Download Antifungal agents

Antifungal agents
Soo-youn Moon
Division of Infectious Diseases
Department of Internal Medicine
Kyung Hee University Hospital
Fungus

Yeast



Mold




Round/oval cells that divide by
budding, pseudohyphae & pseudomycelium
Candida spp., Cryptococcus spp.
Tubular structures (hyphae) that grow by
longitudinal extension and branching
A mass of hyphae  mycelium
Aspergillus spp., zygomycetes (Rhizopus, Fusarium spp.)
Dimorphic fungi


Capable of changing growth to either a mycelial or yeast
phase
Histoplasma, Blastomyces, Coccidioides spp.
Structure of fungus
Antifungal agents
Mechanism
Antifungal agents
Drug
Dosage
Cost/day (70kg patient)
Amphotericin B
deoxycholate
0.3-1 mg/kg/day
14802 원
Liposomal
amphotericin B
3-5 mg/kg/day
913360 원
Fluconazole
400-800 mg/day iv/po
88268 원/21360 원
Itraconazole
200 mg/day iv/po
119582 원
Voriconazole
4mg/kg iv q12h or 200 mg po bid
392781 원
Posaconazole
800 mg/day po
Polyenes
Triazoles
Echinocandins
Caspofungin
70 mg iv loading, 50 mg iv q24h
374000원
Micafungin
150 mg iv q24h
47323원
Anidulafungin
100 mg iv q24h
208000원
CID 2006:43:S28-39
POLYENES

Binding to ergosterol  intercalation of cell membrane
 leakage of intracellular cations and proteins





Binding to human cell cholesterol  adverse effect
Only available in IV form
Poorly water soluble
Renal failure, hepatic failure, HD  혈중 농도 영향 (-)
Spectrum: active against most fungi

Primary resistant: A. terreus, Scedosporium apiospermum,
S. prolificans, Trichosporon spp., C. lusitaniae
Amphotericin B deoxycholate


Amphotericin B + 5% DW for 2-4h
Daily dose






Esophageal candidiasis: 0.3 mg/kg
Candidemia: 0.6-1 mg/kg
Cryptococcal meningitis: 0.7-1 mg/kg ± flucytosine
Empirical Tx for persistant NF: 0.5-1 mg/kg
Mucormycosis, invasive aspergillosis: 1-1.5 mg/kg
Toxicity


Nephrotoxicity – saline loading, correction of electrolyte
Infusion related toxicity – testing dose, AAP, steroid
Liposomal amphotericin B

Daily dose


3-5 mg/kg
Reduced nephrotoxicity and
infusion related toxicity
AZOLES

Inhibition of lanosterol 14-α-demethylase 
Accumulation of toxic sterols in cell membrane


Resistance




Cross-inhibition of human CYP450-dependent enzymes 
adverse effects
Drug efflux ↑
14-α-demethylase modification or increase
Cross-resistance
Oral form available

Drug-drug interaction: cytochrome P450

Decreased concentration of azole by


antacids, H2 blocker, sucralfate, omeprazole, didanosine, INH,
RFP, phenytoin, carbamazepine, phenobarbital
Azole increases concentration of

