Antifungal Medications M A ZE N KHE R A L L AH, M D, FCCP

Outline Azoles

Polyene

Candins

Fungal cell

Cell membrane and cell wall Mannoproteins b-(1,6)-glucan b-(1,3)-glucan Chitin Phospholipid bilayer of cell membrane

• Polyene antibiotics - Amphotericin B, - Lipid-AMB Ergosterol • Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Posoconazole*

b-(1,3)-glucan synthase

Ergosterol

• Echinocandins

- Caspofungin - Micafungin - Anidulafungin

Synthesis Pathway

Squalene

DNA/RNA Synthesis

Flucytosine

Spectra of Activity Amphotericin B Fluconazole Itraconazole Voriconazole

Candins

Candida

++

Variable

Variable

++

++

Aspergillus

++

-

++

++

++

Fusarium

++

-

-

++

-

Mucor

++

-

-

-

-

Cryptococcus

++

++

++

++

-

Spectra of Activity Amphotericin B

Fluconazole

Itraconazole

Voriconazole

Posaconazole

Candins

C.albicans

S

S

S

S

S

S

C. tropicalis

S

S

S

S

S

S

C. parapsilosis

S

S

S

S

S

S to R*

C. glabrata

S to I

S-DD to R

S-DD to R

S

C. krusei

S to I

R

S-DD to R

S

S

S

C. lusitaniae

S to R

S

S

S

S

S

Aspergillus

S

R

S

S

S

S

Fusarium

S

R

R

S

S

R

Mucor

S

R

R

R

S

R

Cryptococcus

S

S

S

S

S

R

S-DD to R S-DD to R

I, intermediately susceptible; R, resistant; S, susceptible; S-DD: susceptible dose-dependent. *Echinocandin resistance among C. parapsilosis isolates is uncommon.

Polyenes Amphotericin B Deoxycholate Lipid-Based Amphotericin B: Amphotericin B Lipid Complex Amphotericin B Colloidal Dispersion Liposomal Amphotericin B

Liposomal Nystatin

Amphotericin B

Ergosterol

Cell membrane

Binding to ergosterol, Intercalation of cell membrane

Ca++ Na+

Ca++ K+

Na+

K+ Leakage of intracellular cations and proteins

Polyenes—Amphotericin B Spectrum of Activity ◦ Fungicida: Broad spectrum antifungal, Active against most molds and yeasts ◦ Holes: Scedosporium, Trichosporon beigelii, Aspergillus terreus, Pseudallescheria boydii, Malassezia furfur, Fusarium spp, C. lusitaniae Coccidioides

Blastomyces

Histoplasma

Zygomycetes

Fusarium

Tricosporon

Scedosporidium

+++

+++

++

+++

++

+

+

+

Apergillus terreus +

Cryptococcus

+++

++

tropicalis

+++

--

krusei

++

lusitanae

glabrata

+++

parapsilosis +++

albicans

Aspergillus

Candida

Amphotericin B Deoxycholate Distributes quickly out of blood and into liver and other organs and slowly reenters circulation ◦ Long terminal-phase half-life (15 days)

Penetrates poorly into CNS, saliva, bronchial secretions, pancreas, muscle, and bone Disadvantages ◦ Glomerular Nephrotoxicity—Dose-dependent decrease in GFR because of vasoconstrictive effect on afferent renal arterioles ◦ Permanent loss of renal function is related to the total cumulative dose

◦ Tubular Nephrotoxicity—K, Mg+, and bicarbonate wasting ◦ Decreased erythropoietin production

Amphotericin B Induced Nephrotoxicity - Incidence: 49 – 65% Constriction of the afferent Efferent arterioles leading to decreased arteriole glomerular filtration Afferent arteriole

Proximal tubule

Glomerulus

Tubular-glomerular feedback: Further constriction of arterioles Wingard JF, Kubilis P, Lee G, et al. CID 1999 29:1402-7 White MH, Bowden RA, Sandler, et al. CID 1998 27:296-302 Luke RG, Boyle JA. AJKD 1998 31:780-5 Walsh TJ, Finberg RW, Arndt C, et al. NEJM 1999 340:764-71

Distal tubule

Direct damage of distal tubular membranes leading to wasting of Na+, K+, and Mg++

Amphotericin B Deoxycholate Infusion Related Reactions: ◦ ◦ ◦ ◦ ◦

Chills / rigors Fever Nausea / vomiting Cardio/respiratory reactions Phlebitis

Support ◦ ◦ ◦ ◦ ◦

Fluids Potassium replacement Avoid concurrent nephrotoxic agents Premed with acetaminophen, diphenhydramine or hydrocortisone Meperidine for rigors

Dosing: 0.3 – 1.5 mg/kg/day given over 4 – 6 hours.

