Antifungal Drugs

Prof. Dr. JAWAD AL-MUSAWI (2024)

I. OVERVIEW
Infectious diseases caused by fungi are called mycoses, and they are often
chronic in nature. Some mycotic infections are superficial and some
involve the skin (cutaneous mycoses extending into the epidermis), but
fungi may also penetrate the skin, causing subcutaneous infections. The
fungal infections that are most difficult to treat are the systemic mycoses,
which are often life threatening. The fungal cell membrane contains
ergosterol rather than the cholesterol found in mammalian membranes.
II. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC
INFECTIONS
A. Amphotericin B
Amphotericin B is a naturally occurring polyene macrolide antibiotic
produced by Streptomyces nodosus. In spite of its toxic potential,
amphotericin B is the drug of choice for the treatment of life-threatening
systemic mycoses.
1. Mechanism of action: Several amphotericin B molecules bind to
ergosterol in the plasma membranes of sensitive fungal cells. There, they
form pores (channels). The pores disrupt membrane function, allowing
electrolytes (particularly potassium) and small molecules to leak from the
cell, resulting in cell death.
2. Antifungal spectrum: Amphotericin B is either fungicidal or
fungistatic, depending on the organism and the concentration of the drug.
It is effective against a wide range of fungi, including Candida albicans,
Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides
immitis, Blastomyces dermatitidis, and many strains of Aspergillus.
[Note:
Amphotericin B is also used in the treatment of the protozoal infection
leishmaniasis.]
3. Resistance: Fungal resistance, although infrequent, is associated with
decreased ergosterol content of the fungal membrane.
4. Pharmacokinetics: Amphotericin B is administered by slow,
intravenous (IV) infusion. The three amphotericin B lipid formulations
marketed in the United States are AMPHOTEC, ABELCET, and
AMBISOME. These liposomal preparations have the primary advantage
of reduced renal and infusion toxicity. Amphotericin B is extensively
bound to plasma proteins and is distributed throughout the body. To
minimize nephrotoxicity, alternatives including sodium loading with
infusions of normal saline and the lipid-based amphotericin B products
are used.
5. Adverse effects: Amphotericin B has a low therapeutic index. The total
adult daily dose should not exceed 1.5 mg/kg. Small test doses may be
administered to assess the degree of negative responses, such as
anaphylaxis or convulsions. Other toxic manifestations include the
following.
a. Fever and chills: These occur most commonly 1 to 3 hours after
starting the IV administration, but they usually subside with repeated
administration of the drug.
b. Renal impairment: Despite the low levels of the drug excreted in the
urine, patients may exhibit a decrease in glomerular filtration rate and
renal tubular function. Creatinine clearance can drop, and potassium and
magnesium are lost.
c. Hypotension: A shock-like fall in blood pressure accompanied by
hypokalemia may occur, requiring potassium supplementation.
d. Anemia: Normochromic, normocytic anemia caused by a reversible
suppression of erythrocyte production may occur.
e. Neurologic effects: Intrathecal administration can cause a variety of
serious neurologic problems.
f. Thrombophlebitis: Adding heparin to the infusion can alleviate this
problem.
B. Flucytosine
1. Mechanism of action: 5-FC enters fungal cells via a cytosinespecific
permease, which is an enzyme not found in mammalian cells. 5-FC is
then converted by a series of steps to
5-fluorodeoxyuridine 5’-monophosphate. This false nucleotide inhibits
thymidylate synthase, thereby depriving the organism of thymidylic acid,
an essential DNA component.
2. Antifungal spectrum: 5-FC is fungistatic. It is effective in combination
with itraconazole for treating chromoblastomycosis and in combination
with amphotericin B for treating candidiasis and cryptococcosis.
3. Resistance: Resistance due to decreased levels of any of the enzymes
in the conversion of 5-FC to 5-fluorouracil (5-FU) and beyond.
4. Pharmacokinetics: 5-FC is well absorbed by the oral route. It
distributes throughout the body water and penetrates well into the CSF.
Excretion of both the parent drug and its metabolites is by glomerular
filtration.
