elsevier inc. items and derived items © 2010 by saunders, an imprint of elsevier inc. chapter 91...

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 91Chapter 91

Antifungal AgentsAntifungal Agents

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. 2

Systemic MycosesSystemic Mycoses

Treatment can be difficult.Treatment can be difficult. Infections often resist treatment.Infections often resist treatment. Treatment may require prolonged therapy Treatment may require prolonged therapy

with drugs that frequently prove toxic.with drugs that frequently prove toxic.


Major Groups of Antifungal AgentsMajor Groups of Antifungal Agents

1.1. Drugs for systemic mycoses infectionsDrugs for systemic mycoses infections2.2. Drugs for superficial mycoses infectionsDrugs for superficial mycoses infections

Note: A few drugs are used for both.Note: A few drugs are used for both.



1.1. Systemic mycoses infectionsSystemic mycoses infections OpportunisticOpportunistic

• Immunocompromised hostImmunocompromised host Candidiasis, aspergillosis, cryptococcosis, mucormycosisCandidiasis, aspergillosis, cryptococcosis, mucormycosis

NonopportunisticNonopportunistic• Can occur in any hostCan occur in any host

Sporotrichosis, blastomycosis, histoplasmosis, Sporotrichosis, blastomycosis, histoplasmosis, coccidioidomycosiscoccidioidomycosis



2.2. Superficial mycoses infections Superficial mycoses infections CandidiasisCandidiasis DermatophytesDermatophytes


Four Classes of Antifungal DrugsFour Classes of Antifungal Drugs

1.1. Polyene antibioticsPolyene antibiotics2.2. AzolesAzoles3.3. EchinocandinsEchinocandins4.4. Pyrimidine analogsPyrimidine analogs


Amphotericin BAmphotericin B

Broad-spectrum antifungal agent (also used Broad-spectrum antifungal agent (also used against some protozoa)against some protozoa)

Highly toxicHighly toxic Infusion reaction and renal damage occur in all Infusion reaction and renal damage occur in all

patients to varying degreespatients to varying degrees Must be given IV – no oral administrationMust be given IV – no oral administration

UsesUses Drug of choice for most systemic mycosesDrug of choice for most systemic mycoses Before ampho B, systemic fungal infections were Before ampho B, systemic fungal infections were

usually fatalusually fatal



Mechanism of actionMechanism of action Binds to ergosterol (much more than cholesterol) Binds to ergosterol (much more than cholesterol)

in fungal cell membranein fungal cell membrane• Bacterial cell membranes lack sterolsBacterial cell membranes lack sterols• Fungi damaged more than human cellsFungi damaged more than human cells

Increases the permeabilityIncreases the permeability Cell leaks intracellular cations (especially Cell leaks intracellular cations (especially

potassium)potassium) Fungistatic or fungicidalFungistatic or fungicidal


Amphotericin B Amphotericin B

Adverse effectsAdverse effects Infusion reactionsInfusion reactions NephrotoxicityNephrotoxicity HypokalemiaHypokalemia



Infusion reactionInfusion reaction Fever, chills, rigors, nausea, and headacheFever, chills, rigors, nausea, and headache Caused by release of proinflammatory cytokinesCaused by release of proinflammatory cytokines Symptoms begin 1-3 hours after starting infusion Symptoms begin 1-3 hours after starting infusion

and last for about 1 hourand last for about 1 hour Less intense with lipid-based ampho B Less intense with lipid-based ampho B

formulations formulations



Infusion reaction (cont’d)Infusion reaction (cont’d) Mild reactions – pretreatment optionsMild reactions – pretreatment options

• Diphenhydramine plus acetaminophenDiphenhydramine plus acetaminophen• Aspirin can help – may increase renal damageAspirin can help – may increase renal damage

IV meperidine or dantrolene can be given if rigors IV meperidine or dantrolene can be given if rigors occur.occur.

Hydrocortisone can be given with caution.Hydrocortisone can be given with caution.



NephrotoxicityNephrotoxicity Extent of kidney damage related to total dose Extent of kidney damage related to total dose

administered over the full course of treatmentadministered over the full course of treatment If total dose >4 g, residual impairment likelyIf total dose >4 g, residual impairment likely Damage minimized by infusing 1 L of saline on Damage minimized by infusing 1 L of saline on

days of treatmentdays of treatment



Nephrotoxicity (cont’d)Nephrotoxicity (cont’d) Avoid other nephrotoxic drugs concurrently.Avoid other nephrotoxic drugs concurrently.

