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Antifungal Agents Lindsay Mayer, PharmD October 26, 2007.

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1 Antifungal Agents Lindsay Mayer, PharmD October 26, 2007

2 Polyenes—Amphotericin B MOA: Binds to ergosterol within the fungal cell membrane resulting in depolarization of the membrane and the formation of pores. The pores permit leakage of intracellular contents. Exhibits concentration dependent killing. MOA: Binds to ergosterol within the fungal cell membrane resulting in depolarization of the membrane and the formation of pores. The pores permit leakage of intracellular contents. Exhibits concentration dependent killing.

3 Polyenes—Amphotericin B Spectrum of Activity Spectrum of Activity –Broad spectrum antifungal –Active against most molds and yeasts –Holes: C. lusitanae, Fusarium, Tricosporon, Scedosporium Candida AspergillusCryptococcusCoccidioidesBlastomycesHistoplasmaFusariumTricosporonScedosporidiumZygomycetes albicansglabratakruseitropicalisparapsilosislusitanae

4 Polyenes—Amphotericin B Resistance Resistance –Susceptibility testing methods have not been standardized –Development of resistance in a previously susceptible species is uncommon –Mechanisms of Resistance  Reductions in ergosterol biosynthesis  Synthesis of alternative sterols that lessen the ability of amphotericin B to interact with the fungal membrane

5 Polyenes—Amphotericin B Formulations Amphotericin B deoxycholate Amphotericin B deoxycholate –Fungizone Amphotericin B colloidal dispersion Amphotericin B colloidal dispersion – Amphotec, Amphocil Amphotericin B lipid complex Amphotericin B lipid complex –Abelect Liposomal amphotericin B Liposomal amphotericin B –Ambisome Isolated from Streptococcus nodosus in 1955 Isolated from Streptococcus nodosus in 1955 Amphotericin B is “amphoteric” Amphotericin B is “amphoteric” –Soluble in both basic and acidic environments –Insoluble in water

6 Amphotericin B deoxycholate Distributes quickly out of blood and into liver and other organs and slowly re-enters circulation Distributes quickly out of blood and into liver and other organs and slowly re-enters circulation –Long terminal-phase half-life (15 days) Penetrates poorly into CNS, saliva, bronchial secretions, pancreas, muscle, and bone Penetrates poorly into CNS, saliva, bronchial secretions, pancreas, muscle, and bone Disadvantages 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 –Acute Reactions—chills, fevers, tachypnea Support Support –Fluids –Potassium replacement –Avoid concurrent nephrotoxic agents –Premed with acetaminophen, diphenhydramine or hydrocortisone –Meperidine for rigors Dose: 0.3 to 1 mg/kg once daily Dose: 0.3 to 1 mg/kg once daily

7 Amphotericin B Colloidal Dispersion (Amphotec) Cholesterol sulfate in equimolar amounts to amphotericin B Cholesterol sulfate in equimolar amounts to amphotericin B Similar kinetics to amphotericin B deoxycholate Similar kinetics to amphotericin B deoxycholate Acute infusion related reactions similar to amphotericin B deoxycholate Acute infusion related reactions similar to amphotericin B deoxycholate Reduced rates of nephrotoxicity compared to amphotericin B deoxycholate Reduced rates of nephrotoxicity compared to amphotericin B deoxycholate Dose Dose –3 to 4 mg/kg once daily

8 Amphotericin B Lipid Complex (Abelcet) Equimolar concentrations of amphotericin and lipid Equimolar concentrations of amphotericin and lipid Distributed into tissues more rapidly than amphotericin B deoxycholate Distributed into tissues more rapidly than amphotericin B deoxycholate –Lower Cmax and smaller AUC than amphotericin deoxycholate –Highest levels achieved in spleen, liver, and lungs –Delivers drug into the lung more rapidly than Ambisome –Lowest levels in lymph nodes, kidneys, heart, and brain Reduced frequency and severity of infusion related reactions Reduced frequency and severity of infusion related reactions Reduced rate of nephrotoxicity Reduced rate of nephrotoxicity Dose Dose –5 mg/kg once daily

9 Liposomal Amphotericin B (AmBisome) Liposomal product Liposomal product –One molecule of amphotericin B per 9 molecules of lipid Distribution Distribution –Higher Cmax and larger AUC –Higher concentrations achieved in liver, lung, and spleen –Lower concentrations in kidneys, brain, lymph nodes and heart –May achieve higher brain concentrations compared to other amphotericin B formulations Reduced frequency and severity of infusion related reactions Reduced frequency and severity of infusion related reactions Reduced rate of nephrotoxicity Reduced rate of nephrotoxicity Dose Dose –3 to 6 mg/kg once daily

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

11 Flucytosine Spectrum of Activity 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 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

