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 ActivityBroad spectrum antifungalActive against most molds and yeastsHoles: C. lusitanae, Fusarium, Tricosporon, ScedosporiumCandidaAspergillusCryptococcusCoccidioidesBlastomycesHistoplasmaFusariumTricosporonScedosporidiumZygomycetesalbicansglabratakruseitropicalisparapsilosislusitanae+++++--+Primary resistance is common for Aspergillus terreus, Scedosporium species and trichosporon species.Also aspergillus terreus is a hole
4 Polyenes—Amphotericin B ResistanceSusceptibility testing methods have not been standardizedDevelopment of resistance in a previously susceptible species is uncommonMechanisms of ResistanceReductions in ergosterol biosynthesisSynthesis 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 1955Amphotericin B is “amphoteric”Soluble in both basic and acidic environmentsInsoluble in waterFormulationsAmphotericin B deoxycholateFungizoneAmphotericin B colloidal dispersionAmphotec, AmphocilAmphotericin B lipid complexAbelectLiposomal amphotericin BAmbisomeAmphotericin 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 circulationLong terminal-phase half-life (15 days)Penetrates poorly into CNS, saliva, bronchial secretions, pancreas, muscle, and boneDisadvantagesGlomerular Nephrotoxicity—Dose-dependent decrease in GFR because of vasoconstrictive effect on afferent renal arteriolesPermanent loss of renal function is related to the total cumulative doseTubular Nephrotoxicity—K, Mg+, and bicarbonate wastingDecreased erythropoietin productionAcute Reactions—chills, fevers, tachypneaSupportFluidsPotassium replacementAvoid concurrent nephrotoxic agentsPremed with acetaminophen, diphenhydramine or hydrocortisoneMeperidine for rigorsDose: 0.3 to 1 mg/kg once daily3 compartment modelInitial half life is hoursTerminal half life 15 daysSufficient levels of amphotericin B can be detected in the liver, spleen, and kidney for up to 12 months after termination of therapyGood distribution—lung, liver, kidney, spleenMechanism 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 aRenal dysfunction is usually reversible, but may take several monthsDecreased erythropoietin production tends to be associated with deterioration of renal function—leads to a reversible normochromic normocytic anemiaDrug 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 BSimilar kinetics to amphotericin B deoxycholateAcute infusion related reactions similar to amphotericin B deoxycholateReduced rates of nephrotoxicity compared to amphotericin B deoxycholateDose3 to 4 mg/kg once daily
8 Amphotericin B Lipid Complex (Abelcet) Equimolar concentrations of amphotericin and lipidDistributed into tissues more rapidly than amphotericin B deoxycholateLower Cmax and smaller AUC than amphotericin deoxycholateHighest levels achieved in spleen, liver, and lungsDelivers drug into the lung more rapidly than AmbisomeLowest levels in lymph nodes, kidneys, heart, and brainReduced frequency and severity of infusion related reactionsReduced rate of nephrotoxicityDose5 mg/kg once daily
9 Liposomal Amphotericin B (AmBisome) Liposomal productOne molecule of amphotericin B per 9 molecules of lipidDistributionHigher Cmax and larger AUCHigher concentrations achieved in liver, lung, and spleenLower concentrations in kidneys, brain, lymph nodes and heartMay achieve higher brain concentrations compared to other amphotericin B formulationsReduced frequency and severity of infusion related reactionsReduced rate of nephrotoxicityDose3 to 6 mg/kg once daily
10 FlucytosineMOAConverted 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 miscodingAlso converted by a series of steps to 5-fluorodeoxyuridine monophosphate which is a noncompetitive inhibitor of thymidylate synthase, interfering with DNA synthesisPharmacodynamicsTime above MICFungistatic at clinically achievable plasma concentrationsFluorinated pyrimidine
