Lippincott Chapter 42: Antifungal Drugs Flashcards
DRUGS FOR SUBCUTANEOUS AND
SYSTEMIC MYCOSES
Amphotericin B VARIOUS
Anidulafungin ERAXIS
Caspofungin CANCIDAS
Fluconazole DIFLUCAN
Flucytosine ANCOBON
Itraconazole SPORANOX
Ketoconazole NIZORAL
Micafungin MYCAMINE
Posaconazole NOXAFIL
Voriconazole VFEND
DRUGS FOR CUTANEOUS MYCOSES
DRUGS FOR CUTANEOUS MYCOSES
Clotrimazole LOTRIMIN AF
Ciclopirox PENLAC
Econazole ECOZA
Griseofulvin GRIFULVIN V, GRIS-PEG
Miconazole FUNGOID, MICATIN, MONISTAT
Nystatin MYCOSTATIN
Oxiconazole OXISTAT
Sertaconazole ERTACZO
Sulconazole EXELDERM
Terconazole TERAZOL
Tioconazole VAGISTAT-1
Tolnaftate TINACTIN
Butenane LOTRIMIN ULTRA
Butoconazole GYNAZOLE
Naftine NAFTIN
Terbinane LAMISIL
Amphotericin B
Amphotericin B
Amphotericin [am-foe-TER-i-sin] B is a naturally occurring polyene
antifungal produced by Streptomyces nodosus. In spite of its toxic
potential, amphotericin B remains the drug of choice for the treatment
of several life-threatening mycoses.
1. Mechanism of action: Amphotericin B binds to ergosterol in
the plasma membranes of sensitive fungal cells. There, it forms
pores (channels) that require hydrophobic interactions between the lipophilic segment of the polyene antifungal and the sterol
(Figure 42.4). 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 fun-
gistatic, 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 associ-
ated with decreased ergosterol content of the fungal membrane.
4. Pharmacokinetics: Amphotericin B is administered by slow, intra-
venous (IV) infusion (Figure 42.5). Amphotericin B is insoluble in
water and must be coformulated with either sodium deoxycholate
(conventional) or a variety of artificial lipids to form liposomes. The
liposomal preparations have the primary advantage of reduced
renal and infusion toxicity. However, due to high cost, liposomal
preparations are reserved mainly as salvage therapy for patients
who cannot tolerate conventional amphotericin B. Amphotericin B
is extensively bound to plasma proteins and is distributed through-
out the body. Inflammation favors penetration into various body
fluids, but little of the drug is found in the CSF, vitreous humor, or
amniotic fluid. However, amphotericin B does cross the placenta.
Low levels of the drug and its metabolites appear in the urine over
a long period of time, and some are also eliminated via the bile.
Dosage adjustment is not required in patients with hepatic dys-
function, but when conventional amphotericin B causes renal dys-
function, the total daily dose is decreased by 50%
Amphotericin B adverse effects
Adverse effects: Amphotericin B has a low therapeutic index. The
total adult daily dose of the conventional formulation should not
exceed 1.5 mg/kg/d, whereas lipid formulations have been given
safely in doses up to 10 mg/kg/d. Toxic manifestations are outlined
below (Figure 42.6).
a. Fever and chills: These occur most commonly 1 to 3 hours
after starting the IV administration but usually subside with
repeated administration of the drug. Premedication with a corti-
costeroid or an antipyretic helps to prevent this problem.
b. Renal impairment: Despite the low levels of the drug excreted
in the urine, patients may exhibit a decrease in glomerular fil-
tration rate and renal tubular function. Serum creatinine may
increase, creatinine clearance can decrease, and potassium
and magnesium are lost. Renal function usually returns with
discontinuation of the drug, but residual damage is likely at high
doses. Azotemia is exacerbated by other nephrotoxic drugs,
such as aminoglycosides, cyclosporine, pentamidine, and van-
comycin, although adequate hydration can decrease its sever-
ity. To minimize nephrotoxicity, sodium loading with infusions of
normal saline and the lipid-based amphotericin B products can
be used.
c. Hypotension: A shock-like fall in blood pressure accompanied
by hypokalemia may occur, requiring potassium supplemen-
tation. Care must be exercised in patients taking digoxin and
other drugs that can cause potassium fluctuations.
d. Thrombophlebitis: Adding heparin to the infusion can alleviate
this problem.
