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Terri Hamlin, Pharmacy May 2011

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1 Terri Hamlin, Pharmacy May 2011
Antifungals Terri Hamlin, Pharmacy May 2011

2 Objectives Review the pharmacology of antifungal classes
Review the pharmacokinetics of the agents Review ADR’s and DI’s of the agents Review the fungal coverage of the agents

3 Mycology 101 Yeasts: Candida, Cryptococcus Moulds (filamentous fungi):
Aspergillus Dimorphic fungi: Blastomyces, Coccidioides, Histoplasmosis Keratinophylic fungi: trychophyton, microsporin, epidermophyton

4 Antifungal Classes Polyene macrolides Azoles Echinocandins Others

5 Ampho B – pharmacology Polyene macrolide - 1958
Binds to ergosterol, a major component of fungal cell membranes, leads to cell lysis and death ‘Gold standard’ of antifungal therapy to which all others are compared Concentration dependent killing Prolonged post-antifungal effect

6 Ampho b - Pharmacokinetics
IV only due to poor oral absorption 91-95% plasma protein bound Distributed to many tissues: good concentrations in liver, spleen, kidney, lungs. Poorly into CNS. Primarily biliary excretion Historically test doses and incremental dosing were used No longer recommended, lack of predictive value, delay of therapy

7 Ampho B – antifungal spectrum
Active vs most pathogenic mycoses: Candida – except: C. lusitaniae Aspergillus – except: A. terreus NOT Scedosporium, Fusarium, Trichosporon Resistance remains uncommon Drug of choice for most serious systemic fungal infections

8 Ampho B – ADR’s Nephrotoxicity, 80% Secondary renal effects:
Dose dependent decrease in GFR and a direct vasoconstrictive effect on afferent renal arterioles Decreased glomerular and renal tubular blood flow risk factors: dose, preexisting renal impairment, hyponatremia, hypovolemia, concurrent use of nephrotoxic medications Secondary renal effects: Hypokalemia, hypomagnesemia - check lytes daily Decreased erythropoietin production

9 Ampho b – management of nephrotoxicity
Pretreat with a saline bolus Give dose over longer duration Potassium and magnesium losses often require replacement Monitor SCr and BUN daily at first Permanent loss of renal function is related to total dose Historically aimed for maximum total doses of 3-4 grams Now more therpeutic choices allow for alternatives if needed

10 Amphotericin – ADR’s Infusion related, affects 80-90% Heme
Fever, chills, rigors Premed w/ acetaminophen, diphenhydramine, hydrocortisone, meperidine Hypotension Premed with saline bolus Heme anemia, hypochromic, normocytic – reversible w/ d/c thrombocytopenia check CBC daily

11 Ampho b – Drug interactions
Additive nephrotoxicity Cyclosporin* Tacrolimus Aminoglycosides Vancomycin Foscarnet Diuretics* When nephrotoxic medications were assessed independently, only cyclosporine and diuretics increased the rate of nephrotoxicity Blyth CC, Palasanthiran P, O'Brien TA Pediatrics 2007;119;

Introduced in 1958 Dose: mg/kg/day usually once daily Administer over 2-4 hours Premed to alleviate infusion related toxicities Introduced in 1958

13 Ampho b – lipid products
Encapsulated within lipid structures Developed in an attempt to minimize side effects Theoretically targets drug delivery to infected tissues and minimizes uptake into other tissues Lower rates of nephrotoxicity Liposomal product associated with the lowest incidence of infusion reactions No evidence of superior efficacy despite higher doses

14 Liposomal amphotericin B - Ambisome®

15 Ampho B – lipid formulations
Liposomal – Ambisome® 1997 Dose: 3-5 mg/kg once daily, max 10 mg/kg Less infusion –related toxicities, less renal toxicities Main use is in patients with pre-existing renal impairment Also in those who fail conventional ampho b therapy, or are unable to tolerate