Utz JP, Bennett JE, Brandriss MW, et al. 1964. Ann. Intern. Med. 61(2):334-354. Maddux MS, Barriere SL. 1980. Drug Intell. Clin. Pharm. 14:177-181. Grasela TH, Goodwin SD, Walawander MK, et al. 1990. Pharmacotherapy. 10(5):341-348. Gallis HA, Drew RH, Pickard WW. 1990. Rev. Infect. Dis. 12(2):308-329

Lipid Amphotericin B Formulations Abelcet ® ABLC

Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size (µm): 1.6-11

Amphotec ® ABCD

Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size (µm): 0.12-0.14

DMPC-Dimyristoyl phospitidylcholine DMPG- Dimyristoyl phospitidylcglycerol

Ambisome ® L-AMB

Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol Particle size (µm) : 0.08

HSPC-Hydrogenated soy phosphatidylcholine DSPG-Distearoyl phosphitidylcholine

Lipid Amphotericin B Formulations Amphotericin B Colloidal Dispersion (Amphotec)

Amphotericin B Lipid Complex (Abelcet)

Liposomal Amphotericin B (AmBisome)

Liposomal Product

Cholesterol sulfate in equimolar amounts to amphotericin B

Equimolar concentrations of amphotericin and lipid

One molecule of amphotericin B per 9 molecules of lipid

Cmax*

Same

Lower

Higher

AUC*

Same

Smaller

Larger

Highest Tissue Concentration

Spleen, liver, and lungs

Spleen, liver, and lungs

Spleen, liver, and lungs

Lowest Tissue Concentration

Lymph nodes, kidneys, heart, and brain

Lymph nodes, kidneys, heart, and brain

Lymph nodes, kidneys, heart, and brain (higher than ampho B)

Acute infusion related reactions *

Similar

Reduced frequency and severity

Reduced frequency and severity

Nephrotoxicity*

Reduced

Reduced

Reduced

Dosing

3 to 4 mg/kg once daily

5 mg/kg once daily

3 to 6 mg/kg once daily

* Compared to Amphotericin B

Aggregate Efficacy Estimates of AMB Formulations in OpenLabel Studies Invasive Aspergillosis

Invasive Candidiasis AMB-deoxy

AMB-deoxy

L-AmB

L-AmB ABLC

ABLC

ABCD

ABCD 5

15 25 35 45 55 65 75 85 95

% Complete and Partial Response

5

15 25 35 45 55 65 75 85 95

% Complete and Partial Response

The efficacy of the lipid-based amphotericin B products appears to be comparable to AMB or better

Ostrosky-Zeichner et al. Clin Infect Dis 2003;37:415-25.

Azoles

Triazole:

Fluconazole Itraconazole Voriconazole Ravuconazole Posaconazole Imidazole:

Ketoconazole

Azole Cell membrane Ergosterol Ergosterol Synthesis Pathway

Squalene

Accumulation of toxic sterols in cell membrane Toxic sterols Inhibition of 14-alpha-demethylase

Spectra of Activity Fluconazole

C. albicans

Itraconazole

Voriconazole

Posaconazole

Ravuconazole

++

+++

+++

+++

C. glabrata

+

+

++

++

++

C. krusei

--

+

++

++

++

C. tropicalis

+++

++

+++

+++

+++

C. parapsilosis

+++

++

+++

+++

+++

C. lusitanae

++

++

+++

+++

+++

Aspergillus

--

++

+++

+++

+++

Cryptococcus

+++

+++

+++

+++

+++

Coccidioides

+++

+++

+++

+++

+++

Blastomyces

++

+++

++

+++

+++

Histoplasma

+

+++

++

+++

+++

Fusarium

--

--

++

++

+/-

Scedosporium

--

+/-

+

+/-

+

Zygomycetes

-

-

-

++

-

Cryptococcus data: Pfaller AAC 45:2862, ’01; Yildiran EJCMID 19:317. ’00; Yamazumi AAC 44:2883, ‘00

