ANTIFUNGAL AGENTS

Increased number of patients at risk for fungal

infection
 Advances in surgery
 Cancer treatment
 Treatment of patients with solid organ and bone
marrow transplantation
 HIV epidemic, and
 Increasing use of broad-spectrum antimicrobial
therapy in critically ill patients

Fungal infections Antifungal drugs presently available fall into the

 Difficult to treat following categories
 Immunocompromised  Systemic drugs (oral or parenteral) for systemic
 Neutropenic infections
 Resistant to conventional antimicrobial agents  Oral systemic drugs for mucocutaneous
 Selective toxicity infections, and
 Ergosterol-sterol unique to fungal cell  Topical drugs for mucocutaneous infections
membrane
SYSTEMIC ANTIFUNGAL DRUGS FOR SYSTEMIC
ASPERGILLOSIS INFECTIONS
• A. fumigatus  Amphotericin B
• Infects open spaces of the pulmonary cavities  Flucytosine
• Cough, hemoptysis, pleuritic chest pain  Azole antifungal agents
• X-ray: fungus ball or aspergilloma  Echinocandins

CANDIDIASIS
• C. albicans
• Mucocutaneous lesions
• Affects esophagus, vagina, skin and mucous
membranes
• Symptoms depend on the affected body part

CHROMOBLASTOMYCOSIS
• Caused by a pigmented fungi
• Ulcerating nodules usually on lower extremities
• Mucutaneous infection affecting normal,
immunocompetent people mostly in tropical or
subtropical areas

HISTOPLASMOSIS
• Histoplasma capsulatum
• Often chronic and usually follows an  SYSTEMIC ANTIFUNGAL DRUGS FOR
asymptomatic primary infection SYSTEMIC INFECTIONS
• Symptoms are those of pneumonia or of A. Amphotericin
nonspecific chronic illness.  Amphotericin A and B
• Diagnosis is by identification of the organism in  Produced by Streptomyces nodosus
sputum or tissue or use of specific serum and  Amphotericin A is not in clinical use
urine antigen