11 Combination therapy is necessary FlucytosineSpectrum of ActivityActive againstCandida species except C. kruseiCryptococcus neoformansAspergillus speciesSynergy with amphotericin B has been demonstratedThe altered permeability of the fungal cell membrane produced by amphotericin allows enhanced uptake of flucytosineMechanisms of ResistanceLoss of cytosine permease that permits flucytosine to cross the fungal cell membraneLoss of any of the enzymes required to produce the active forms that interfere with DNA synthesisResistance occurs frequently and rapidly when flucytosine is given as monotherapyCombination therapy is necessaryMuch narrower spectrum of action than amphotericin BIn 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 FlucytosineHalf-life2 to 5 hours in normal renal function85 hours in patients with anuriaDistributes into tissues, CSF, and body fluidsToxicitiesBone marrow suppression (dose dependent)Hepatotoxicity (dose dependent)EnterocolitisToxicities occur more commonly in patients with renal impairmentDoseAdministered orally (available in 250 and 500 mg capsules)100 to 150 mg/kg/day in 4 divided dosesDose adjust for creatinine clearanceFlucytosine concentrations should be monitored especially in patients with changing renal functionContraindicated in pregnancyPeaks of 40 to 60 mg/LTroughs—keep level over 25 ug/mLToxicities are seen when levels are over ug/mLIt 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 alternativeNon-albicans candidiasisBlastomycosisHistoplasmosisNot for immunocompromised hosts due to high failure rateCoccidioidomycosisNot for meningitis or for severely illParacoccidioidomycosisInactive against non-albicans candida and AspergillusNeeds acidic environment for absorptionOnly available PODistributes into epidermis, synovial fluid, saliva, and lungs. Poor distribution into CSF and eye.Dose200 to 400 mg once dailyDecrease 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 DCdUsually occurs within first 4 months of treatmentDose-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 synthesisHypermineralocorticoid stateCan cause HTN in patients on long-term high dose ketoconazoleTeratogenic in animalsDrug InteractionsAntacids, H2 blockers, proton pump inhibitors, sucralfateDecreases absorption of ketoconazoleRifampin decreases ketoconazole concentrations by 33%CYP inhibitionCyclosporine levels increasedWarfarinPhenytoinMethylprednisoloneIsoniazidTerfenadineAstemizoleCisapride
15 TriazolesMOA: 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 membranesN 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/MICCompared 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
17 Triazoles—ADME Fluconazole Itraconazole Voriconazole Posaconazole AbsorptionIV and POGood bioavailabilityPOCapsule ≠ SuspensionCapsules best absorbed with food.Suspension best absorbed on empty stomach.90% oralbioavailabilityPO--Absorptionenhanced withhigh fat mealDistributionWide.Good CNSpenetrationLow urinary levelsPoor CNSWidelydistributed intotissuesMetabolismHepatic/RenalHepaticCYP 2C9, 2C19,3A4SaturablemetabolismNot a substrate ofor metabolized byP450, but it is anInhibitor of 3A4Elimination80% excreted unchanged in the urineExcreted in fecesMinimal renalexcretionexcretion of parentcompound66% excreted in feces
18 Triazoles—Fluconazole Dose100 to 400 mg dailyRenal impairment:CrCl >50 ml/min, give full doseCrCl<50 ml/min, give 50% of doseDialysis: replace full dose after each sessionDrug InteractionsMinor inhibitor of CYP 3A4Moderate inhibitor of CYP 2C9Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureasAdverse Drug ReactionsWell toleratedNauseaElevated LFTsHigher doses have been used with good tolerabilityUNC Hospital Formulary