Key Biopharmaceutical Characteristics of the Triazole Antifungals Fluconazole

Itraconazole

Voriconazole

Posaconazole

Absorption (bioavailability)

Good (90%)

Capsule (6-25%) with food Solution (20-60%): empty stomach.

Good (90%)

Enhanced with high fat meal

IV Formulation

Available, no solubilizer

Available, cyclodextrin

Available, cyclodextrin

Available

Distribution

Wide

Low urinary levels

Wide

Wide

CNS Penetration

Good

Poor

Good

Unknown

Metabolism

Hepatic/Renal

Hepatic 3A4

CYP 2C9, 2C19, 3A4.

Not a substrate of or metabolized by P450,

CYP 3A4 inhibition

Weak

Strong

Strong

Moderate

Serum t1/2 (hr)

24

24 - 30

6 - 24

8 – 24

Elimination

80% excreted unchanged in the urine

Excreted in feces

Minimal renal excretion

Minimal renal excretion, 66% excreted in feces

Adverse events

N&V, hepatic

N&V, diarrhea (solution), hepatic, CHF

N&V, visual disturbances, hepatic, rash, QTC prolongation

N&V, fever, hepatic

R.E. Lewis 2002. Exp Opin Pharmacother 3:1039-57.

Azole Inhibition of CYP P450

Azole Antifungals – Pharmacokinetic DDI Isozyme

Common Substrates

Inhibitors

Inducers

Fluvastatin, Ibuprofen, Losartan, Rosiglitazone, Warfarin

Amiodarone, Cimetidine, Cotrimoxazole, Isoniazid

Barbiturates, Rifampin

CYP2C19

Citalopram, Diazepam, Lansoprazole, Omeprazole, Pantoprazole

Fluoxetine, Flovoxamine, Omeprazole

Barbiturates, Rifampin

CYP3A4

Alprazolam, Atorvastatin, Buspirone, Cyclosporine, Felodipine, Lidocaine, Lovastatin, Midazolam, Nifedipine, Quinidine, Ritonavir, Sertraline, Simvastatin, Sirolimus, Tacrolimus, Triazolam, Warfarin, Zolpidem

Amiodarone, Azithromycin, Clarithromycin, Diltiazem, Erythromycin, Grape Fruit Juice, Indinavir, Nefazodone, Ritonavir, Verapamil

Barbiturates, Corticosteroids, Carbamazepine, Nevirapine, Phenytoin, Rifampin

CYP2C9

Glucan Synthesis Inhibitors (Echinocandins)

Caspofungin Micafungin Anidulafungin

Echinocandins General Characteristics ◦ ◦ ◦ ◦ ◦

Poor bioavailability, IV only Water soluble, no need for carrier Long half life, once daily dosing Extensively metabolized, little renal clearance. Linear Pharmacokinetics, no drug accumulation

Mannoproteins ß(1,6)-glucan ß(1,3)-glucan Chitin Phospholipid bilayer of cell membrane ß(1,3) glucan synthase

Glucan Synthase Inhibitor

Depletion of ß(1,3) glucans in cell wall

Inhibition of ß(1,3) glucan synthase

Spectra of Activity Caspofungin

Micafungin

Anidulafungin

Candida

++

++

++

Aspergillus

++

++

++

Fusarium

-

-

-

Mucor

-

-

-

Cryptococcus

-

-

-

Blasto/Histo/Cocci: Mycelial Form Blasto/Histo/Cocci: Yeast Form

++

++

++

-

-

-

In vitro activity of the Echinocandins vs. Common Candida spp.