• Aminoglycosides, cyclosporinsAminoglycosides, cyclosporins NSAIDs should also be avoided.NSAIDs should also be avoided. Monitor serum creatinine q 3-4 days.Monitor serum creatinine q 3-4 days.

• Reduce dosage if >3.5 mg/dLReduce dosage if >3.5 mg/dL



HypokalemiaHypokalemia Results from damage to the kidneysResults from damage to the kidneys May need potassium supplementsMay need potassium supplements Monitor serum levelsMonitor serum levels

Hematologic effectsHematologic effects Can cause bone marrow suppressionCan cause bone marrow suppression

• Anemia Anemia –– monitor hematocrit monitor hematocrit


AzolesAzoles

Broad-spectrum antifungal drugsBroad-spectrum antifungal drugs 5/14 5/14 – can be an– can be an alternative to ampho B for alternative to ampho B for

most systemic mycosesmost systemic mycoses Lower toxicityLower toxicity Can be given orallyCan be given orally DisadvantageDisadvantage

Inhibit P450 drug-metabolizing enzymes and can Inhibit P450 drug-metabolizing enzymes and can increase the levels of many other drugsincrease the levels of many other drugs


Itraconazole (Sporanox)Itraconazole (Sporanox)

Azole group of antifungal agentsAzole group of antifungal agents Lower toxicity levelLower toxicity level Uses Uses

Systemic mycoses (alternative to ampho B)Systemic mycoses (alternative to ampho B) Mechanisms of actionMechanisms of action

Inhibits the synthesis of ergosterolInhibits the synthesis of ergosterol Inhibits fungal cytochrome P450-dependent Inhibits fungal cytochrome P450-dependent

enzymesenzymes


Itraconazole (Sporanox)Itraconazole (Sporanox)

Side effects (well tolerated in usual doses)Side effects (well tolerated in usual doses) CardiosuppressionCardiosuppression

• Transient decrease in ventricular ejection fractionTransient decrease in ventricular ejection fraction Liver damageLiver damage

• Watch for signs of liver dysfunctionWatch for signs of liver dysfunction Can inhibit drug metabolizing enzymesCan inhibit drug metabolizing enzymes GI effectsGI effects

• Nausea, vomiting, diarrheaNausea, vomiting, diarrhea


Fluconazole (Diflucan)Fluconazole (Diflucan)

Azole group of antifungal agentsAzole group of antifungal agents FungistaticFungistatic Same mechanism of action as itraconazoleSame mechanism of action as itraconazole Oral absorption goodOral absorption good

IV and oral dosage the sameIV and oral dosage the same


Fluconazole (Diflucan)Fluconazole (Diflucan)

Adverse effectsAdverse effects NauseaNausea HeadacheHeadache VomitingVomiting Abdominal painAbdominal pain DiarrheaDiarrhea


Voriconazole (Vfend)Voriconazole (Vfend)

Azole group of antifungal agentsAzole group of antifungal agents Broad spectrum of fungal pathogensBroad spectrum of fungal pathogens UsesUses

CandidemiaCandidemia Invasive aspergillosisInvasive aspergillosis Esophageal candidiasisEsophageal candidiasis Scedosporium apiospermumScedosporium apiospermum––resistant infectionsresistant infections

Mechanism of actionMechanism of action Suppresses synthesis of ergosterolSuppresses synthesis of ergosterol


Voriconazole (Vfend)Voriconazole (Vfend)

Adverse effectsAdverse effects HepatotoxicityHepatotoxicity Visual disturbances, hallucinationsVisual disturbances, hallucinations Fetal injuryFetal injury Hypersensitivity reactionsHypersensitivity reactions Nausea, vomiting, and abdominal painNausea, vomiting, and abdominal pain HeadacheHeadache Drug interactionsDrug interactions


Ketoconazole (formerly Nizoral)Ketoconazole (formerly Nizoral)

Azole group of antifungal agentsAzole group of antifungal agents Mechanism of actionMechanism of action

