Antifungal Agents

Dr M Dhoro
Clinical Pharmacology
 Fungi
• microscopic organisms, invade epithelial tissue
• yeasts, molds, rusts and mushrooms
• Heterotrophic- obtain nutrients from environment
• introduced into skin through wounds, lungs, nasal
passages if inhaled.
• grow best in acidic environment ( tolerate acidic pH)
• Cell wall composed of chitin
• Cell membrane consists of ergosterol
• More than 100 fungi responsible for human infections
 Fungal infections
• Superficial (outer skin layer)
– involve cutaneous surfaces: skin, nails, hair (tinea
versicolor, tinea pedis ,ring worm infection)
– mucous membrane surfaces (oral thrush, vulvo-
vaginitis , nail infections)
– Caused by dermatophytes
 Fungal infections
• Subcutaneous
– Subdermal layers- surgical intervention
– sporotrichosis, chromomycosis, mycetoma
– enter tissue, usually through trauma.
• Disseminated/ systemic
– cryptococcal meningitis, endocarditis, pulmonary
aspergillosis
– Affect internal organs: lung ,heart , brain
Opportunistic Infections
 Fungal infections
• Clinically important fungi:
– Yeasts - Cryptococcus neoformans (meningitis)
– Yeast-like - Candida albicans (thrush – 75% of infections)
– Filamentous - Aspergillus fumigatus (Pulmonary
aspergillosis)
– Dimorphic- Coccidioides immitis (Coccidiomycosis)
• increase in incidence of serious secondary systemic infections
– widespread use of broad-spectrum antibiotics
– intensive care units, patients with AIDS, autoimmune
diseases, burns, radiotherapy, chemotherapy,
transplantation, major surgical procedures
• Vulnerable groups
– Older people, diabetics, pregnant women, burn wound
victims
 Antifungal drugs
• three general mechanisms of action
– cell membrane disruption- target ergosterol,
fungal membrane sterol
– inhibition of cell division- target microtubule
effects in forming mitotic spindle OR inhibit DNA
transcription
– inhibition of cell wall formation- target β-glucan
synthesis
 Classification of Antifungal Drugs

1. Antifungal Antibiotics
• Polyenes : Amphotericin B, Nystatin,
Natamycin
• Nonpolyenes: Griseofulvin
• Echinocandins
 Amphotericin B

• derived from cultures of Streptomyces.

• Active against most fungi and yeasts:
• Mennengitis, thrush, systemic candidiasis,
pulmonary aspergillosis
• gold standard for treating disseminated infections
(1958)
• interferes with permeability + transport functions
of cell membrane
– forms large pores in membrane
– disturbances in ion balance, loss of intracellular K+
• long elimination half-life (>15 days).
 Amphotericin B
• poorly absorbed when given orally- infections
of upper GIT
• slow IV injection complexed with liposomes or
other lipid-containing preparations (1990s)-
systemic infections
• Reduces toxicity profile
• liposomal amphotericin B (L-AmB) and
amphotericin B lipid complex (ABLC)
• L-AmB- enhanced ability to penetrate CNS,
preferred formulation for treatment of
Candida meningitis
 Amphotericin B

• IV amphotericin + flucytosine to treat cryptococcal

meningitis (first-line therapy)
• enhances antifungal effect of flucytosine - synergistic
combination
• highly protein bound, excreted very slowly via kidney
• lipid-based formulations preferred for organ transplant
recipients
• A/Es: renal toxicity, hypokalaemia, thrombocytopenia,
neurotoxicity, skin rash, I.V induced chills + fever,
hypotension
• Few drug-drug interactions- not metabolized by
hepatic CYP450 enzymes
 Nystatin

