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;

12. AMPHO B (CONVENTIONAL) - FUNGIZONE®
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
Qtdrugs.org
Many formulations contain cyclodextrin solubilizer, can accumulate in renal dysfunction
Azoles are on the qtdrug.org 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.