CRYPTOCOCCOSIS A. Amphotericin B
• Pulmonary or disseminated infection acquired by 1. Classification and Pharmacokinetics
inhalation of soil contaminated with the  Amphoteric polyene macrolide related to
encapsulated yeast  Nystatin
• Cryptococcus neoformans or C. gattii  Poorly absorbed from the GIT
• Symptoms are those of pneumonia, meningitis,  Nearly insoluble in water
or involvement of skin, bones, or viscera
 Administered IV as
• Diagnosis is clinical and microscopic, confirmed
by culture or fixed-tissue staining  Nonlipid colloidal suspension
 Lipid complex
 Liposomal formulation
  Oral amphotericin B
 Effective only on fungi within the lumen
of the tract
 Cannot be used for treatment of
systemic disease
 Widely distributed to all tissues except
 CNS
 90% protein bound
 Half life approximately 15 days
 Hepatic and renal impairment, and dialysis
have little impact on drug concentrations
 No dose adjustment is required
2. Mechanism of Action
 Fungicidal
 Binds to ergosterol and causes the formation of
B-associated pores in the cell membrane
 Resistance
 Decreasing the membrane
concentration of ergosterol
 Modifying the sterol target molecule
3. Clinical Uses
 Broadest spectrum of action
 Remains a useful agent for nearly all life
threatening fungal infections
 Initial induction regimen then follow-up treatment
with an azole (chronic therapy or to prevent
relapse)
 Given by slow IV infusion
 Intrathecal administration for fungal
 meningitis is poorly tolerated
 Local with minimal toxicity for mycotic corneal
ulcer and keratitis
4. Toxicity
Infusion related
Fever Vomiting
Chills Shock like fall in BP
Muscle spasm
 Slow infusion rate and decrease daily dose
 Premedication with antihistamine, antipyretics,
meperidine or glucocorticoids
Cumulative
 Renal damage is the most significant toxic
reaction
 In the setting of prolonged
administration (>4 g cumulative dose)
 Renal tubular acidosis with Mg+2
and K+ wasting
 Anemia due to reduced erythropoietin
production
 Intrathecal administration
 Seizures
 Chemical arachnoiditis
B. Flucytosine (5- fluorocytosine [5-FC])
1. Classification and Pharmacokinetics
 Water soluble pyrimidine antimetabolite
 Related to the anticancer drug 5-FU
 Given orally
 Distributed to most body tissues including the
CNS
 Eliminated intact in the urine
 Levels rise rapidly with renal impairment and
can lead to toxicity
2. Mechanism of Action
 Accumulates in fungal cells by the action of
membrane cytosine permease
 Converted by cytosine deaminase to 5-FU then
to5-fluorodeoxyuridine monophosphate
(FdUMP) and fluorouridine triphosphate (FUTP),
which inhibit DNA and RNA synthesis
 Selective toxicity
 Mammalian cells have low levels of
permease and deaminase
 Resistance
 Mediated through altered metabolism of
flucytosine
 When given with amphotericin B
 Emergence of resistance is decreased
 Synergistic antifungal effects
3. Clinical Uses
 Narrow spectrum
 Restricted to the treatment of
 Cryptococcus neoformans
 Systemic candidal infections
 Chromoblastomycosis
 Not used as a single agent; in combination with
amphotericin or fluconazole
4. Toxicity
 Reversible bone marrow depression
 Alopecia
 Liver dysfunction is less
C. Azole Antifungal Agents
1. Classifications and Pharmacokinetics
 Synthetic compounds that can be classified
depending on the number of nitrogen atoms in
the five-membered azole ring
Imidazoles
 Ketoconazole, miconazole, and clotrimazole
Triazoles
 Itraconazole, fluconazole, voriconazole,
and posaconazole
  Variable oral bioavailability
 Normal gastric acidity is required
 Fluconazole and voriconazole
 More reliably absorbed via oral route
than the other azoles
 Distributed to most body tissues
 Except fluconazole
 Very low CNS drug levels
 Ketoconazole, itraconazole and voriconazole
 Eliminated by liver metabolism
 Enzyme inducers decrease bioavailability of
itraconazole
 Fluconazole is eliminated unchanged by the
kidneys
2. Mechanism of Action
 Reduction of ergosterol synthesis by inhibition of
fungal cytochrome P450 enzymes
 Acts at the step of 14-alpha-demethylation of
lanosterol
 Imidazoles exhibit a lesser degree of selectivity
than the triazoles
 Higher incidence of drug interactions and
adverse effects
 Resistance
 Changes in the sensitivity of the target
enzymes
 Occurs in long term prophylaxis among
immunocompromised and neutropenic
patients
3. Clinical Uses
 Ketoconazole
 1st azole drug
 Narrow antifungal spectrum
 More adverse effects than other azoles
 Rarely used for systemic mycoses
 Commonly used for mucocutaneous
candidiasis
 Given orally
 Itraconazole
 Drug of choice
 Systemic infections caused by
Histoplasma, Blastomyces and
Sporothrix
 Subcutaneous chromoblastomycosis