Inhibits ergosterolInhibits ergosterol Uses: Alternative to ampho B for systemic Uses: Alternative to ampho B for systemic

mycosesmycoses Less toxic and only somewhat less effectiveLess toxic and only somewhat less effective Slower effectsSlower effects More useful in suppressing chronic infections than More useful in suppressing chronic infections than

in treating severe, acute infectionsin treating severe, acute infections


Ketoconazole (formerly Nizoral)Ketoconazole (formerly Nizoral)

Adverse effects (generally well tolerated)Adverse effects (generally well tolerated) GI (can be reduced if given with food)GI (can be reduced if given with food) HepatotoxicityHepatotoxicity

• Rare but potentially fatal hepatic necrosisRare but potentially fatal hepatic necrosis Effect on sex hormonesEffect on sex hormones

• Can inhibit steroid synthesis in humansCan inhibit steroid synthesis in humans Other adverse effectsOther adverse effects

• Rash, itching, dizziness, fever, chills, constipation, Rash, itching, dizziness, fever, chills, constipation, diarrhea, photophobia, and headachediarrhea, photophobia, and headache


Flucytosine (Ancobon)Flucytosine (Ancobon)

Pyrimidine analogPyrimidine analog UsesUses

Serious infections of susceptible strains of Serious infections of susceptible strains of CandidaCandida and and CryptococcusCryptococcus neoformansneoformans

Resistance common Resistance common Often used with ampho BOften used with ampho B

Extreme caution in patient with renal Extreme caution in patient with renal impairment or hematologic disordersimpairment or hematologic disorders


Flucytosine (Ancobon)Flucytosine (Ancobon)

Adverse effectsAdverse effects HematologicHematologic

• Bone marrow suppressionBone marrow suppression HepatotoxicityHepatotoxicity

• Inhibits hepatic drug-metabolizing enzymesInhibits hepatic drug-metabolizing enzymes


Drugs for Superficial MycosesDrugs for Superficial Mycoses

Mycoses caused by two groups of organismsMycoses caused by two groups of organisms CandidaCandida species species

• Usually in mucous membranes and moist skinUsually in mucous membranes and moist skin• Chronic infections may involve scalp, skin, and nailsChronic infections may involve scalp, skin, and nails

Dermatophytic infections (eg, ringworm)Dermatophytic infections (eg, ringworm)• Usually confined to skin, hair, and nailsUsually confined to skin, hair, and nails• More common than More common than CandidaCandida infections in nails infections in nails



Oral candidiasis (thrush)Oral candidiasis (thrush) Vulvovaginal candidiasisVulvovaginal candidiasis

75% of women experience at least once75% of women experience at least once Risk factorsRisk factors

• Pregnancy, obesity, diabetes, debilitation, HIV, oral Pregnancy, obesity, diabetes, debilitation, HIV, oral contraceptives, systemic glucocorticoids, anticancer contraceptives, systemic glucocorticoids, anticancer agents, and systemic antibioticsagents, and systemic antibiotics

OnychomycosisOnychomycosis



Dermatophytic infections (eg, ringworm)Dermatophytic infections (eg, ringworm) Tinea pedis (feet)Tinea pedis (feet) Tinea corporis (body)Tinea corporis (body) Tinea cruris (groin)Tinea cruris (groin) Tinea capitis (scalp)Tinea capitis (scalp)

DrugsDrugs Clotrimazole Clotrimazole – – topicaltopical Griseofulvin Griseofulvin – – oraloral


Griseofulvin (Grifulvin)Griseofulvin (Grifulvin)

UsesUses Superficial mycosesSuperficial mycoses Ineffective systemic mycosesIneffective systemic mycoses

Inhibits fungal mitosisInhibits fungal mitosis Adverse effectsAdverse effects

Transient headacheTransient headache RashRash GastrointestinalGastrointestinal InsomniaInsomnia TirednessTiredness


Nystatin (Mycostatin)Nystatin (Mycostatin)

Polyene antibioticPolyene antibiotic Used only for candidiasisUsed only for candidiasis Drug of choice for intestinal candidiasisDrug of choice for intestinal candidiasis Also used for candidal infections in skin, Also used for candidal infections in skin,

mouth, esophagus, and vaginamouth, esophagus, and vagina Can be administered orally or topicallyCan be administered orally or topically

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