12 Flucytosine Half-life Half-life –2 to 5 hours in normal renal function –85 hours in patients with anuria Distributes into tissues, CSF, and body fluids Distributes into tissues, CSF, and body fluids Toxicities Toxicities –Bone marrow suppression (dose dependent) –Hepatotoxicity (dose dependent) –Enterocolitis Toxicities occur more commonly in patients with renal impairment Dose 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 Flucytosine concentrations should be monitored especially in patients with changing renal function Contraindicated in pregnancy Contraindicated in pregnancy

13 Azoles—Ketoconazole Uses Uses –Used in U.S. as an alternative –Non-albicans candidiasis –Blastomycosis –Histoplasmosis  Not for immunocompromised hosts due to high failure rate –Coccidioidomycosis  Not for meningitis or for severely ill –Paracoccidioidomycosis Inactive against non-albicans candida and Aspergillus Inactive against non-albicans candida and Aspergillus Needs acidic environment for absorption Needs acidic environment for absorption Only available PO Only available PO Distributes into epidermis, synovial fluid, saliva, and lungs. Poor distribution into CSF and eye. Distributes into epidermis, synovial fluid, saliva, and lungs. Poor distribution into CSF and eye. Dose Dose –200 to 400 mg once daily –Decrease dose for severe liver failure

14 Azoles—Ketoconazole Adverse Effects Adverse Effects –GI distress (17-43%) –Rash (4-10%) –Increased transaminases (2-10%) –Hepatitis (1 in 10,000)  Can be fatal if drug is not DCd  Usually occurs within first 4 months of treatment –Dose-dependent inhibition of synthesis of testosterone (5-21% of patients will have symptoms such as impotence or gynecomastia) –Menstrual Irregularities (16% of women) –Alopecia (8%) –Dose-related decrease in cortisol synthesis –Hypermineralocorticoid state  Can cause HTN in patients on long-term high dose ketoconazole –Teratogenic in animals Drug Interactions Drug Interactions –Antacids, H2 blockers, proton pump inhibitors, sucralfate  Decreases absorption of ketoconazole –Rifampin decreases ketoconazole concentrations by 33% –CYP inhibition  Cyclosporine levels increased  Warfarin  Phenytoin  Methylprednisolone  Isoniazid  Terfenadine  Astemizole  Cisapride

15 Triazoles MOA: Inhibits 14-α- sterol demethylase, which is a microsomal CYP450 enzyme. This MOA: Inhibits 14-α- sterol demethylase, which is a microsomal CYP450 enzyme. This enzyme is responsible for conversion of lanosterol to ergosterol, the major sterol of most fungal cell membranes

16 Triazoles—Spectrum of Activity FluconazoleItraconazoleVoriconazolePosaconazole C. albicans C. glabrata++++ C. krusei C. tropicalis C. parapsilosis C. lusitanae Aspergillus Cryptococcus+++ Coccidioides+++ Blastomyces Histoplasma Fusarium-- ++ Scedosporium--+/-+ Zygomycetes---++

17 Triazoles—ADME FluconazoleItraconazoleVoriconazolePosaconazole AbsorptionIV and PO Good bioavailability PO Capsule ≠ Suspension Capsules best absorbed with food. Suspension best absorbed on empty stomach. IV and PO 90% oral bioavailability PO--Absorption enhanced with high fat meal DistributionWide. Good CNS penetration Low urinary levels Poor CNS penetration Wide. Good CNS penetration Widely distributed into tissues MetabolismHepatic/RenalHepatic CYP 2C9, 2C19, 3A4 Saturable metabolism Not a substrate of or metabolized by P450, but it is an Inhibitor of 3A4 Elimination80% excreted unchanged in the urine Excreted in fecesMinimal renal excretion Minimal renal excretion of parent compound 66% excreted in feces

18 Triazoles—Fluconazole Dose Dose –100 to 400 mg daily –Renal impairment:  CrCl >50 ml/min, give full dose  CrCl<50 ml/min, give 50% of dose  Dialysis: replace full dose after each session Drug Interactions Drug Interactions –Minor inhibitor of CYP 3A4 –Moderate inhibitor of CYP 2C9  Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureas Adverse Drug Reactions Adverse Drug Reactions –Well tolerated –Nausea –Elevated LFTs UNC Hospital Formulary

19 Triazoles—Itraconazole Dose Dose –200 to 400 mg/day (capsules)  doses exceeding 200 mg/day are given in 2 divided doses  Loading dose: 200 mg 3 times daily can be given for the first 3 days –Oral solution is 60% more bioavailable than the capsules Drug Interactions Drug Interactions –Major substrate of CYP 3A4 –Strong inhibitor of CYP 3A4 –Many Drug Interactions Adverse Drug Reactions Adverse Drug Reactions –Contraindicated in patients with CHF due to negative inotropic effects –QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest in the setting of drug interactions –Hepatotoxicity –Rash –Hypokalemia –Nausea and vomiting