 Reduced bioavailability when taken with
rifamycins
 Utilized cyclodextran as a carrier
molecule to enhance solubility and
bioavailability
 Fluconazole
 High degree of water solubility
 Good CSF penetration
 High oral bioavailability
 Drug interactions are also less common
 Widest therapeutic index of the azoles
 Drug of choice
 Esophageal and oropharyngeal
candidiasis
 Infections caused by Coccidioides
 Treatment and secondary prophylaxis
against cryptococcal meningitis
 Single oral dose for vaginal candidiasis
 Alternative drug of choice (with
amphotericin B)
 Active disease due to
Cryptococcus neoformans
 Equivalent to amphotericin B in
candidemia
 Voriconazole
 Newer, with wider spectrum of activity
 Well absorbed orally
 Bioavailability exceeding 90%
 Exhibits less protein binding
 Inhibitor of mammalian CYP3A4
 Dose reduction of a number of
medications is required
 Treatment of choice for treatment of
invasive aspergillosis
 Alternative drug in candidemia and in
AIDS patients
 Posaconazole
 Newest triazole
 Broadest spectrum
 With activity against most species of
Candida and Aspergillus
 Only azole with significant activity
against the agents of mucormycosis
 Salvage therapy in invasive aspergillosis
 Prophylaxis of fungal infections
 Induction chemotherapy for
leukemia
 Allogeneic bone marrow
transplant
4. Toxicity
  Relatively nontoxic A. Griseofulvin
 Minor GI upset 1. Pharmacokinetics
 Vomiting  Oral absorption depends on
 Diarrhea  Physical state of the drug
 Abnormalities in liver enzymes  Ultra-microsize formulations
 Notorious inhibitor of CP450  Finer crystals or
 Increase the plasma level of the particles
following drugs  More effectively
 Cyclosporine absorbed
 Hypoglycemics  Aided by high-fat
 Phenytoin containing foods
 Warfarin  Binds to keratin
 Inhibition of cytochrome P450 by ketoconazole  Elimination is via biliary excretion
 Interferes with the synthesis of adrenal 2. Mechanism of Action
and gonadal steroids  MOA at the cellular level is unclear
 Gynecomastia, menstrual  Deposited in newly forming skin where it binds
irregularities, infertility to keratin, protecting the skin from new infection
 Voriconazole causes transient visual  Resistance
disturbances of unknown cause  Decrease in the energy-dependent
transport of the drug
D. Echinocandins 3. Clinical Uses
 Caspofungin, micafungin, and anidulafungin  2–6 weeks for skin and hair infections
1. Classification and Pharmacokinetics 4. Toxicity
 New class of antifungal agents  Headache, mental confusion, GI irritation,
 Used IV photosensitivity, changes in liver function
 Wide tissue distribution  Decreases the bioavailability of warfarin
 Eliminated largely via hepatic metabolism  Disulfiram-like reactions with ethanol
 Half-life of 8-12 hours
2. Mechanism of Action B. Terbinafine
 Inhibits the synthesis of beta (1-3) glycan 1. Mechanism of Action
 Critical component of fungal cell walls  Inhibits a fungal enzyme, squalene epoxidase
3. Clinical Uses  Accumulation of toxic levels of squalene
 Caspofungin which can interfere with ergosterol synthesis
 Disseminated and mucocutaneous  Fungicidal
candidal infections 2. Clinical Uses
 Invasive aspergillosis only as salvage  Accumulates in keratin
therapy in patients who have failed to  More effective than griseofulvin in
respond to amphotericin B onychomycosis for 12 weeks
 Micafungin 3. Toxicity
 Mucocutaneous candidiasis,  GI upsets, rash, headache, taste disturbances
candidemia, and prophylaxis of candidal
infections C. Azoles
 Anidulafungin  Azoles other than voriconazole
 Esophageal candidiasis and invasive  Used orally for treatment of
candidiasis, including candidemia dermatophytoses
4. Toxicity  Pulse or intermittent dosing with itraconazole
 Remarkably nontoxic  Onychomycosis
 GI effects and flushing  As effective as continuous dosing
 Drug persist in the nails for several
ORAL SYSTEMIC ANTIFUNGAL DRUGS FOR months
MUCOCUTANEOUS INFECTIONS  Treatment for 1 week is followed by 3
1. Griseofulvin weeks without drug
2. Terbinafine  Advantages
3. Azoles
  Lower incidence of side effects
 Cost savings
 Similar dosing regimen maybe applicable to
fluconazole and terbinafine

TOPICAL ANTIFUNGAL THERAPY

A. Nystatin
 Polyene macrolide
 Toxicity precludes systemic use
 Creams, ointments, suppositories, and other
forms for application to skin and mucous
membrane
 Disrupts fungal membranes by binding to
ergosterol
 Topically
 To suppress local candidal infections
 Orally
 GI fungal infections in patients with
impaired defense mechanism
B. Topical Azoles
 Miconazole
 Clotrimazole
 Vulvovaginal candidiasis
 Oral thrush
 Tinea corporis, tinea pedis, and tinea cruris
C. Topical Allyamines
 Terbinafine
 Naftifine
 Tinea corporis, tinea and tinea
cruris