Species (n)

Caspofungin (mcg/mL) MIC50 MIC90

Micafungin (mcg/mL) MIC50 MIC90

Anidulafungin (mcg/mL) MIC50 MIC90

C. albicans (733) C. glabrata (458) C. parapsilosis (391) C. krusei (50) C. lusitaniae (20) C. dubliniensis (18)

0.5 0.5 2 1 1 0.5

0.03 0.03 1 0.03 0.13 0.06

0.03 0.03 2 0.03 0.06 0.03

0.5 1 2 2 2 0.5

0.03 0.06 2 0.06 0.25 2

Ostroskey-Zeichner. Antimicrobial Agents Chemother. 2003, p. 3149–3154

0.03 0.03 2 0.13 0.25 0.06

Key Characteristics of the Echinocandin Antifungals Caspofungin

Micafungin

Anidulafungin

Distribution (Vd)

9.67 L

0.39 L/kg

30-50 L

Protein binding

97% albumin

99.8% albumin

84% albumin

Dosing (MTD)

35 – 70 mg (100 mg)

50 – 150 mg (896 mg)

50 – 200 mg (400 mg)

Major metabolic pathway

Peptide hydrolysis, slow N-acetylation

COMT

Slow chemical degradation

t 1/2

9-11 hours

~14 hours

40 – 50 hours

CNS penetration

Apparently poor

Apparently poor

Apparently poor

Elimination

Limited urinary excretion. Not dialyzable

Dosage adjustment

Moderate hepatic insufficiency (CP 7-9) No renal adjustment Not adequately studied in < 18 ys

No hepatic adjustment No renal adjustment Children < 8 years of age

•No hepatic adjustment •No renal adjustment •No pediatric dose adjustment (dosed on mg/kg basis)

Common ADR

•Hepatotoxicity •Myelosuppression

•Hepatotoxicity •Myelosuppression

•Hepatotoxicity •Myelosuppression •Histamine-release (rare if infused at < 1.1 mg/min)

Clinical Efficacy Esophageal Candidiasis Candidemia

Aspergillosis (salvage) Empiric Therapy in FN

Caspofungin

Micafungin

Anidulafungin

√ √ √ √

√ * *

√ √

Prophylaxis in HSCT √ = FDA approved indication * = clinical data available to support its use

√

Invasive Candidiasis Studies: Designs Caspofungin Study*

Anidulafungin Study*

Micafungin Study*

Study Design

Double-blind, randomized, controlled

Double-blind, randomized, controlled

Double-blind, randomized, controlled

Sample Size

N=239

N=245

N=537

Daily Dose of Echinocandin

50 mg QD (70 mg load)

100 mg QD (200 mg load)

100 to 200 mg/day for patients >40 kg 2 mg/kg/day for patients ≤40 kg

Comparator Daily Dose

Amphotericin B 0.6–1 mg/kg

Fluconazole 400 mg (800 mg load)

L-AmB 3 mg/kg/day

Complete OR partial response

Complete OR partial response

Microbiological eradication

Presumed or documented microbiological eradication

Presumed or documented microbiological eradication

MITT PP (≥5 days of treatment)

MITT

PP (≥5 days of treatment)

Primary Efficacy End Point

Efficacy Populations

Only complete resolution of signs and symptoms

*Separate studies. PP = per protocol. Adapted from Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029; Anidulafungin US Prescribing Information; Reboli AC et al. N Engl J Med. 2007;356:2472–2482; Kuse E-R et al. Lancet. 2007;369:1519–1527.

Invasive Candidiasis Studies: Efficacy Results Caspofungin Study

Anidulafungin Study

Micafungin Study

Caspofungin

AmB

Anidulafungin

Fluconazole

Micafungin

L-AmB

50 mg QDa

0.6– 0.7 mg/kgb

100 mgc

400 mgd

100–200 mge

3–5 mg/kgf

MITT End of IV Therapy

73%

62%

76%

60%

74%

70%

PP Results Independent Review Board

81%

65%

N/A

N/A

81%

80%

PP Results Investigator Adjudicated

N/A

N/A

N/A

N/A

90%

90%

Mortality Due to Fungal Infection

4%

7%

2%

4%

13%

9%

Daily Dose

aLoading

dose of 70 mg; b0.7–1.0 mg/kg/d in patients with neutropenia; cLoading dose 200 mg; dLoading dose 800 mg; e100 mg for patients >40 kg and 2 mg/kg for patients ≤40 kg. After 5 days, dose could be increased to 200 mg; fStarting dose of 3 mg/kg could be increased to 5 mg/kg after day 5.