cyclosporine, tacrolimus, phenytoin, sulfonylureas, loratadine,
warfarine, chlordiazepoxide, triazolam, alprazolam, midazolam,
nortryptyline, felodipine, nifedipine, rifabutin, lovastatin,
zidovudine, indinavir, saquinavir, ritonavir, digoxin
CYP3A4
Inhibit
or
Substr
ate
CYP2C8/9
Inhibit
or
Flu
++
Itra
+++
+++
+
Vori
+
+
++
Posa
++
Substr
ate
++
항암제
Busulfan
Vinca alkaloids
Docetaxcel
Cyclophosphamide
CYP2C19
Inhibit
or
Substr
ate
+
+
++
+++
PgP
Inhibit
or
Substr
ate
No
Yes
Yes
Yes
No
No
Yes
Yes
Azoles
항암제 농도
Itraconazole
25% ↑
Voriconazole
↑
Itraconazole
↑
Voriconazole
↑
Itraconazole
↑
Voriconazole
↑
Itraconazole
↑
면역억제제
MPD
Cyclosporin
Tacrolimus
sirolimus
Azoles
농도변화
itraconazole
2-3x ↑
voriconazole
↑?
itraconazole
50% ↑
voriconazole
2x ↑
fluconazole
50%↑
itraconazole
5x ↑
voriconazole
3x ↑
fluconazole
↑
itraconazole
↑↑↑
voriconazole
↑↑↑
fluconazole
↑
주의사항
Dexamethasone으로
변경
Cyclosporin 량 ½로 감
량, 매일 혈중농도 측정
Tacrolimus량 ½로 감량,
매일 혈중 농도 측정
Azole은 금기증
sirolimus 용량 감소
Fluconazole


IV formulation, tablet, syrup
Phamacokinetics




Oral bioavailability: tablet >90%
Excellent tissue penetration: CSF penetration >60%
Water soluble
90% renal excretion



Dose reduction for renal dysfunction
No does adjustment for hepatic dysfunction
Spectrum


active against Candida spp., C. neoformans, Trichosporon
spp., dimorphic fungi
Not active against Aspergillus spp. & other molds

Daily dosage

Mucocutaneus candidiasis: 100-200 mg






150 mg tablet for vulvovaginal candidiasis
Candidemia, IE: 400-800 mg (6-12 mg/kg)
Chronic disseminated candidiasis: 6 mg/kg
Maintenance for cryptococcal meningitis: 400 mg
Prophylaxis for neutropenic patients: 400 mg
Adverse effect




Well tolerated
GI trouble
Reversible AST/ALT elevation
Reversible alopecia
Itraconazole


IV formulation and oral solution (cyclodextrin), capsule
Pharmacokinetics

Oral bioavailability






Capsule: Reduced by H2 blocker or fasting
Oral solution: Best when fasting
High concentration in tissue, pus, bronchial secretion
Low CSF penetration <10%
IV contraindicated when CrCl <30 mL/min
Spectrum

Active against Aspergillus spp., Candida spp.

Dosage


200 mg iv q12h x4  200 mg iv q24h for 12 days
Adverse effect




Cyclodextrin  nausea, diarrhea
Transient hepatotoxicity
Hypokalemia, edema, hypertension (older patients)
Negative inotropic effects
Voriconazole


IV formulation (cyclodextrin), tablet, syrup
Pharmacokinetics







Oral bioavailability: tablet ~96%
Fasting  absorption ↑
No dose adjustment for renal dysfuction
Caution with IV for CrCl <50 mL/mn
Mild to moderate LC – standard loading dose  50%
reduced maintenance dose
CSF penetration 50%
Spectrum


Active against most fungi
Not active against zycomycetes

Dosage



IV: 6 mg/kg iv q12h x2  4 mg/kg iv q12h
Oral: 200 mg po bid (weight >40mg)
Adverse effect


Generally well tolerated, similar to other traizoles
Visual disturbances (~30%)





Decreased vision, photophobia, altered color perception and
ocular discomfort
Mild and transient
Abates with continued treatment
Associated with higher dose
Rash: reversible phototoxicity-related rash
Posaconazole






Not yet in Korea
Only oral syrup
High fat diet  absorption ↑
CSF penetration – low
Spectrum: active against most of all fungi
Dosage


400 mg po bid
Adverse effects


GI discomfort
Elevated liver enzyme
ECHINOCANDINS



Noncompetitive inhibition of β-(1,3)-glucan synthase
Only IV formulation
Pharmacokinetics




Poor oral bioavailability
CSF penetration <5%
Resistance mechanism: FKS1 mutation
Spectrum



Fungicidal against most Candida spp.
Fungistatic agaisnt Aspergillus
Not active against Zygomycetes, Cryptococcus, Fusarium
and Trichosporon
Caspofungin