16 Ampho b – lipid formulations
Lipid complex - Abelcet® 1995 nonformulary within AHS sites Dose 2.5 – 5 mg/kg once daily Both are much more $$$ than conventional ampho B Medication safety issue Confusion of dose and formulation Conventional ampho b dosed at 5 mg/kg

17 Azoles - systemic Ketoconazole Fluconazole Itraconazole Voriconazole
Posaconazole Ravuconazole

18 Azoles - pharmacology Interfere with synthesis and permeability of fungal cell wall membranes Inhibit fungal CYP-450 enzymes responsible for conversion of lanosterol to ergosterol Also inhibits human CYP-450 enzymes leading to the many drug interactions seen with this antifungal class Fungistatic

19 Azoles – ADR’s N/V/D – 10% Hepatotoxicity, monitor AST, ALT, alk phos, bili Rashes QT prolongation – in pts with underlying risks, highest w/ voriconazole DI with other high risk drugs Many formulations contain cyclodextrin solubilizer, can accumulate in renal dysfunction Azoles are on the lists as possibly causing or avoid in pts with predisposing conditions

20 Azoles – drug interactions
CYP enzyme inhibitors Increases levels of other enzyme substrates Phenytoin, carbamazepine, phenobarbital Midazolam Rifampin Cyclophosphamide Cisapride – prolonged QT, Torsade Oral hypoglycemic agents Rifampin toxicity: hepatic function: AST, ALT, hematology: CBC

21 ketoconazole Rarely used systemically due to unacceptable adverse effects a/n/v up to 45% Hepatitis: 1 in 10,000-15,000 Impotence, decreased libido, gynecomastia: 5-21% Due to CYP-450 binding causing inhibition of testosterone synthesis in mammalian cells Menstrual irregularities: 16% Alopecia: 8% Lots of drug interactions

22 Fluconazole – diflucan 1990
PO and IV forms are available Bioavailability 90% - PO prefered if patient can tolerate Widely distributed into body fluids, CSF Water soluble: renal excretion dosage adjustment if poor renal function Minimal metabolism T1/2 20h in peds, 30h in adults – once daily dosing Peds dosing 3-12 mg/kg/day, adults mg/day Levels in CSF are 80% of serum urine conc’ns x higher than serum, excellent choice for fungal UTI’s Obese pts: adult recommendations are to use 6-12 mg/kg vs the fixed dose of mg/day Neonates up to q72 hours depending on gestational age

23 Fluconazole – fungal coverage
Yeasts: most Candida species, C. neoformans Not Candida krusei, Candida glabrata According to 2010 CHR antibiogram, 97% of C. Albicans was sensitive to fluconazole NOT Aspergillus

24 Fluconazole – common uses
oncology antifungal prophylaxis 3 mg/kg once daily up to 200 mg/day NICU antifungal prophylaxis Infants <1000g, w/ CVC/intubated Treatment of Candida albicans infections Oropharyngeal, esophageal GU – renal excretion Candidemia, disseminated Up to 12 mg/kg/day given once daily Oncology includes BMT until engraftment, GVHD on hi-dose steroids, acute leukemias on chemo Obese pts: adult recommendations are to use 6-12 mg/kg vs the fixed dose of mg/day Neonates up to q72 hours depending on gestational age

25 Fluconazole – ADR’s Well tolerated GI distress 1-4% Headache 1-2%
Rash 1-2% Increased liver enzymes 1% Rarely: reversible alopecia Category C pregnancy drugs: reports of congenital abnormalities Most ADR’s are dose-related

26 Fluconazole – drug interactions
CYP inhibitor: 2C9, 2C18, 2C19, 3A3/4 – increases levels of: Cyclosporin, tacrolimus – monitor levels Phenytoin – monitor levels Midazolam – monitor sedation level

27 Itraconazole –Sporanox 1990
Fungicidal- similar coverage as fluconazole with addition of Aspergillus Available as PO only Capsules – with food, requires acidic medium for absorption oral liquid – best absorbed on empty stomach Large Vd, extensive tissue distribution, lipid soluble Not in CSF, but in meningeal tissue Elimination mainly hepatic, T1/ hrs Potent CYP 3A4 inhibitor – lots of DI’s Not distributed into CSF but is present in meningeal tissue Eliminated slowly from tissues