• similar in structure to amphotericin B + same

mechanism of action
• Use mainly limited to Candida infections of
skin, mucous membranes, GIT.
• Too toxic for systemic use
• Available in oral tablets, powder for
suspension, vaginal tablets, pastilles
• A/Es: nausea, vomiting, diarrhoea, itching
 Natamycin
• supplied as a 5% ophthalmic suspension
• Suspension intended for the treatment of fungal
conjunctivitis, blepharitis and keratitis
• cause both K leakage and cell lysis at same
concentration
• Adverse Effects: Eye irritation, redness and
swelling
 Griseofulvin
• narrow-spectrum - isolated from cultures of
Penicillium griseofulvum
• dermatophyte infections of skin or nails
(Athlete’s foot , scalp ringworm)
• inhibits formation of mitotic spindle during
mitosis
• binds to keratin precursor cells + newly
synthesized keratin in skin, hair, nails - stops
progression of infection.
• given orally, absorption varies with type of
preparation
 Griseofulvin
• 500mg once a day- 2weeks (ringworm) or 8
weeks (athlete’s foot)
• Take with food or milk
• potently induces CYP450 enzymes- many drug
interactions (give examples)
• A/Es: GI upsets, headache, photosensitivity,
allergic reactions (rashes, fever)
• Should not be used in pregnancy
 Echinocandins
• Semisynthetic lipopeptides, introduced in the 2000s
• fungicidal against some yeasts (most species of Candida), Aspergillus ,
Histoplasma.
• synergistic activity with amphotericin B + additive activity with fluconazole
• Inhibit synthesis of 1,3-β-glucan (glucose polymer necessary for
maintaining structure of fungal cell walls)
• Dose dependent non-competitive inhibition
• poor absorption after oral administration limits use to IV.
• Few drug-drug interactions
– Caspofungin- candidiasis, invasive aspergillosis that are refractory to
amphotericin B
– Given I.V, once daily.
– List 2 other examples
– A/Es: nausea, vomiting, diarrhoea, skin rash, vein irritation
2. Synthetic Antifungals
• Azoles :
– Imidazoles : Ketoconazole , Miconazole,
cotrimazole
– Triazoles : Fluconazole , Itraconazole
• Fluorinated pyrimidines: Flucytosine
• Allylamines : Terbinafine, Naftifine
 Azoles
• broad spectrum
• topically to treat superficial dermatophytic and yeast
infections.
• systemically to treat severe fungal infections
• antibacterial , antiprotozoal, anthelminthic & antifungal
activity
• Inhibit fungal CYP450 3A enzyme, lanosine 14α-demethylase
• Inhibits conversion of lanosterol to ergosterol,
• depletion of ergosterol alters fluidity of membrane
• net effect - inhibition of replication.
 Azoles
• *Depletion of membrane ergosterol reduces
binding of amphotericin.
• toxicity of drugs depends on relative affinities for
mammalian and fungal CYP450 enzyme
• Triazoles - fewer side effects, better absorption,
better drug distribution in body tissues, fewer
drug interactions
• most available as topical preparations for the
treatment of vaginal candidiasis or cutaneous
fungal infection
 Imidazoles
• Ketoconazole (first effective oral therapy for Candida)
• treatment of cutaneous and mucous membrane dermatophyte +
yeast infections,
• 2nd line treatment of tinea versicolor (200 -400mg daily for 5 dys)
• given orally,
• cream or in shampoos at 1-2% for treatment of tinea pedis, tinea
corporis, tinea cruris and cutaneous candidiasis.
• Needs acidic environment for absorption
• A/Es: liver toxicity, GI distrubance, pruritis
• Monitor liver function before and during treatment
• Inhibition of adrenocortical steroid + testosterone synthesis at high
doses
• Ciclosporin, astemizole increase plasma concentrations of
ketoconazole
• Rifampicin, histamine H2 receptor antagonists and antacids
decrease absorption of ketoconazole.
 Imidazoles
• Miconazole
• skin infections such as athlete’s foot, tinea cruris, vulvovaginitis,
body ringworm, tinea versicolor
• Available as cream, lotion, powder, spray liquid, spray powder,
suppository form for vaginal use
• short plasma half-life, given every 8 h.
• used once or twice a day for one month for tinea pedis or two
weeks for other skin infections
• For vaginal infections used once a day at bedtime for three or seven
days.
• reaches therapeutic concentrations in bone, joints, lung tissue but
not in CNS
• inactivated in liver.
• A/Es: pruritus, blood dyscrasias, hyponatraemia, liver damage, fever
 Imidazoles
• Cotrimazole
• broad-spectrum fungistatic
• active against a wide range of fungi
• topical treatment of oral, skin, vaginal infections with C.
albicans, cutaneous dermatophytes, tinea pedis, body
ringworm
• binds to phospholipids in cell membrane – inhibits
biosynthesis of ergosterol + other sterols required for cell
membrane production
• A/Es: nausea, itchness, redness, burning , vomiting
• any medication metabolized by CYP3A4 enzyme will
potentially have elevated levels when oral clotrimazole is
used
 Imidazoles
• ECONAZOLE
• topical cream applied to skin to treat tinea corporis, tinea pedis, tinea cruris, and
superficial candidiasis.
• Adverse effects include: Burning, itching, stinging, redness and skin rash.