Dosage: 70 mg loading  50 mg iv q24h

Dose modification: hepatic dysfunction




Drug interaction




Child-Pugh 5-6: none
Child-Pugh 7-9: 35 mg/day
Child-Pugh >9: no data
Tacrolimus 20%↓
Cyclosporin A  caspofungin 35%↑
Rifampin  caspofungin 30%↓
Adverse effects

Histamine related reaction, phlebitis, elevation of
AST/ALT
Micafungin

Dosage


100mg iv q24h
Adverse effects

Histamine related reaction, phlebitis, elevation of AST/ALT
Anidulafungin


Dosage: 200 mg loading  100mg iv q24h
Adverse effects



Nausea, vomitin, headache
Hypokalemia
GGT↑
Fungal infection
Comment
Caspofungin
Candidemia & invasive candidiasis As efficacious as Amphotericin B (RCT)
Candida esophagitis
As efficacious as fluconazole (RCT)
Aspergillosis, refractory
Effecacious as salvage, 2nd line Tx
Empiric treatment of persistent NF
Shown to be effective (RCT)
Micafungin
Candidemia & invasive candidiasis As efficacious as L-amphotericin B
Candida esophagitis
As efficacious as fluconazole (RCT)
Aspergillosis, refractory
Salvage trial
Prophylaxis of IFI
Effective in HSCT patients (RCT)
Anidulafungin
Candidemia & invasive candidiasis More effective than fluconazole (RCT)
Candida esophagitis
As effecacious as fluconazole (RCT)
Aspergillosis
No trial reported
FLUCYTOSINE

Pyrimidine analogue



Toxicity, rapid development of resistance, limited
spectrum  Combination therapy
Pharmacokinetics



Inhibition of DNA synthesis and protein synthesis
Oral availability: 80%
CSF penetration 75%
Dosage: 100-150 mg/kg/day #4

Modification for renal function


GFR 26-50 mL/min: 75mg/kg
GFR 13-25 mL/min: 37mg/kg

Adverse effect




Liver dysfunctioin (5-7%)
Leukopenia, thrombocytopenia
GI trouble: diarrhea
Teratogenic effect  contraindicated during pregnancy
항진균제 보험 인정기준

Neutropenic fever
Emprical
1st line
Emprical
2nd line
comment
Amphotericin B
deoxycholate
(Fugizone)
O
치료 실패: 7일 또는 500mg 이상 투여 후에도 증
상 지속/악화
투여 불가능: 1) s-Cr >2.5mg/dL 또는 약제 투여
전 수치의 2배 이상 상승 2) 다른 투여관련 이상
반응/간수치 상승: 소견서
Itraconazole iv
O
투여기간: neutropenia 회복 또는 해열된 경우 최
대 2주 또는 해열 후 5-7일
Caspofungin
X
O
Fungizone 또는 itraconazole iv 치료 실패 또는
투여 불가능한 경우
투여기간: itraconazole과 동일
Ambisome
X
O
Caspofungin과 동일

Invasive fungal infection
Targeted
1st line
Targeted
2nd line
comment
Ambisome iv
X
O
Fungizone 치료 실패 또는 투여 불가능한 경우
Itraconazole iv
X
O
Fungizone 치료 실패 또는 투여 불가능한 경우 –
Aspergillosis
Voriconazole iv
(PO: fungizone,
voriconazole 후
필요시)
X
O
Fungizone 치료 실패 또는 투여 불가능한 경우 Invasive aspergillosis, S. apiospemum 감염,
Fusarium spp. 감염, invasive candidiasis,
esophageal candidiasis(po)
Caspofungin iv
X
O
Fungizone 치료 실패 또는 투여 불가능한 경우 Invasive aspergillosis, invasive candidiasis,
esophageal candidiasis
Micafungin iv
X
O
Caspofungin과 동일, HSCT 환자에서 candidiasis 예
방
Anidulafungin
iv
X
O
Fungizone 치료 실패 또는 투여 불가능한 경우 Invasive candidiasis