5. Adverse effects: 5-FC causes reversible neutropenia,
thrombocytopenia, and dose related bone marrow depression. Caution
must be exercised in patients undergoing radiation or chemotherapy with
drugs that depress bone marrow. Reversible hepatic dysfunction with
elevation of serum transaminases and alkaline phosphatase may occur.
Gastrointestinal disturbances, such as nausea, vomiting, and diarrhea, are
common, and severe enterocolitis may also occur.
C. Ketoconazole
Ketoconazole was the first orally active azole available for the treatment
of systemic mycoses.
1. Mechanism of action: Azoles are predominantly fungistatic. They
inhibit C-14 α- demethylase (a cytochrome P450 [CYP450] enzyme),
thereby blocking the demethylation of lanosterol to ergosterol, the
principal sterol of fungal membranes. This inhibition disrupts membrane
structure and function, which, in turn, inhibits fungal cell growth. The
drug also inhibits human gonadal and adrenal steroid synthesis, leading to
decreased testosterone and cortisol production.
2. Antifungal spectrum: Oral ketoconazole is active against many fungi,
including:- Histoplasma, Blastomyces, Candida, and Coccidioides, but
not aspergillus species.
Itraconazole has largely replaced ketoconazole in the treatment of most
mycoses because of its broader spectrum, greater potency, and fewer
adverse effects.
Topical ketoconazole is used to treat tinea corporis, tinea cruris, and tinea
pedis. Also, topical ketoconazole is used to treat tinea versicolor,
cutaneous candidiasis caused by Candida species. It is also used topically
in the treatment of seborrheic dermatitis and dandruff.
3. Resistance: Identified mechanisms of resistance include mutations in
the C-14 α-demethylase gene, which cause decreased azole binding.
Additionally, some strains of fungi have developed the ability to pump
the azole out of the cell.
4. Pharmacokinetics: When ketoconazole is administered orally, it
requires gastric acid for dissolution and is absorbed through the intestinal
mucosa. Administering acidifying agents before taking the drug can
improve absorption in patients with achlorhydria. Ketoconazole is
extensively bound to plasma proteins. Extensive metabolism occurs in
the liver, and excretion is primarily through the bile.
5. Adverse effects: In addition to allergies, dose-dependent
gastrointestinal disturbances, including nausea, anorexia, and vomiting,
are the most common adverse effects of ketoconazole treatment.
Endocrine effects, such as gynecomastia, decreased libido, impotence,
and menstrual irregularities, result from the blocking of androgen and
adrenal steroid synthesis by ketoconazole. Frank hepatitis occurs rarely,
but requires immediate cessation of ketoconazole treatment.
6. Drug interactions and contraindications: By inhibiting CYP450,
ketoconazole can potentiate the toxicities of drugs such as cyclosporine.
Rifampin, an inducer of the CYP450 system, can shorten the duration of
action of ketoconazole. Drugs that decrease gastric acidity, such as H2-
receptor blockers, antacids, and proton-pump inhibitors, can decrease
absorption of ketoconazole. Finally, ketoconazole is teratogenic in
animals, and it should not be given during pregnancy.
D. Fluconazole
Fluconazole is a member of the triazole class of antifungal products. It is
clinically important because of its lack of the endocrine side effects of
ketoconazole and its excellent penetrability into the CSF of both normal
and inflamed meninges. Fluconazole is employed prophylactically, with
some success, for reducing fungal infections in recipients of bone marrow
transplants. It inhibits the synthesis of fungal membrane ergosterol in the
same manner as ketoconazole and is the drug of choice for Cryptococcus
neoformans after therapy with amphotericin B, for most candidemias, and
for coccidioidomycosis. Fluconazole is effective against most forms of
mucocutaneous candidiasis. Fluconazole is administered orally or
intravenously. For the treatment of vaginal candidiasis, the dose is 150
mg as a single oral dose. The adverse effects caused by fluconazole
treatment are less of a problem than those with ketoconazole. However, it
can inhibit the P450 cytochromes that metabolize other drugs. Nausea,
vomiting, and rashes are a problem. There is a caution for patients with
liver dysfunction. Fluconazole is teratogenic, as are other azoles, and
should not be used in pregnancy.
