Transcript Antifungals - ACH Pediatric Residents

ANTIFUNGALS
Terri Hamlin, Pharmacy
May 2011
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

MYCOLOGY 101
Yeasts:
 Candida, Cryptococcus
 Moulds (filamentous fungi):
 Aspergillus
 Dimorphic fungi:
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
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Blastomyces, Coccidioides, Histoplasmosis
Keratinophylic fungi:

trychophyton, microsporin, epidermophyton
ANTIFUNGAL CLASSES
Polyene macrolides
 Azoles
 Echinocandins
 Others

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

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
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
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AMPHO B – ADR’S

Nephrotoxicity, 80%

Dose dependent decrease in GFR and a direct
vasoconstrictive effect on afferent renal arterioles
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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

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

AMPHOTERICIN – ADR’S

Infusion related, affects 80-90%
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Fever, chills, rigors
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Hypotension

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Premed w/ acetaminophen, diphenhydramine,
hydrocortisone, meperidine
Premed with saline bolus
Heme
anemia, hypochromic, normocytic – reversible w/ d/c
 thrombocytopenia


check CBC daily
AMPHO B – DRUG INTERACTIONS

Additive nephrotoxicity
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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;772-784
AMPHO B (CONVENTIONAL) - FUNGIZONE®
Introduced in 1958
 Dose: 0.5-1.5 mg/kg/day usually once daily
 Administer over 2-4 hours
 Premed to alleviate infusion related toxicities

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
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LIPOSOMAL AMPHOTERICIN B AMBISOME®
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

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
AZOLES - SYSTEMIC
Ketoconazole
 Fluconazole
 Itraconazole
 Voriconazole
 Posaconazole
 Ravuconazole

AZOLES - PHARMACOLOGY
Interfere with synthesis and permeability of
fungal cell wall membranes
 Inhibit fungal CYP-450 enzymes responsible for
conversion of lanosterol to ergosterol
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Also inhibits human CYP-450 enzymes leading to the
many drug interactions seen with this antifungal
class
Fungistatic
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

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AZOLES – DRUG INTERACTIONS
CYP enzyme inhibitors
 Increases levels of other enzyme substrates
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Phenytoin, carbamazepine, phenobarbital
Midazolam
Rifampin
Cyclophosphamide
Cisapride – prolonged QT, Torsade
Oral hypoglycemic agents
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%
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Lots of drug interactions
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 200-400
mg/day
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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
FLUCONAZOLE – COMMON USES

oncology antifungal prophylaxis
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NICU antifungal prophylaxis
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3 mg/kg once daily up to 200 mg/day
Infants <1000g, w/ CVC/intubated
Treatment of Candida albicans infections
Oropharyngeal, esophageal
 GU – renal excretion
 Candidemia, disseminated
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Up to 12 mg/kg/day given once daily
FLUCONAZOLE – ADR’S

Well tolerated
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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
FLUCONAZOLE – DRUG INTERACTIONS

CYP inhibitor: 2C9, 2C18, 2C19, 3A3/4 –
increases levels of:
Cyclosporin, tacrolimus – monitor levels
 Phenytoin – monitor levels
 Midazolam – monitor sedation level
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ITRACONAZOLE –SPORANOX 1990
Fungicidal- similar coverage as fluconazole with
addition of Aspergillus
 Available as PO only
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Capsules – with food, requires acidic medium for
absorption
 oral liquid – best absorbed on empty stomach
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Large Vd, extensive tissue distribution, lipid
soluble
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Not in CSF, but in meningeal tissue
Elimination mainly hepatic, T1/2 15-42 hrs
 Potent CYP 3A4 inhibitor – lots of DI’s
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ITRACONAZOLE
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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
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
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Variation in population: poor vs extensive
metabolizers
ADR: dose dependent, reversible visual
disturbances in 20-30%
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
NEW AZOLES: POSACONAZOLE, OTHERS

Posaconazole- Posanol 2007
Covers Aspergillus and Candida
 PO only so far, cherry suspension, tablet form poorly
absorbed compared to susp

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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,
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
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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
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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
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Reported ADR’s based on few patients, so true
picture not fully appreciated yet
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
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Max 70 mg on day 1, max 50 mg thereafter
ADRs: fever (12-26%), phlebitis (12-18%), incr
AST
 Drug Interactions:
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Caspo + Tac = ↓ Tac by 20%
 Caspo + CSA = ↑ caspo by 35%
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MICAFUNGIN – MYCAMINE 2007
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HC indication:
Tx of esophageal or invasive candidiasis,
 Px of fungal inf’n in HSCT
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2-4 mg/kg/day, up to 12 mg/kg/day, ped dose
investigations ongoing, adults 50-150 mg QD
 Metabolized to inactive metabolites
 Fecal elimination
 ADR’s: rash, headache, arthralgias,
hypophosphatemia, nausea, vomiting, increased
AST, ALT, alkaline phosphatase levels
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ANIDULAFUNGIN – ERAXIS 2008
HC indication: candidiasis/candidemia in adult,
non-neutropenic patients
 T1/2 40-50 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
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IDSA GUIDELINES – CANDIDIASIS 2009

Proven candidemia:
L-ampho B, echinocandin
 Fluconazole in less ill pts
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Empiric therapy of suspected candidemia
L-ampho b, caspo, vori if neutropenic
 Fluconazole as an alternative
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Prophylaxis
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Fluconazole, posa, or echinocandin
Neonatal
Conventional ampho b
 Fluconazole as alternative, echinocandins only if
resistance/toxicity
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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
OTHER ANTIFUNGALS
Nystatin
 Miconazole
 Flucytosine
 Terbinafine
 Griseofulvin
 Gentian Violet

NYSTATIN
Polyene – structure similar to amphotericin
 Used topically for tx of Candida infections

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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

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
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TERBINAFINE - LAMISIL
Therapy of dermatomycoses: Trychophyton,
 Oral:

tinea capitis,
 onychomycoses (nail infections)

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Topical:
tinea pedis (athletes foot),
 tinea corporis (ringworm),
 tinea cruris (jock itch)


ADR’s: rashes including TEN, GI, heme, hepatic

Monitor if oral therpy
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

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, estrogenlike effects in children, photosensitivity rxns

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
REFERENCES
Zaoutis TE, Benjamin DK, Steinbach WJ.
Antifungal treatment in pediatric patients. Drug
resistance updates, 2005;8:235-245
 Wong-Berringer A, Kriengkauykiat J. Systemic
antifungal therapy: new options, new challenges.
Pharmacotherapy 2003;23(11):1441-1462.
 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;772-784.

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:
2009 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.