Flucytosine
. Antimetabolite antifungals
Flucytosine [floo-SYE-toe-seen] (5-FC) is a synthetic pyrimidine anti-
metabolite that is often used in combination with amphotericin B. This
combination of drugs is administered for the treatment of systemic
mycoses and for meningitis caused by C. neoformans and C. albicans.
1. Mechanism of action: 5-FC enters the fungal cell via a cytosine-
specific permease, an enzyme not found in mammalian cells. It
is subsequently converted to a series of compounds, including
5-fluorouracil and 5-fluorodeoxyuridine 5′-monophosphate, which
disrupt nucleic acid and protein synthesis (Figure 42.7). [Note:
Amphotericin B increases cell permeability, allowing more 5-FC to
penetrate the cell and leading to synergistic effects.]
2. Antifungal spectrum: 5-FC is fungistatic. It is effective in combi-
nation with itraconazole for treating chromoblastomycosis (causes
skin and subcutaneous infections) and in combination with
amphotericin B for treating candidiasis and cryptococcosis.
Flucytosine can also be used for Candida urinary tract infections
when fluconazole is not appropriate; however, resistance can
occur with repeated use.
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 or from increased synthesis of cytosine can develop dur-
ing therapy. This is the primary reason that 5-FC is not used as a
single antimycotic drug. The rate of emergence of resistant fungal
cells is lower with a combination of 5-FC plus a second antifungal
agent than it is with 5-FC alone.
4. Pharmacokinetics: 5-FC is well absorbed by the oral route. It dis-
tributes throughout the body water and penetrates well into the CSF.
5-FU is detectable in patients and is probably the result of metabo-
lism of 5-FC by intestinal bacteria. Excretion of both the parent drug
and its minimal metabolites is by glomerular filtration, and the dose
must be adjusted in patients with compromised renal function.
Flucytosine adverse effects
Adverse effects: 5-FC causes reversible neutropenia, thrombo-
cytopenia, and dose-related bone marrow depression. Caution
must be exercised in patients undergoing radiation or chemo-
therapy with drugs that depress bone marrow. Reversible hepatic
dysfunction with elevation of serum transaminases and alkaline
phosphatase may occur. Gastrointestinal disturbances (nausea,
vomiting, and diarrhea) are common, and severe enterocolitis may
also occur.
Azole antifungals
Azole antifungals are made up of two different classes of drugs—
imidazoles and triazoles. Although these drugs have similar mecha-
nisms of action and spectra of activity, their pharmacokinetics and
therapeutic uses vary significantly. In general, imidazoles are given
topically for cutaneous infections, whereas triazoles are given system-
ically for the treatment or prophylaxis of cutaneous and systemic fun-
gal infections. [Note: Imidazole antifungals are discussed in the section
on agents for cutaneous mycotic infections.] The triazole antifungals
include fluconazole, itraconazole, posaconazole, and voriconazole.
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 (Figure 42.8). The inhibition of
ergosterol biosynthesis disrupts membrane structure and function,
which, in turn, inhibits fungal cell growth.
2. Resistance: Resistance to azole antifungals is becoming a signif-
icant clinical problem, particularly with protracted therapy required
in immunocompromised patients, such as those who have advanced
HIV infection or bone marrow transplant. Mechanisms of resis-
tance include mutations in the C-14 α-demethylase gene that lead
to decreased azole binding. Additionally, some strains of fungi
have developed efflux pumps that pump the azole out of the cell.
3. Drug interactions: All azoles inhibit the hepatic CYP450 3A4
isoenzyme to varying degrees. Patients on concomitant medica-
tions that are substrates for this isoenzyme may have increased
concentrations and risk for toxicity. Several azoles, including itra-
conazole and voriconazole, are metabolized by CYP450 3A4 and
other CYP450 isoenzymes. Therefore, concomitant use of potent
CYP450 inhibitors (for example, ritonavir) and inducers (for example,
rifampin) can lead to increased adverse effects or clinical failure of
these azoles, respectively.
4. Contraindications: Azoles are considered teratogenic, and they
should be avoided in pregnancy unless the potential benefit out-
weighs the risk to the fetus.
Fluconazole
Fluconazole
Fluconazole [floo-KON-a-zole] was the first member of the triazole
class of antifungal agents. It is the least active of all triazoles, with
most of its spectrum limited to yeasts and some dimorphic fungi.