E. Itraconazole
Itraconazole is an antifungal agent with a broad antifungal spectrum. Like
fluconazole, it is a synthetic triazole and also lacks the endocrinologic
side effects of ketoconazole. Its mechanism of action is the same as that
of the other triazoles. Itraconazole is the drug of choice for the treatment
of blastomycosis, sporotrichosis, paracoccidioidomycosis, and
histoplasmosis. Itraconazole is well absorbed orally, but it requires acid
for dissolution.
Food increases the bioavailability of some preparations. Adverse effects
include nausea and vomiting, rash, hypokalemia, hypertension, edema,
and headache. Itraconazole should be avoided in pregnancy. The capsules
should not be taken by patients with evidence of ventricular dysfunction.
F. Voriconazole
Voriconazole, a triazole, has the advantage of being a broad-spectrum
antifungal agent. It is available for both IV and oral administration and is
approximately 96 percent bioavailable. Voriconazole is approved for the
treatment of invasive aspergillosis and has replaced amphotericin B as the
treatment of choice for this indication. Voriconazole is also approved for
treatment of serious infections. Side effects are similar to those of the
other azoles. High trough concentrations are associated with visual and
auditory hallucinations.
G. Posaconazole
Posaconazole, a triazole, is a new oral, broadspectrum antifungal agent
with a chemical structure similar to that of itraconazole. It was approved
in 2006 to prevent Candida and Aspergillus infections. Due to its
spectrum of activity, posaconazole could possibly be used in the
treatment of fungal infections caused by Mucor species and other
zygomycetes. To date, amphotericin B formulations are the only other
antifungal agents available for treatment of zygomycete infections. The
most common side effects observed were gastrointestinal issues (nausea,
vomiting, diarrhea, and abdominal pain) and headaches. Rare cases of
hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and
pulmonary embolus have been reported. To be effective, posaconazole
must be administered with a high fat meal.
H. Echinocandins
Echinocandins interfere with the synthesis of the fungal cell wall by
inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis and cell
death. Caspofungin, micafungin, and anidulafungin are available for IV
adminstration once daily.
1. Caspofungin: Caspofungin is the first approved member of the
echinocandins class of ntifungal drugs. Caspofungin has activity against
Aspergillus and most Candida species, including those species resistant to
azoles. Adverse effects include fever, rash, nausea, and phlebitis.
Flushing occurs. The dose of caspofungin does not need to be adjusted in
renal impairment but is warranted with moderate hepatic dysfunction.
Caspofungin is a second-line antifungal for those who have failed or
cannot tolerate amphotericin B or an azole.
2. Micafungin and anidulafungin: Micafungin and anidulafungin are the
newer members of the echinocandins class of antifungal drugs.
Micafungin and anidulafungin have similar efficacy against Candida
species. The dose of micafungin and anidulafungin does not need to be
adjusted in renal impairment or mild-to-moderate hepatic dysfunction.
Also, they are not substrates for CYP450 enzymes and do not have any
associated drug interactions.
III. DRUGS FOR CUTANEOUS MYCOTIC INFECTIONS
A. Squalene epoxidase inhibitors
These agents act by inhibiting squalene epoxidase, resulting in the
blocking of the biosynthesis of ergosterol, an essential component of
fungal cell membrane.
1. Terbinafine: Oral terbinafine is the drug of choice for treating
dermatophytoses and, especially, onychomycoses (fungal infections of
nails). It is better tolerated, requires shorter duration of therapy, and is
more effective than either itraconazole or griseofulvin.
a. Mechanism of action: Terbinafine inhibits fungal squalene epoxidase,
thereby decreasing the synthesis of ergosterol. This plus the accumulation
of toxic amounts of squalene result in the death of the fungal cell.
b. Antifungal spectrum: The drug is primarily fungicidal. Topical
terbinafine is active against Trichophyton. It may also be effective against
Candida albicans, Epidermophyton floccosum. Topical terbinafine 1%
cream and solution are used to treat tinea pedis, tinea corporis, and tinea
cruris. Therapy is prolonged (usually about 3 months) but considerably
shorter than that with griseofulvin.
c. Pharmacokinetics: Terbinafine is available for oral and topical
administration, although its bioavailability is only 40 percent due to first-
pass metabolism. Absorption is not significantly enhanced by food.