28 Itraconazole Negative inotropic effect – caution in pts with heart failure Drawbacks are lack of IV formulation, erratic oral absorption in high risk patients and frequent drug interactions May be more useful as prophylaxis, 2nd line agent for therapy

29 Voriconazole – vfend 2002 Fungicidal vs Aspergillus, fungistatic vs Candida, also effective vs Fusarium, Scedosporium Available as PO and IV IV form contains renally toxic solubilizer, avoid in renal insufficiency Excellent oral absorption Extensively metabolized by CYP2C19 Variation in population: poor vs extensive metabolizers ADR: dose dependent, reversible visual disturbances in 20-30% Photophobia, color vision changes, blurred vision

30 Voriconazole Preferred agent for treatment of invasive aspergillosis
Candida resistant or refractory to fluconazole Ped dose higher than adult dose: up to 14 mg/kg/day vs 8 mg/kg/day div q12 Restricted to ID – consult required Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for imary therapy of invasive for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–15. Pediatric dose not firmly established in the literature

31 New azoles: posaconazole, others
Posaconazole- Posanol 2007 Covers Aspergillus and Candida PO only so far, cherry suspension, tablet form poorly absorbed compared to susp Ravuconazole- not available in Canada T1/2 >100 h, this is the only advantage over other azoles, potential for once weekly prophylaxis Others in development: isavuconazole, PO posaconazole: cherry flavored 40 mg/mL susp avail, indicated for patients aged 13 and up, indicated for prophylaxis of Candida and Aspergillus, tx of refractory aspergillus (to ampho or itra) or pt intolerance to those, and oropharyngeal candidiasis

32 Echinocandins Caspofungin Micafungin Anidulafungin
Introduced in 2001 – first unique mechanism of action vs. fungal infections in 40 years Pharmacology: inhibits a cell wall building enzyme, 1,3 ß-D-glucan synthase, found only in fungal cells ‘Cidal vs Candida, ‘static vs Aspergillus Not useful for Cryptococcus, Fusarium or Zygomycetes

33 Echinocandins - pharmacokinetics
Poor PO absorption, IV only Highly protein bound No CYP enzyme metabolism, so minimal DI’s Hepatic metabolism by O-methyl-transferase Recommended to reduce doses in hepatic impairment T1/2 varies with the agents

34 Echinocandins – adr’s Inhibits 1,3-β-glucan, found only in fungal cell wall, not in human cell Therefore few adverse effects, overall favorable toxicity profile Reported ADR’s based on few patients, so true picture not fully appreciated yet

35 Caspofungin – cancidas 2001
HC indication: Tx esophageal/ or invasive candidiasis, empiric tx FN, 2nd line tx aspergillosis 70 mg/m2 on day 1, followed by 50 mg/m2/day given once daily thereafter Max 70 mg on day 1, max 50 mg thereafter ADRs: fever (12-26%), phlebitis (12-18%), incr AST Drug Interactions: Caspo + Tac = ↓ Tac by 20% Caspo + CSA = ↑ caspo by 35% Walsh 2002, Antimicrob Agents Chemother

36 Micafungin – mycamine 2007 HC indication:
Tx of esophageal or invasive candidiasis, Px of fungal inf’n in HSCT 2-4 mg/kg/day, up to 12 mg/kg/day, ped dose investigations ongoing, adults mg QD Metabolized to inactive metabolites Fecal elimination ADR’s: rash, headache, arthralgias, hypophosphatemia, nausea, vomiting, increased AST, ALT, alkaline phosphatase levels

37 Anidulafungin – Eraxis 2008
HC indication: candidiasis/candidemia in adult, non-neutropenic patients T1/ hours, 99% PPB’g, No hepatic metabolism Undergoes slow chemical degradation Minimal renal excretion, mainly fecal elimination Common ADR’s: diarrhea, incr liver enzymes, hypokalemia Ped dosing: little data: 1.5 mg/kg/day