It has no role in the treatment of aspergillosis or zygomycosis. It is
highly active against Cryptococcus neoformans and certain species
of Candida, including C. albicans and C. parapsilosis. Resistance
is a concern, however, with other species, including C. krusei and
C. glabrata. Fluconazole is used for prophylaxis against invasive fun-
gal infections in recipients of bone marrow transplants. It also is the
drug of choice for Cryptococcus neoformans after induction therapy
with amphotericin B and flucytosine and is used for the treatment of
candidemia and coccidioidomycosis. Fluconazole is effective against
most forms of mucocutaneous candidiasis. It is commonly used as a
single-dose oral treatment for vulvovaginal candidiasis. Fluconazole
is available in oral or IV dosage formulations. It is well absorbed after
oral administration and distributes widely to body fluids and tissues.
The majority of the drug is excreted unchanged via the urine, and
doses must be reduced in patients with renal dysfunction. The most
common adverse effects with fluconazole are nausea, vomiting,
headache, and skin rashes. Hepatotoxicity can also occur, and the
drug should be used with caution in patients with liver dysfunction.
Itraconazole
Itraconazole
Itraconazole [it-ra-KON-a-zole] is a synthetic triazole that has a broad
antifungal spectrum compared to fluconazole. Itraconazole is the
drug of choice for the treatment of blastomycosis, sporotrichosis,paracoccidioidomycosis, and histoplasmosis. It is rarely used for treat-
ment of infections due to Candida and Aspergillus species because
of the availability of newer and more effective agents. Itraconazole is
available in two oral dosage forms, a capsule and an oral solution.
The oral capsule should be taken with food, and ideally an acidic
beverage, to increase absorption. In contrast, the solution should be
taken on an empty stomach, as food decreases the absorption. The
drug distributes well in most tissues, including bone and adipose tis-
sues. Itraconazole is extensively metabolized by the liver, and the
drug and inactive metabolites are excreted in the feces and urine.
Adverse effects include nausea, vomiting, rash (especially in immu-
nocompromised patients), hypokalemia, hypertension, edema, and
headache. Hepatotoxicity can also occur, especially when given with
other drugs that affect the liver. Itraconazole has a negative inotropic
effect and should be avoided in patients with evidence of ventricular
dysfunction, such as heart failure.
Posaconazole
Posaconazole
Posaconazole [poe-sa-KONE-a-zole], a synthetic triazole, is a broad-
spectrum antifungal structurally similar to itraconazole. It is available
as an oral suspension, oral tablet, or IV formulation. Posaconazole is
commonly used for the treatment and prophylaxis of invasive Candida
and Aspergillus infections in severely immunocompromised patients.
Due to its broad spectrum of activity, posaconazole is also used in
the treatment of invasive fungal infections caused by Scedosporium
and Zygomycetes. Posaconazole has a low oral bioavailability and
should be given with food. Even though posaconazole has a long
half-life, the suspension is usually given in divided doses throughout
the day due to saturable absorption in the gut, whereas the tablet is
given once daily. Unlike other azoles, posaconazole is not metabo-
lized in the liver by CYP450 but is eliminated via glucuronidation. The
most common adverse effects include gastrointestinal disturbances
(nausea, vomiting, and diarrhea) and headaches. Like other azoles,
posaconazole can cause an elevation in serum hepatic transami-
nases. Drugs that affect the gastric pH (for example, proton pump
inhibitors) may decrease the absorption of oral posaconazole and
should be avoided if possible. Due to its potent inhibition of CYP3A4,
concomitant use of posaconazole with a number of agents (for exam-
ple, ergot alkaloids, atorvastatin, citalopram, risperidone, pimozide,
and quinidine) is contraindicated.