Terbinafine is greater than 99 percent bound to plasma proteins. It is
deposited in the skin, nails, and fat. Terbinafine accumulates in breast
milk and should not be given to nursing mothers. A prolonged terminal
half-life of 200 to 400 hours may reflect the slow release from these
tissues.
d. Adverse effects: The most common adverse effects from terbinafine
are gastrointestinal disturbances (diarrhea, dyspepsia, and nausea),
headache, and rash. Taste and visual disturbances have been reported.
Rarely, terbinafine may cause hepatotoxicity and neutropenia.
2. Naftifine: Naftifine is active against Trichophyton and
Epidermophyton floccosum.
Naftifine 1% cream and gel is used for topical treatment of tinea corporis,
tinea cruris, and tinea pedis.
3. Butenafine: Butenafine is active against Trichophyton,
Epidermophyton, and
Malassezia. Butenafine 1% cream is used for topical treatment of tinea
corporis, tinea cruris, interdigital tinea pedis, and tinea versicolor.
B. Griseofulvin
Griseofulvin has been largely replaced by oral terbinafine for the
treatment of dermatophytic infections of the nails, although it is still used
for ringworm and dermatophytosis of the skin and hair. Griseofulvin
requires treatment of 6 to 12 months in duration. Griseofulvin
accumulates in newly synthesized, keratin-containing tissue, where it
causes disruption of the mitotic spindle and inhibition of fungal mitosis,
and absorption is enhanced by high-fat meals. Griseofulvin induces
hepatic CYP450 activit. It also increases the rate of metabolism of a
number of drugs, including anticoagulants.
C. Nystatin
Nystatin is a polyene antibiotic, and its structure, chemistry, mechanism
of action, and resistance profile resemble those of amphotericin B. Its use
is restricted to topical treatment of Candida infections because of its
systemic toxicity. The drug is negligibly absorbed from the
gastrointestinal tract, and it is never used parenterally. It is administered
as an oral agent (“swish and swallow” or “swish and spit”) for the topical
treatment of oral candidiasis. Excretion in the feces. Adverse effects are
rare because of its lack of absorption orally, but nausea and vomiting
occasionally occur.
D. Imidazoles
Imidazoles are azole derivatives, which currently include butoconazole,
clotrimazole, econazole, ketoconazole, miconazole, oxiconazole,
sertaconazole, sulconazole, terconazole, and tioconazole. As a class of
topical agents, they have a wide range of activity against
Epidermophyton, Microsporum, Trichophyton, Candida albicans, and
Malassezia furfur, depending on the agent. Topical use is associated with
contact dermatitis, vulvar irritation, and edema. Miconazole is a potent
inhibitor of warfarin metabolism and has produced bleeding in warfarin-
treated patients even when applied locally to the vaginal area. No
significant difference in clinical outcomes is associated with any azole or
nystatin in the treatment of vulvar candidiasis.
E. Ciclopirox
Ciclopirox inhibits the transport of essential elements in the fungal cell,
disrupting the synthesis of DNA, RNA, and protein. Ciclopirox is active
against Trichophyton, Epidermophyton, Microsporum, Candida albicans,
and Malassezia. Ciclopirox 1% shampoo is used for treatment of
seborrheic dermatitis. Ciclopirox 0.77% gel is used for treatment of
interdigital tinea pedis, tinea corporis, and seborrheic dermatitis.
Ciclopirox 8% solution is used for treatment of onychomycosis of nails
without lanula involvement. Ciclopirox 0.77% cream and suspension is
used for treatment of dermatomycosis, candidiasis, and tinea versicolor.
F. Tolnaftate
Tolnaftate distorts the hyphae and stunts mycelial growth in susceptible
fungi. Tolnaftate is active against Epidermophyton, Microsporum, and
Malassezia furfur. [Note: Tolnaftate
is not effective against Candida.] Tolnaftate is used to treat tinea pedis,
tinea cruris, and tinea corporis. It is available as a 1% solution, cream,
and powder.

THE END