• OXICONAZOLE
• cream or lotion applied to skin in treatment of tinea corporis, tinea pedis and tinea cruris.
• Adverse effects include: Burning, itching, blistering, crusting, dryness or flaking of the
skin, scaling, severe redness, soreness, swelling and pain in hairy areas with pus at the
root of hair.

• SULCONAZOLE
• topical cream or solution to treat tinea corporis, tinea pedis and tinea cruris.
• Adverse effects include: Burning, stinging, itching and redness of the skin.

• TIOCONAZOLE
• cream to treat tinea corporis, tinea pedis, tinea cruris and cutaneous candidiasis.
• Adverse effects include: Burning, itching, redness, skin rash and swelling
 Triazoles
• Fluconazole

• best tolerated and most widely used triazole

• well absorbed, given orally or IV, bioavailability is >80%.
• Good CNS penetration
• once-daily dosing in patients with normal renal function
• mainly excreted renally with 60-75% unchanged in the urine.
• Dose adjustment necessary in patients with renal disease.
• Effective against fungal meningitis + infections with most Candida spp
(thrush, esophageal candidiasis)
• no activity against Aspergillus sp or mucormycosis
• alternative to amphotericin B in initial treatment of mild meningitis
• taken prophylactically by end-stage AIDS patients
• reduces incidence of cryptococcal meningitis, esophageal candidiasis,
superficial fungal infections.
• A/Es: nausea, headache, abdominal pain, exfoliative skin lesions, hepatitis
• Minor inhibitor of CYP450 enzymes, increases phenytoin serum levels
 Triazoles
• Itraconazole
• long-term suppressive treatment of disseminated histoplasmosis in AIDS + oral
treatment of nonmeningeal blastomycosis.
• drug of choice for all forms of sporotrichosis except meningitis.
• Available orally (capsules, solution), IV
• oral solution is coformulated with cyclodextrin to improve solubility and absorption
(30% greater than capsules).
• Oral absorption of the capsules is improved with food while the solution is best absorbed
on an empty stomach.
• requires a low gastric pH for absorption
• highly protein bound (99%)
• primarily metabolized in liver by CYP3A4 and also inhibits this enzyme system (drug-
drug interactions)
• half-life is ~30-40 hours and will be prolonged in patients with severe liver disease
• excreted into the bile.
• A/Es: hepatoxicity, Stevens-Johnson syndrome, GI disturbance, headache, dizziness,
bleeding gums, fever, chills, difficulty breathing or swallowing.
• Contraindicated in patients with CHF
• proton pump inhibitors reduce bioavailability of itraconazole
 Second-generation azole
drugs
• Voriconazole –introduced 2002
• oral suspension, tablets or parenteral injection
• expands on fluconazole’s clinical activity to include fluconazole-resistant
Candida sp., Aspergillus sp., and rare molds (Scedosporium sp., Fusarium
sp.)
• oral formulation is best absorbed on an empty stomach with >90%
bioavailability.
• I.V formulation is formulated with sulfobutyl ether -cyclodextrin sodium
(SBECD) to increase solubility
• metabolized in liver via CYP450 system, specifically CYP2C9, CYP3A4,
and CYP2C19
• usual half-life is ~6 hours. Dosage adjustment necessary in patients with
liver dysfunction
• Adverse effects include: rash, bloating or swelling of face, arms, hands,