38 IDSA Guidelines – Candidiasis 2009
Proven candidemia: L-ampho B, echinocandin Fluconazole in less ill pts Empiric therapy of suspected candidemia L-ampho b, caspo, vori if neutropenic Fluconazole as an alternative Prophylaxis Fluconazole, posa, or echinocandin Neonatal Conventional ampho b Fluconazole as alternative, echinocandins only if resistance/toxicity

39 IDSA guidelines – aspergillosis 2008
For suspected or proven Aspergillus infections voriconazole is the 1A recommendation Salvage therapy- consider change of drug class: L-ampho B, echinocandin

40 Other antifungals Nystatin Miconazole Flucytosine Terbinafine
Griseofulvin Gentian Violet

41 Nystatin Polyene – structure similar to amphotericin
Used topically for tx of Candida infections Diaper rash, oropharyngeal candidasis Available as topical cream, oint, vag cream, vag tablet, topical powder, oral susp (swish and swallow), tablet Oral products for ‘topical application’ little systemic absorption Tablet for gut sterilization

42 flucytosine Fluorinated analogue of cytosine, metabolized by fungal cells to analogues that inhibit RNA and DNA synthesis Synergistic with Ampho B: first-line tx for cryptococcal meningitis Good oral absorption, extensive distribution to body tissues, including CSF ADR’s due to conversion to 5-FU: myelosuppression Resistance develops quickly, never used as monotherapy

43 Terbinafine - Lamisil Therapy of dermatomycoses: Trychophyton, Oral:
tinea capitis, onychomycoses (nail infections) Topical: tinea pedis (athletes foot), tinea corporis (ringworm), tinea cruris (jock itch) ADR’s: rashes including TEN, GI, heme, hepatic Monitor if oral therpy

44 Gentian violet Last resort therapy for cutaneous or mucocutaneous Candida infections refractory to other therapies Topical antiseptic/germicidal effect Stains everything purple 0.5-1% solution

45 griseofulvin binds to the proteins involved in microtubule formation and prevents separation of chromosomes at mitosis used in the treatment of ringworm and other fungal infections of the skin and hair Oral susp and tablets CYP1A2 inducer: drug interactions ADR’s: lots, bad: lupus-like syndrome, estrogen- like effects in children, photosensitivity rxns

46 Costs/day – to treat a 20 kg child
Agent Dose Cost Ampho B conv 1 mg/kg/day $28.20 Ampho B liposomal 5 mg/kg/day $220.00 Fluconazole – IV 12 mg/kg/day $13.38 Fluconazole - PO 6 mg/kg/day $12.12 Voriconaxole - IV 8 mg/kg/day $134.40 Voriconazole - PO 100 mg q12h $47.50 Caspofungin 50 mg/m2/day $178.40 Nystatin 500,000 iu po qid $1.00

47 References Zaoutis TE, Benjamin DK, Steinbach WJ. Antifungal treatment in pediatric patients. Drug resistance updates, 2005;8: Wong-Berringer A, Kriengkauykiat J. Systemic antifungal therapy: new options, new challenges. Pharmacotherapy 2003;23(11): Dodds –Ashley EJ. Treatment options for invasive fungal infections. Pharmacotherapy 2006;(6 pt 2):55S-60S. Christopher C. Blyth, Pamela Palasanthiran, Tracey A. O’Brien. Antifungal therapy in children with invasive fungal infections: A systematic review. Pediatrics 2007;119;

48 References – cont’d John Mohr, etal. Current Options in Antifungal Pharmacotherapy. Pharmacotherapy 2008;28(5):614–645. Peter G. Pappas, et al. Clinical Practice Guidelines for the Management of Candidiasis: Update by the Infectious Diseases Society of America. Clinical Infectious Diseases 2009; 48:503–35. Thomas J. Walsh, et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clinical Infectious Diseases 2008; 46:327–60.

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