Voriconazole
Voriconazole
Voriconazole [vor-i-KON-a-zole], a synthetic triazole related to flu-
conazole, has the advantage of being a broad-spectrum antifungal
agent that is available in both IV and oral dosage forms. Voriconazole
has replaced amphotericin B as the drug of choice for invasive asper-
gillosis. It is also approved for treatment of invasive candidiasis, as
well as serious infections caused by Scedosporium and Fusarium
species. Voriconazole has high oral bioavailability and penetrates
into tissues well. Elimination is primarily by metabolism through the
CYP450 enzymes. Voriconazole displays nonlinear kinetics, which
can be affected by drug interactions and pharmacogenetic variability, particularly CYP450 2C19 polymorphisms. Adverse effects are
similar to those of the other azoles; however, high trough concen-
trations are associated with visual and auditory hallucinations and
an increased incidence of hepatotoxicity. Voriconazole is not only a
substrate but also an inhibitor of CYP2C19, 2C9, and 3A4 isoen-
zymes. Inhibitors and inducers of these enzymes may impact levels
of voriconazole, leading to toxicity or clinical failure, respectively. In
addition, drugs that are substrates of these enzymes are impacted
by voriconazole (Figure 42.9). Due to significant interactions, use
of voriconazole is contraindicated with many drugs (for example,
rifampin, rifabutin, carbamazepine, and the herb St. John’s wort).
Figures 42.10 and 42.11 summarize the azole antifungal agents.
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 administration once daily. Micafungin is the only echinocandin
that does not require a loading dose. The echinocandins have potent
activity against Aspergillus and most Candida species, including
those species resistant to azoles. However, they have minimal activity
against other fungi. All three agents are well tolerated, with the most
common adverse effects being fever, rash, nausea, and phlebitis at the
infusion site. They can also cause a histamine-like reaction (flushing)
when infused too rapidly.
Caspofungin
Caspofungin: Caspofungin [kas-poh-FUN-jin] was the first mem-
ber of the echinocandin class of antifungal drugs. Caspofungin is
a first-line option for patients with invasive candidiasis, including
candidemia, and a second-line option for invasive aspergillosis in
patients who have failed or cannot tolerate amphotericin B or an
azole. The dose of caspofungin does not need to be adjusted in renal
impairment, but adjustment is warranted with moderate hepatic
dysfunction. Concomitant administration of caspofungin with cer-
tain CYP450 enzyme inducers (for example, rifampin) may require
an increase in the daily dose. Caspofungin should not be coad-
ministered with cyclosporine due to a high incidence of elevated
hepatic transaminases with concurrent use.
Micafungin and anidulafungin:
Micafungin and anidulafungin: Micafungin [mi-ka-FUN-jin] and
anidulafungin [ay-nid-yoo-la-FUN-jin] are newer members of the
echinocandin class of antifungal drugs. Micafungin and anidulafun-
gin are first-line options for the treatment of invasive candidiasis,
including candidemia. Micafungin is also indicated for the prophy-
laxis of invasive Candida infections in patients who are undergoing
hematopoietic stem cell transplantation. Micafungin and anidula-
fungin do not need to be adjusted in renal impairment or mild to
moderate hepatic dysfunction. Anidulafungin can be administered
in severe hepatic dysfunction, but micafungin has not been stud-
ied in this condition. These agents are not substrates for CYP450
enzymes and do not have any associated drug interactions.
Squalene epoxidase inhibitors: Terbinafine
Terbinafine: Oral terbinafine [TER-bin-a-feen] is the drug of
choice for treating dermatophyte onychomycoses (fungal infec-
tions of nails). It is better tolerated, requires a shorter duration of
therapy, and is more effective than either itraconazole or griseoful-
vin. Therapy is prolonged (usually about 3 months) but consider-
ably shorter than that with griseofulvin. Oral terbinafine may also
be used for tinea capitis (infection of the scalp). [Note: Oral antifun-
gal therapy (griseofulvin, terbinafine, itraconazole) is needed for
tinea capitis. Topical antifungals are ineffective.] Topical terbinafine
(1% cream, gel or solution) is used to treat tinea pedis, tinea cor-
poris (ringworm), and tinea cruris (infection of the groin). Duration
of treatment is usually 1 week.
a. Antifungal spectrum: Terbinafine is active against Trichophyton.
It may also be effective against Candida, Epidermophyton, and
Scopulariopsis, but the efficacy in treating clinical infections due
to these pathogens has not been established.
b. Pharmacokinetics: Terbinafine is available for oral and topical
administration, although its bioavailability is only 40% due to
first-pass metabolism. Terbinafine is highly protein bound and
is deposited in the skin, nails, and adipose tissue. 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. Oral terbinafine is
extensively metabolized by several CYP450 isoenzymes and is
excreted mainly via the urine (Figure 42.13). The drug should
be avoided in patients with moderate to severe renal impair-
ment or hepatic dysfunction.
