis S S S S S S C. S S S S S S to R (?) Colloidal Dispersion Elongated disk structure. parapsilosis ABCD; Molecular ratio (drug:lipid) = 1:1 Amphocil® or C. glabrata S-DD to R S-DD to R S to I S S to I S Amphotec® Particle size = 120 - 140 nm. C. krusei R S-DD to R S to I I to R S to I S Liposomal Closed, fluid-filled liposome. L-AmB; Molecular ratio (drug:lipid) = 1:9 C. lusitaniae S S S S S to R S Ambisome® Particle size = 45 - 80 nm. Pappas et al. CID 2004; 38: 161-89. Lipid Amphotericin B Product Azole Antifungals Spectrum of Activity Comparison Organism Ketoconazole Fluconazole Itraconazole Voriconazole Amphotericin B Amphotericin B lipid Amphotericin B colloidal Liposomal amphotericin B Factor complex deoxycholate dispersion (ABCD, (Ambisome) (ABLC, Abelcet®) Yeast Amphotec®) Liposomes, small Particle Micelle Lipid disks Ribbons, sheets C. albicans ++ ++++ +++ ++++ unilamellar vesicles Size (nm) <25 100 500-5000 90 Resistant yeasts + ++ ++ +++ Infusion related toxicity High High Moderate Mild Other yeasts + +++ +++ +++ Nephrotoxicity ++++ ± ± ± Cryptococcus ++ ++++ +++ ++++ Moulds Serum concentrations compared to conventional ↓ ↓ ↑ amphotericin Aspergillus 0 0 +++ ++++ Tissue concentrations Liver: ↑ Liver: ↑ Liver: ↑ Other moulds 0 0 + +++ compared to conventional Lungs: ↔ Lungs: ↑ Lungs: ↔ amphotericin Kidney: ↔ Kidney: ↔ Kidney: ↔ Zygomycetes 0 0 0 0 0.5-1.5 Dosage 3-4 mg/kg/day 5 mg/kg/day 3-5 mg/kg/day mg/kg/day Endemic fungi ++ +++ ++++ +++ 3 Voriconazole Fluconazole Precautions (AND LIMITATIONS?) Adverse effects Favorable pharmacokinetic and toxicity profile – Transient, dose related visual disturbances (30%) – Low mw and high water solubility → rapid absorption and ↑ bioavailability Mechanism unknown – ↓ electrical currents in retina >90% bioavailability (IV and PO interchangeable) – Elevated liver function tests (~13%) – No dependence on low gastric pH May be dose-related – Effectively penetrates CSF (50-90% plasma levels) – Skin reactions (6%) Brain and eye too! – >90% renal excretion Dosing Adverse effects – Intravenous 6 mg/kg IV q12h x 2 doses, then 4 mg/kg IV q12h – Very well tolerated –Oral (>95% bioavailability on empty stomach) Even up to 1600 mg/day <40 kg – 100 mg PO q12h – GI, reversible transaminase elevations >40 kg – 200 mg PO q12h Dose – 100-800 mg/d (max 1600 mg/d) Organ dysfunction 6 mg/kg/d for susceptible strains (400 mg/d) – Renal disease 12 mg/kg/d for S-DD strains (800 mg/d) Oral dosing recommended in patients with CrCL<50 ml/min – IV and oral interchangeable (>90% bioavailability) IV vehicle, sulfobutyl ether beta-cyclodextrin, accumulates – Hepatic disease Maintenance dose should be halved in patients with mild/moderate liver disease Itraconazole Flucytosine (5-FC) LIMITATIONS Drug Interactions Pharmacokinetics – Propensity and extent greater than – Only ionized at low pH → wide interpatient fluconazole variability in plasma concentrations – Substrate of CYP3A4 and inhibitor of – Nonlinear serum PK CYP3A4 Mechanism of action – Extensively liver metabolized Rifampin, phenytoin, phenobarbital Adverse effects CYA – Flucytosine is deaminated to 5-fluorocytosine (5-FC) – Transient GI upset, dizziness, headache IV itraconazole – Incorporated into RNA and disrupts protein synthesis – Hepatotoxicity (~5%) – Formulated in hydroxypropyl-β- – Negative inotrope cyclodextrin – Increases solubility of itraconazole Resistance – Renal dysfunction A 6-fold ↓ cyclodextrin clearance in – Develops during therapy, especially monotherapy pts with CrCL<20 ml/min (therefore Single point mutation not recommended in pts with CrCL<30 ml/min) – Loss of permease necessary for cytosine transport – ↓ activity of UMP pyrophosphorylase or cytosine deaminase Spectrum – Paraccoccidiodomycosis, blastomycosis, histoplasmosis and sporotrichosis, cutaneous and mucosal candidiasis, Aspergillosis Spectrum Dosing – Cryptococcus neoformans – 200 mg IV q12h x 4 doses, then 200 mg IV q24h followed by 200 mg PO q12h oral solution – Candida sp. (except C. krusei) Target troughs >0.5 mcg/mL – Little to no activity against Aspergillus sp. and other molds Voriconazole Flucytosine Second generation synthetic derivative of fluconazole Pharmacokinetics – Addition of methyl group to the propyl backbone – Oral only – Substitution of triazole moiety with a fluropyrimidine group – Distribution CSF levels ~75% of serum levels –Elimination 90% excreted via glomerular filtration Half-life ~3-6 hours – Renal/hepatic disease Dose adjust in renal dysfunction Active against yeast and moulds Adverse effects – Fungicidal in vitro against Aspergillus spp., Scedosporium spp., Fusarium spp. – Dose-dependent bone marrow suppression (↓ WBC, ↓ platelets) – Fungistatic in vitro against Candida spp. – GI (nausea/vomiting/diarrhea) Clinical uses Indications – Cryptococcal meningitis, hepatosplenic