IV = intravenous.

Adapted from Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029; Reboli AC et al. N Engl J Med. 2007;356:2472–2482; AnidulafunginSlide 35 Injection. US Prescribing Information; Kuse E-R et al. Lancet. 2007;369:1519–1527

Echinocandin—Drug Interactions Caspofungin ◦ Not an inducer or inhibitor of CYP enzymes ◦ CYP inducers (i.e. phenytoin, rifampin, carbamazepine) ◦

Reduced caspofungin levels ◦

Increase caspofungin dose

◦ Cyclosporine ◦

Increases AUC of caspofungin

◦

Hepatotoxicity ◦

Avoid or monitor LFTs

◦ Tacrolimus ◦

Reduced tacrolimus levels by 20% ◦

Monitor levels of tacrolimus

Micafungin ◦ Minor substrate and weak inhibitor of CYP3A4 ◦ Nifedipine ◦

Increased AUC (18%) and Cmax (42%) of nifedipine

◦ Sirolimus ◦

Increased concentration of sirolimus

Anidulafungin ◦ No clinically significant interactions

Cappelletty et al. Pharmacotherapy 2007;27:369-88

Echinocandins—Adverse Effects Generally well tolerated Phlebitis, GI side effects, Hypokalemia Abnormal liver function tests Caspofungin ◦ Tends to have higher frequency of liver related laboratory abnormalities ◦ Higher frequency of infusion related pain and phlebitis

Flucytosine MOA ◦ Converted by cytosine deaminase into 5-fluorouracil which is then converted through a series of steps to 5fluorouridine triphosphate and incorporated into fungal RNA leading to miscoding ◦ Also converted by a series of steps to 5fluorodeoxyuridine monophosphate which is a noncompetitive inhibitor of thymidylate synthase, interfering with DNA synthesis DNA/RNA Synthesis

Flucytosine Fluorinated pyrimidine

Fungal cell

Cell membrane and cell wall Mannoproteins b-(1,6)-glucan b-(1,3)-glucan Chitin Phospholipid bilayer of cell membrane

• Polyene antibiotics - Amphotericin B, - Lipid-AMB Ergosterol • Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Posoconazole*

b-(1,3)-glucan synthase

Ergosterol

• Echinocandins

- Caspofungin - Micafungin - Anidulafungin

Synthesis Pathway

Squalene

DNA/RNA Synthesis

Flucytosine

Flucytosine Spectrum of Activity ◦ Active against ◦ Candida species except C. krusei ◦ Cryptococcus neoformans ◦ Aspergillus species

◦ Synergy with amphotericin B has been demonstrated ◦ The altered permeability of the fungal cell membrane produced by amphotericin allows enhanced uptake of flucytosine

Mechanisms of Resistance ◦ Loss of cytosine permease that permits flucytosine to cross the fungal cell membrane ◦ Loss of any of the enzymes required to produce the active forms that interfere with DNA synthesis ◦ Resistance occurs frequently and rapidly when flucytosine is given as monotherapy ◦ Combination therapy is necessary

Flucytosine Half-life ◦ 2 to 5 hours in normal renal function ◦ 85 hours in patients with anuria

Distributes into tissues, CSF, and body fluids Toxicities ◦ ◦ ◦ ◦

Bone marrow suppression (dose dependent) Hepatotoxicity (dose dependent) Enterocolitis Toxicities occur more commonly in patients with renal impairment

Dose ◦ Administered orally (available in 250 and 500 mg capsules) ◦ 100 to 150 mg/kg/day in 4 divided doses ◦ Dose adjust for creatinine clearance

Flucytosine concentrations should be monitored especially in patients with changing renal function

Contraindicated in pregnancy

Conclusion Amphotericin B Fluconazole Itraconazole Voriconazole

Candins

Candida

++

Variable

Variable

++

++

Aspergillus

++

-

++

++

++

Fusarium

++

-

-

++

-

Mucor

++

-

-

-

-

Cryptococcus

++

++

++

++

-