Antifungal agents

Drugs/drug class: Amphotericin B, Flucytosine, Azoles,

Echinocandins
Amphotericin B
 Amphotericin B is produced by Streptomyces nodosus.
 It is nearly insoluble in water
– Prepared as a colloidal suspension of amphotericin B and
sodium deoxycholate for IV.
 Lipid Formulation of Amphotericin B
 Liposomal amphotericin preparations package the active drug in lipid
delivery vehicles
 Formulated to reduce drug-induced renal impairment

– lipid-packaged drug binds to the mammalian membrane less

readily
– Amphotericin binds to the lipids in vehicles with an affinity
between that for fungal ergosterol and that for human cholesterol.
– The lipid vehicle then serves as an amphotericin reservoir,
• some fungi contain lipases that may liberate free amphotericin B directly at
the site of infection.
 Lipid Formulation of Amphotericin B

Lipid formulations compared to convetional preparation

 Better efficacy and
 Less related toxicities
 Expensive
– Limited to patients not responding/ tolerated conventional
preparation
 Amphotericin B

Amphotericin B is poorly absorbed from the GIT

 Oral amphotericin B has effective only on fungi within the
lumen of GI
 cannot be used for treatment of systemic disease.
PK
 IV….. 0.6 mg/kg/d ……..result in 0.3–1 mcg/mL
 Protein binding…..> 90 %
 The serum half-life > 15 days.
 widely distributed in most tissues, but
 only 2–3% reached in cerebrospinal fluid,
 occasionally necessitating intrathecal therapy for certain types of
fungal meningitis
 Mechanisms of Action & Resistance

Amphotericin B is selective in its fungicidal effect

 it exploits the difference in lipid composition of fungal and
mammalian cell membranes.
– Act on Ergostero…a cell membrane sterol, is found in the
cell membrane of fungi,
MOA….It binds to ergosterol and alters the permeability of the
cell
Interaction/binding….
– with lipids (ergosterol) along the double bond–rich side
– with water molecules along the hydroxyl-rich side.
• This amphipathic characteristic facilitates pore …leakage of ……
intracellular ions and macromolecules……cell death.
Targets of antifungal drugs.
 Mechanisms of Action & Resistance…
Resistance to amphotericin B occurs
 If ergosterol binding is impaired, due to
– decreasing concentration of ergosterol/or modifications of sterol target
Antifungal Activity & Clinical Uses
It has broadest spectrum and activeagainst
 Yeasts
– Candida albicans and
– Cryptococcus neoformans;
 the organisms causing endemic mycoses,
– Histoplasma capsulatum,
– Blastomyces dermatitidis, and
– Coccidioides immitis;
 pathogenic molds….Aspergillus fumigatus and the agents of
mucormycosis.
Resistance to Candida lusitaniae and Pseudallescheria boydii
 Clinical use

Due to broad spectrum of activity ..used for all life-threatening mycotic

infections,
– but less toxic agents have largely replaced it for most conditions.

It is often used as the initial induction regimen….then replaced by azoles

(maintenance therapy)

Dose…. (0.5–1 mg/kg)…slow Iv infusion

Intrathecal amphoterIcin B……fungal meningitis ….if not responded by

other agents
 Clinical use…
Local or topical amphotericin B
 For Mycotic corneal ulcers and keratitis can be cured with
– direct subconjunctival injection.
 Fungal arthritis…..direct injection to joint.
 Candiduria…..bladder irrigation with amphotericin B
Adverse Effects
 The toxicity of amphotericin B can be
– Infusion-related reactions
– Cumulative toxicity
 Adverse effects

Infusion-related toxicity
Infusion-related reactions are nearly universal
– These are fever, chills, muscle spasms, vomiting, headache, and
hypotension.
– ameliorated by slowing the infusion rate or decreasing the daily dose.
– Premedication with antipyretics, antihistamines, meperidine, or
corticosteroids can be helpful. When
– starting therapy……IV 1 mg (as a guide /know severity )
Cumulative toxicity
Renal damage is the most significant toxic reaction
reversible component
– decreased renal perfusion and represents a form of prerenal renal
failure
– Can be attenuated with sodium loading,
irreversible component with (>4 g cumulative dose)
 Adverse effects…
Anemia due to reduced erythropoietin production by damaged,

seizures
Flucytosine

Mechanism of action

 First it undergoes deamination (Flucytosine….to 5-FU)

 Fluorouracil….then…..metabolized to 5-fluorouracil-ribose monophosphate (5-FUMP)

(by uracil phosphoribosyl transferase (UPRTase).