19 Triazoles—Itraconazole Dose200 to 400 mg/day (capsules)doses exceeding 200 mg/day are given in 2 divided dosesLoading dose: 200 mg 3 times daily can be given for the first 3 daysOral solution is 60% more bioavailable than the capsulesDrug InteractionsMajor substrate of CYP 3A4Strong inhibitor of CYP 3A4Many Drug InteractionsAdverse Drug ReactionsContraindicated in patients with CHF due to negative inotropic effectsQT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest in the setting of drug interactionsHepatotoxicityRashHypokalemiaNausea and vomitingCapsules and solution are not interchangeableCoadministration 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 DoseIV6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 hoursPO> 40 kg— mg PO every 12 hours< 40 kg— mg PO every 12 hoursCirrhosis: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 hoursRenal impairment:if CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizerCyclodextrin solubilizeraccumulates in renalNo, BUT: IV should not be used for CrCl< 50
21 Triazoles—Voriconazole Drug InteractionsMajor substrate of CYP 2CD and 2C19Minor substrate of CYP 3A4Weak inhibitor of CYP 2C9 and 2C19Moderate inhibitor of CYP 3A4Dose AdjustmentsEfavirenzPhenytoinCyclosporineWarfarinTacrolimusCommon Adverse EffectsPeripheral edemaRash (6%)N/V/DHepatotoxicityHeadacheVisual disturbance (30%)FeverSerious Adverse EventsStevens-Johnson SyndromeLiver failureAnaphylaxisRenal failureQTc prolongationVisual disturbance is an important counseling point for patients!!
22 Triazoles—Posaconazole Dosing (only available PO)Prophylaxis of invasive Aspergillus and Candida species200 mg 3 times/dayTreatment of oropharyngeal candidiasis100 mg twice daily for 1 day, then 100 mg once daily for 13 daysTreatment or refractory oropharyngeal candidiasis400 mg twice dailyTreatment of refractory invasive fungal infections (unlabeled use)800 mg/day in divided dosesDrug InteractionsModerate inhibitor of CYP3A4Adverse ReactionsHepatotoxicityQTc prolongationGI: Diarrhea
23 EchinocandinsMOAIrreversibly 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 IVPeak/MIC concentration dependent killing
24 Echinocandins—Spectrum of Activity CandidaAspergillusCryptococcusCoccidioidesBlastomycesHistoplasmaFusariumScedosporidiumZygomycetesalbicansglabratakruseitropicalisparapsilosislusitanaeguilliermondii++++--++-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 CaspofunginMicafunginAnidulafunginAbsorptionNot orally absorbed. IV onlyDistributionExtensive into the tissues, minimal CNS penetrationMetabolismspontaneous degradation, hydrolysis and N-acetylationChemical degradatedNot hepatically metabolizedEliminationLimited urinary excretion. Not dialyzableHalf-life9-23 hours11-21 hours26.5 hoursDose70 mg IV on day1, then 50 mg IVdaily thereafter100 mg IVonce daily200 mg IV on day 1,then 100 mg IVDose AdjustmentChild-Pugh 7-970 mg IV on day 1, then 35 mg IV daily thereafterCYP inducers70 mg IV dailyNone
26 Echinocandin—Drug Interactions CaspofunginNot an inducer or inhibitor of CYP enzymesCYP inducers (i.e. phenytoin, rifampin, carbamazepine)Reduced caspofungin levelsIncrease caspofungin doseCyclosporineIncreases AUC of caspofunginHepatotoxicityAvoid or monitor LFTsTacrolimusReduced tacrolimus levels by 20%Monitor levels of tacrolimusMicafunginMinor substrate and weak inhibitor of CYP3A4NifedipineIncreased AUC (18%) and Cmax (42%) of nifedipineSirolimusIncreased concentration of sirolimusAnidulafunginNo clinically significant interactionsCappelletty et al. Pharmacotherapy 2007;27:369-88
27 Echinocandins—Adverse Effects Generally well toleratedPhlebitis, GI side effects, HypokalemiaAbnormal liver function testsCaspofunginTends to have higher frequency of liver related laboratory abnormalitiesHigher frequency of infusion related pain and phlebitis
28 ReferencesGallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:UNC Hospital FormularyPatel 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.