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Lindsay Mayer, PharmD October 26, 2007

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1 Lindsay Mayer, PharmD October 26, 2007
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. Amphotericin is a lipophilic molecule that exerts its antifungal effect by insertion into the lipid bi-layer fungal cytoplasmic membrane. Specifically, it binds to ergosterol in the fungal cell membrane. This binding results in depolarization of the membrane and formation of pores that increase permeability to proteins and monovalent and divalent cations, eventually leading to cell death. Amphotericin B may also induce oxidative damage in fungal cells and has been reported to stimulate of host immune cells.

3 Polyenes—Amphotericin B
Spectrum of Activity Broad spectrum antifungal Active against most molds and yeasts Holes: C. lusitanae, Fusarium, Tricosporon, Scedosporium Candida Aspergillus Cryptococcus Coccidioides Blastomyces Histoplasma Fusarium Tricosporon Scedosporidium Zygomycetes albicans glabrata krusei tropicalis parapsilosis lusitanae +++ ++ -- + Primary resistance is common for Aspergillus terreus, Scedosporium species and trichosporon species. Also aspergillus terreus is a hole

4 Polyenes—Amphotericin B
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
Isolated from Streptococcus nodosus in 1955 Amphotericin B is “amphoteric” Soluble in both basic and acidic environments Insoluble in water Formulations Amphotericin B deoxycholate Fungizone Amphotericin B colloidal dispersion Amphotec, Amphocil Amphotericin B lipid complex Abelect Liposomal amphotericin B Ambisome Amphotericin B deoxycholate gets bound to cholesterol containing membranes and is stored in liver and other organs

6 Amphotericin B deoxycholate
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 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 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 3 compartment model Initial half life is hours Terminal half life 15 days Sufficient levels of amphotericin B can be detected in the liver, spleen, and kidney for up to 12 months after termination of therapy Good distribution—lung, liver, kidney, spleen Mechanism of nephrotoxicity—combination of factors—changes in tubular cell permeability to ions, renal arteriolar spasm, calcium depletion direct tubular or renal cellular toxicity, possibly a role of prostaglandin and TNF a Renal dysfunction is usually reversible, but may take several months Decreased erythropoietin production tends to be associated with deterioration of renal function—leads to a reversible normochromic normocytic anemia Drug interactions—concurrent administration of other nephrotoxic agents, Hypokalemia can potentiate digoxin toxicity and can increase the activity of neuromuscular blocking agents

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

8 Amphotericin B Lipid Complex (Abelcet)
Equimolar concentrations of amphotericin and lipid 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 rate of nephrotoxicity Dose 5 mg/kg once daily

9 Liposomal Amphotericin B (AmBisome)
Liposomal product One molecule of amphotericin B per 9 molecules of lipid 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 rate of nephrotoxicity Dose 3 to 6 mg/kg once daily

10 Flucytosine 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 Pharmacodynamics Time above MIC Fungistatic at clinically achievable plasma concentrations Fluorinated pyrimidine

11 Combination therapy is necessary
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 Much narrower spectrum of action than amphotericin B In most laboratories, an MIC of 20 ug/mL or less is considered susceptible for flucytosine

12 Toxicities occur more commonly in patients with renal impairment
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 Peaks of 40 to 60 mg/L Troughs—keep level over 25 ug/mL Toxicities are seen when levels are over ug/mL It is available as IV in other countries, but only the oral formulation in approved in the US

13 Azoles—Ketoconazole 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 Needs acidic environment for absorption Only available PO Distributes into epidermis, synovial fluid, saliva, and lungs. Poor distribution into CSF and eye. Dose 200 to 400 mg once daily Decrease dose for severe liver failure