20 Triazoles—Voriconazole Dose Dose –IV  6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 hours –PO  > 40 kg— mg PO every 12 hours  < 40 kg— mg PO every 12 hours Cirrhosis: Cirrhosis: –IV  6 mg /kg IV for 2 doses, then 2 mg/kg IV every 12 hours –PO  > 40 kg—100 mg PO every 12 hours  < 40 kg— 50 mg PO every 12 hours Renal impairment: Renal impairment:  if CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizer

21 Triazoles—Voriconazole Common Adverse Effects Common Adverse Effects –Peripheral edema –Rash (6%) –N/V/D –Hepatotoxicity –Headache –Visual disturbance (30%) –Fever Serious Adverse Events Serious Adverse Events –Stevens-Johnson Syndrome –Liver failure –Anaphylaxis –Renal failure –QTc prolongation Drug Interactions Major substrate of CYP 2CD and 2C19 Minor substrate of CYP 3A4 Weak inhibitor of CYP 2C9 and 2C19 Moderate inhibitor of CYP 3A4 Dose Adjustments EfavirenzPhenytoinCyclosporineWarfarinTacrolimus

22 Triazoles—Posaconazole Dosing (only available PO) Dosing (only available PO) –Prophylaxis of invasive Aspergillus and Candida species  200 mg 3 times/day –Treatment of oropharyngeal candidiasis  100 mg twice daily for 1 day, then 100 mg once daily for 13 days –Treatment or refractory oropharyngeal candidiasis  400 mg twice daily –Treatment of refractory invasive fungal infections (unlabeled use)  800 mg/day in divided doses Drug Interactions Drug Interactions –Moderate inhibitor of CYP3A4 Adverse Reactions Adverse Reactions –Hepatotoxicity –QTc prolongation –GI: Diarrhea

23 EchinocandinsMOA Irreversibly inhibits B-1,3 –D glucan synthase, the enzyme complex that forms glucan polymers in the fungal cell wall. Glucan polymers are responsible for providing rigidity to the cell wall. Disruption of B- 1,3-D glucan synthesis leads to reduced cell wall integrity, cell rupture, and cell death.

24 Echinocandins—Spectrum of Activity Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2: Candida AspergillusCryptococcusCoccidioidesBlastomycesHistoplasmaFusariumScedosporidiumZygomycetes albicansglabratakruseitropicalisparapsilosislusitanaeguilliermondii

25 Echinocandins CaspofunginMicafunginAnidulafungin AbsorptionNot orally absorbed. IV only DistributionExtensive into the tissues, minimal CNS penetration Metabolismspontaneous degradation, hydrolysis and N-acetylation Chemical degradated Not hepatically metabolized EliminationLimited urinary excretion. Not dialyzable Half-life9-23 hours11-21 hours26.5 hours Dose70 mg IV on day 1, then 50 mg IV daily thereafter 100 mg IV once daily 200 mg IV on day 1, then 100 mg IV daily thereafter Dose Adjustment Child-Pugh mg IV on day 1, then 35 mg IV daily thereafter CYP inducers 70 mg IV daily None

26 Echinocandin—Drug Interactions Caspofungin 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 Micafungin –Minor substrate and weak inhibitor of CYP3A4 –Nifedipine  Increased AUC (18%) and Cmax (42%) of nifedipine –Sirolimus  Increased concentration of sirolimus Anidulafungin Anidulafungin –No clinically significant interactions Cappelletty et al. Pharmacotherapy 2007;27:369-88

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

28 References   Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:  UNC Hospital Formulary  Patel R. Antifungal Agents. Part I. Amphotericin B Preparations and Flucytosine. Mayo Clin Proc 1998;73:  Terrel CL. Antifungal Agents. Part II. The Azoles. Mayo Clin Proc 1999;74:  Mehta J. Do variations in molecular structure affect the clinical efficacy and safety of lipid based amphotericin B preparations? Leuk Res. 1997;21:  Groll AH et al. Penetration of lipid formulations of amphotericin B into cerebral fluid and brain tissue. 37 th ICAAC, Abstract A90.  Gallagher JC et al. Recent advances in antifungal pharmacotherapy for invasive fungal infections. Expert Rev. Anti-infect. Ther 2004; 2:  Groll AH et al. Antifungal Agents: In vitro susceptibility testing, pharmacodynamics, and prospects for combination therapy. Eur J Clin Microbiol Infect Dis 2004;23:  Capelletty D et al. The echinocandins. Pharmacotherapy 2007;27:  Spanakis EK et al. New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis 2006;43:  Rex JH, Stevens DA. Systemic Antifungal Agents. In: Mandell GL, Bennet JE, Dolin R, eds. Mandell, Douglas, and Bennett’s: Principles and Practice of Infectious Diseases. Vol 1. 6 th ed. New York, NY: McGraw-Hill;2005:502.


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