 5-FUMP then is either incorporated into RNA (via synthesis of 5-fluorouridine

triphosphate) or metabolized to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP),
– a potent inhibitor of thymidylate synthetase and thus of DNA synthesis.

– The selective action of flucytosine is due to the lack of cytosine deaminase in mammalian
cells.
 Flucytosine

Figure: Mechanisms of Flucytosine

 Chemistry & Pharmacokinetics

 Dosage….. 100 mg/kg/d in divided doses (normal renal

function)
 absorption ……>90%,
 half-life….. 3–4 hours
 Toxicity is more likely to occur in AIDS patients and those
with renal insufficiency concentration be..(50 and 100
mcg/m)L.
 Mechanisms of resistance

• Resistance is thought to be mediated through altered

metabolism of flucytosine,
– develops rapidly in the course of flucytosine monotherapy.
 Clinical Uses & Adverse Effects

 Spectrum of activity
– C neoformans,
– some Candida sp, and the
– dematiaceous molds that cause chromoblastomycosis.
 Flucytosine is rarely used as a single agent
– with amphotericin B…..for cryptococcal meningitis
– with Itraconazole….for chromoblastomycosis.
 Adverse Effects

 ADR of flucytosine is resulted from

Metabolism to…..fluorouracil. And thecommon adverse effects
are
– Bone marrow toxicity with anemia,
– leukopenia, and
– thrombocytopenia.
• A form of toxic enterocolitis can occur.
 Azoles

Chemistry & Pharmacokinetics

can be classified as either
 imidazoles
 ketoconazole, miconazole, and clotrimazole
 Less selective to fungal enzyme
– Higher incidence of drug interaction
 triazoles
itraconazole, fluconazole, voriconazole, isavuconazole, and
posaconazole.
Mechanisms of Action & Resistance
MOA…. results from the reduction of ergosterol synthesis by
inhibition of fungal cytochrome P450 enzymes
Selectivity….. their greater affinity for fungal than for human
cytochrome P450 enzymes
 Clinical Uses,
The spectrum of action……They do have broad spectrum of
activity
 Candida (C neoformans)
 mycoses (blastomycosis, coccidioidomycosis, histoplasmosis),
the
 Dermatophytes
 Aspergillus….. itraconazole, posaconazole, isavuconazole, and
voriconazole
 amphotericin-resistant organisms such as P boydii.
 Adverse Effects, & Drug Interactions

 As a group….they are relatively nontoxic.

minor Gl upset……most common

 cause abnormalities in liver enzymes
 Hepatitis (very rarely)
 They are prone to drug interactions
 affect the mammalian P450 to some extent.
 Ketoconazole

 the first oral azole introduced into clinical use.

 Compared to other triazoles by its
• Greatly inhibit mammalian cytochrome P450 enzymes
– less selective for fungal P450 than are the newer azoles.

– It is no longer recommended for the treatment of fungal nail or skin

infections.
 Itraconazole

 available in oral and IV formulations and is used at a

– dosage of 100–400 mg/d.
 Drug interaction…..bioavailability reduced with
– rifamycins (rifampin, rifabutin, rifapentine).
 Bioavailability can be increased with cyclodextrin as a
carrier molecule
Itraconazole is the azole of choice for treatment of due to the
– dimorphic fungi Histoplasma ⸻ Blastomyces

– Sporothrix ⸻dermatophytoses
– Aspergillus sp ⸻onychomycosis.
• But replaced by voriconazol
 Fluconazole

 available in oral and IV formulations

dosage of 100–800 mg/d.
 Oal bioavalablity >> than itra and keto
 Drug interactions ….. fluconazole has the least effect of all the
azoles on hepatic microsomal enzymes.
 better gastrointestinal tolerance,
– has the widest therapeutic index of the azoles,
• more aggressive dosing in a variety of fungal infections possible.
 Fluconazole…
Clinical use
 For secondary prophylaxis of cryptococcal meningitis. 4

 IV fluconazole = amphotericin B in treatment of candidemia in

ICU, but
– echinocandins may have superior activity for this indication.

 mucocutaneous candidiasis. But

– no activity against Aspergillus or other filamentous fungi.

 Prophylactic….in bone marrow transplant recipients and AIDS

patients
 Voriconazole

 available in intravenous and oral (BA>90 %).

 dosage is 400 mg/d.

 Drug interaction…..It inhibits CYP3A4

– (+) concentrations of cyclosporine, tacrolimus, and HMG-CoA reductase
inhibitors.

Adverse drug interaction

 rash and elevated hepatic enzymes.