hepatotoxicity
 Second-generation azole
drugs
• Posaconazole -2006
– broad-spectrum, with additional activity against
filamentous fungi while retaining anti-Candida
activity
• Isavuconazole - 2015
– similarly broad activity, more favorable
pharmacologic properties, improved
bioavailability, more predictable drug levels, fewer
drug interactions.
 Fluorinated pyrimidines
• Flucytosine (5-flucytosine, 5-FC)
• analogue of cytosine
• Well absorbed & distributed, available I.V or
orally
• penetrates well into CSF (~75% of serum levels) and
penetrates well into aqueous humor, joints, bronchial
secretions, peritoneal fluid, brain, bile, and bone.
• excreted renally with ~90% excreted unchanged in the urine,
requires dose adjustment in patients with renal disease
• highly bioavailable (80%–90%)
• 4 times daily, due to its short half-life ( ~3-6
hours), but may be increased to ~200 hours in
patients with renal failure.
 Flucytosine
• Originally synthesized as antitumour agent
• converted to 5-fluorouracil inside cell by fungal enzyme
cytosine deaminase
• incorporated into RNA causing faulty RNA synthesis
• inhibits thymidylate synthesis
• first-line therapy for treatment of cryptococcal meningitis
• activity against Candida spp. + fungal organisms responsible
for chromomycosis.
• Combined with ampho B to avoid rapid resistance
• Also combined with itraconazole and fluconazole
• A/Es: GI upset, bone marrow suppression (Leukopenia and
thrombocytopenia) , liver toxicity
 Allylamines
• Terbinafine
• reversible noncompetitive inhibitor of fungal enzyme
squalene monooxygenase, which converts squalene to
lanosterol
• decrease in lanosterol production = decrease in ergosterol
production
• accumulation of squalene within cell is toxic to organism
• only effective against dermatophytes – skin, nails
• Given orally and topically
• Limited clinical use- poor PK properties
• A/Es: GI disturbances, rashes, pruritus, headache, dizziness,
Joint and muscle pains, hepatitis, fever, chills
• Drug interactions: warfarin, antidepressant drugs, beta-
blockers, proton pump inhibitors
 Allylamines
• Naftifine
• similar in action to terbinafine
• available for topical use only in treatment of
cutaneous dermatophyte
• Effective for treatment of tinea cruris +
Candida infections
• Skin irritation may occur
5FC, flucytosine; AMB, amphotericin B; ANI, anidulafungin; CAS, caspofungin; FLU, fluconazole; ISA,
isavuconazole; ITR, itraconazole; MICA, micafungin; POS, posaconazole; VOR, voriconazole.
 Antimicrobial resistance
• Overuse of drugs (clinical suspicion without
microbiological confirmation)
• target alterations + reduced access to target
important mechanisms
• main mechanism of azole resistance for
Aspergillus, Candida, and Cryptococcus spp-
mutation of lanosterol 14a-demethylase
• Efflux of drugs and reduced intracellular
accumulation- upregulation of efflux pumps
 Reducing emergence of drug resistance
• Positive ID of pathogen + susceptibility testing
• Choice of agent:
– Spectrum of activity
– Efficacy + safety
– Previous clinical experience
– Severity of illness
• Use of limited range of agents for prophylaxis
• Directed therapy
• Completion of treatment courses
• Design & development of new drugs e.g efflux pump
inhibitors