14 Azoles—Ketoconazole Adverse Effects Drug Interactions
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 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 enzyme is responsible for conversion of lanosterol to ergosterol, the major sterol of most fungal cell membranes N substitution of the imidazoles such as ketoconazole has created a family of drugs called the triazoles that have the same MOA as imidazoles, a similar or broader spectrum of activity and less effect on human sterol synthesis. Pharmacodynamics—AUC/MIC Compared to ketoconazole, newer azoles have fewer drug interactions, broader spectrum, less hormonal inhibition (testosterone and glucocorticoids), better distribution into body fluids, less GI distress, and less hepatotoxicity

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

17 Triazoles—ADME Fluconazole Itraconazole Voriconazole Posaconazole
Absorption IV and PO Good bioavailability PO Capsule ≠ Suspension Capsules best absorbed with food. Suspension best absorbed on empty stomach. 90% oral bioavailability PO--Absorption enhanced with high fat meal Distribution Wide. Good CNS penetration Low urinary levels Poor CNS Widely distributed into tissues Metabolism Hepatic/Renal Hepatic CYP 2C9, 2C19, 3A4 Saturable metabolism Not a substrate of or metabolized by P450, but it is an Inhibitor of 3A4 Elimination 80% excreted unchanged in the urine Excreted in feces Minimal renal excretion excretion of parent compound 66% excreted in feces

18 Triazoles—Fluconazole
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 Minor inhibitor of CYP 3A4 Moderate inhibitor of CYP 2C9 Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureas Adverse Drug Reactions Well tolerated Nausea Elevated LFTs Higher doses have been used with good tolerability UNC Hospital Formulary

19 Triazoles—Itraconazole
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 Major substrate of CYP 3A4 Strong inhibitor of CYP 3A4 Many Drug Interactions 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 Capsules and solution are not interchangeable Coadministration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) with itraconazole capsules, injection or oral solution is contraindicated. Itraconazole, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors .

20 Triazoles—Voriconazole
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: 6 mg /kg IV for 2 doses, then 2 mg/kg IV every 12 hours > 40 kg—100 mg PO every 12 hours < 40 kg— 50 mg PO every 12 hours Renal impairment: if CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizer Cyclodextrin solubilizer accumulates in rena lNo, BUT: IV should not be used for CrCl< 50

21 Triazoles—Voriconazole
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 Efavirenz Phenytoin Cyclosporine Warfarin Tacrolimus Common Adverse Effects Peripheral edema Rash (6%) N/V/D Hepatotoxicity Headache Visual disturbance (30%) Fever Serious Adverse Events Stevens-Johnson Syndrome Liver failure Anaphylaxis Renal failure QTc prolongation Visual disturbance is an important counseling point for patients!!

22 Triazoles—Posaconazole
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 Moderate inhibitor of CYP3A4 Adverse Reactions Hepatotoxicity QTc prolongation GI: Diarrhea

23 Echinocandins MOA 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. Cyclic lipopeptides that must be given IV Peak/MIC concentration dependent killing

24 Echinocandins—Spectrum of Activity
Candida Aspergillus Cryptococcus Coccidioides Blastomyces Histoplasma Fusarium Scedosporidium Zygomycetes albicans glabrata krusei tropicalis parapsilosis lusitanae guilliermondii +++ + -- ++ - Spectrum of activity of all of the echinocandins is similar. Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:

25 Echinocandins Caspofungin Micafungin Anidulafungin Absorption
Caspofungin Micafungin Anidulafungin Absorption Not orally absorbed. IV only Distribution Extensive into the tissues, minimal CNS penetration Metabolism spontaneous degradation, hydrolysis and N-acetylation Chemical degradated Not hepatically metabolized Elimination Limited urinary excretion. Not dialyzable Half-life 9-23 hours 11-21 hours 26.5 hours Dose 70 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 Dose Adjustment Child-Pugh 7-9 70 mg IV on day 1, then 35 mg IV daily thereafter CYP inducers 70 mg IV daily None

26 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

27 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

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. 37th 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. 6th ed. New York, NY: McGraw-Hill;2005:502.

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