 IV fluconazole…Visual disturbances (in up to 30%)

 Chronic Oral use….Photosensitivity dermatitis

 Voriconazole…

Spectrum of activity…..similar to itraconazole

– Candida sp (including some fluconazole-resistant
species such as Candida krusei)
– dimorphic fungi.
– invasive aspergillosis
 Posaconazole

 Has broadest-spectrum activity and active

 against most species of Candida and Aspergillus.
 mucormycosis.
 prophylaxis of fungal infections during
– induction chemotherapy for leukemia, and for
– allogeneic bone marrow transplant
Dose….dosage of 800 mg/d, divided (BID/QID)
 Absorption is increased with meals high in fat.
 Available with IV and SR tablet
Drug interaction……inhibitor of CYP3A4 substrates
 Isavuconazole (isavuconazonium sulfate)

 Isavuconazonium sulfate is a prodrug of

isavuconazole;
 It is available as capsules and an IV formulation.
 Food does not significantly affect absorption
 Spectrum of activity……similar to posaconazole.

Clinical use…. for the treatment of invasive

aspergillosis and invasive mucormycosis.
 Echinocandins

Drugs In this class…... Caspofungin, micafungin, and

anidulafungin
MOA……act at the level of the fungal cell wall by inhibiting the
synthesis of β(1–3)-glucan
– results in disruption of the fungal cell wall and cell death.

 active against Candida and Aspergillus, but not

 C neoformans or the agents of zygomycosis and
mucormycosis.
 are available only in intravenous formulations.
 Clinical Uses

Caspofungin is indicated for

 disseminated and mucocutaneous candidal infections
 empiric antifungal therapy during febrile neutropenia (now
replaced AMB)
 invasive aspergillosis only as salvage therapy
– in patients who have failed to respond to amphotericin B
Micafungin is indicated for
 mucocutaneous candidiasis,
 candidemia, and
 prophylaxis of candidal infections in bone marrow transplant
patients.
Anidulafungin……esophageal candidiasis and invasive
candidiasis, including candidemia.
 Adverse Effects
 Echinocandin agents are extremely well tolerated
But minor gastrointestinal side effects and flushing
Caspofungin +cyclosporine
Elevated liver enzymes…..combination should be
avoided.
Micafungin has been shown to (+)
 levels of nifedipine, cyclosporine, and sirolimus.
Anidulafungin does not have significant drug
interactions, but
– histamine release may occur during Iv infusion.
 Oral systemic antifungal drugs for mucocutaneous infections
Drugs in this class: Griseofulvin, Terbinafine
Griseofulvin
 Mechanism of Griseofulvin’s ……at the cellular level
 inhibits microtubule function……disrupts fungal cell
division
 Deposited in newly forming skin binds to keratin,
protecting the skin from new infection.
 must be administered for 2–6 weeks for skin and hair
 Nail may require therapy for months
 Absorption is improved with fatty foods
 Griseofulvin

Adverse effects include

 an allergic syndrome much like
 serum sickness,
 skin reactions,
 a lupus-like syndrome,
 Hepatotoxicity
 Drug interactions
– with warfarin and phenobarbital.
 Griseofulvin has been largely replaced by newer antifungal
medications such as itraconazole and terbinafine
 Terbinafine

 Terbinafine is a synthetic allylamine

 oral formulation……250 mg/d.
 It is used in the treatment of dermatophytoses, especially
onychomycosis
 It is a keratophilic medication, but unlike griseofulvin,
– it is fungicidal.
– for onychomycosis >>>griseofulvin or itraconazole
MOA…it interferes with ergosterol biosynthesis,
– inhibits the fungal enzyme squalene epoxidase
– leads to the accumulation of the sterol squalene (toxic to the
organism).
 Adverse effects….rare...GI upset and headache and and serious
hepatotoxicity
 Nystatin

 It is a polyene macrolide
 It is too toxic for parenteral
 only used topically.
 available in creams, ointments, suppositories
 has little toxicity, but
 oral use is often limited by the unpleasant taste.
 Spectrum of activity ….active against most
 Candida sp and
 common indications include
– oropharyngeal thrush,
– vaginal candidiasis, and
– intertriginous candidal infections.
 Topical Azoles

 clotrimazole and miconazole are used topically

 Vaginal pessaries…..for vulvovaginal candidiasis.
 Oral clotrimazole troches…..for treatment of oral thrush and
 both agents are useful for dermatophytic infections

– Tinea corporis,
– Tinea pedis, and
– Tinea cruris.
 shampoo forms of ketoconazole
 For seborrheic dermatitis and pityriasis versicolor.