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 Antifungal Drugs
Lindsey Childs-Kean 33
DRUGS FOR SUBCUTANEOUS AND
SYSTEMIC MYCOSES
Amphotericin B
Ecinocandin derivatives
I. OVERVIEW Anidulafungin
Caspofungin
Infectious diseases caused by fungi are called mycoses, and they are Micafungin
often chronic in nature. Mycotic infections may involve only the skin (cuta-
Pyrimidine analog
neous mycoses extending into the epidermis), or may cause subcutane-
Flucytosine
ous or systemic infections. Unlike bacteria, fungi are much more complex
organisms, are eukaryotic, with rigid cell walls composed largely of chitin
Azole derivatives
Ketoconazole
rather than peptidoglycan (a characteristic component of most bacterial cell
Fluconazole
walls), and often grow slowly. Consequently, only a few drugs are aimed
Itraconazole
at interfering with cell division and have limited use. In addition, the fun- Isavuconazole
gal cell membrane contains ergosterol rather than the cholesterol found in Posaconazole
mammalian membranes. These structural characteristics are useful targets Voriconazole
for chemotherapeutic agents against mycoses. Fungi are generally resis- DRUGS FOR CUTANEOUS MYCOSES
tant to antibiotics; conversely, bacteria are resistant to antifungal agents. (Topical agents)
The incidence of mycoses such as candidemia, though not as frequent as Nystatin
bacterial or viral infections, has been on the rise for the last few decades. Naftifine
This is attributed to an increased number of patients with chronic immuno-
Topical azole derivatives
suppression due to organ transplantation, cancer chemotherapy, or human Clotrimazole
immunodeficiency virus (HIV) infection. In the past decade, there have been Miconazole
several advances in antifungal therapy. Figure 33.1 summarizes clinically Econazole
­useful agents for cutaneous and systemic mycoses. A new class of antifun- Butoconazole
gal agents (echinocandins) and safer and/or more bioavailable formulations Oxiconazole
of itraconazole and amphotericin B have been developed. Figure 33.2 lists Efinaconazole
the common pathogenic organisms of the Kingdom Fungi, and Figure 33.3 Sertaconazole
provides an overview of the mechanism of action of the various antifun- Sulconazole
gal agents. Antifungal agents are sufficiently diverse in activity, toxicity, and Terconazole
drug ­interaction potential. These characteristics allow clinicians to differen- Tioconazole
tiate among agents when tailoring therapy to meet the needs of a particular Topical allylamine derivatives
patient. Terbinafine
Butenafine
Tolnaftate
II. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC Naftifine
MYCOTIC INFECTIONS OTHER ANTIFUNGAL AGENTS
Ciclopirox
A. Amphotericin B Tavaborole
Griseofulvin
Amphotericin [am-foe-TER-i-sin] B is a naturally occurring polyene
antifungal produced by Streptomyces nodosus. In spite of its toxic Figure 33.1
potential, amphotericin B remains the drug of choice for the treatment Summary of antifungal agents, class,
of several life-threatening mycoses. route of administration, and therapeu-
1. Mechanism of action: Amphotericin B binds to ergosterol in the tic dosages. (For drug dosages, refer
plasma membranes of fungal cells. There, it forms pores (channels) to Appendix at the end of the book.)

565

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 566 33. Antifungal Drugs

Fungi

Yeast Molds
Dimorphic

Candida spp. Pneumocystis Aspergillus spp. Mucormycosis

jirovecii

Cryptococcus Blastomycosis Dermatophytes Rhizopus

neoformans Coccidioidomycosis Mucor
Histoplasmosis Absidia
Sporotrichosis

Figure 33.2
Common pathogenic organisms of Kingdom Fungi.

A. Target cell membrane

Polyenes
• Amphotericin B Endoplasmic reticulum
• Nystatin (inhibit ergosterol synthesis)
• Natamycin Azole derivatives
Polyenes
Azoles derivatives Nucleus Allylamine drugs
• Clotrimazole
• Econazole
• Fluconazole
• Itraconazole
Ribosome (inhibit
• Ketoconazole
protein synthesis)
• Voriconazole Tavaborole
• Posaconazole A Hyphal distortion
Tolnaftate
Allylamine drugs
• Terbninafin C
• Naftifine
B
• Butenafine
B. Target cell wall
Echinocandin drugs
• Caspofungin Mitotic spindle
• Micafungin Griseofulvin Cell wall
Echinocandins
• Antidulafungin
DNA synthesis
C. Target intracellular Flucytosine
Pyrimidine analog Ciclopirox Plasma membrane
Polyenes (amphotericin B, nystatin)
• Flucytosine
Mitotic inhibitor
• Griseofulvin

Figure 33.3
Cellular targets of antifungal drugs.

that require hydrophobic interactions between the ­ lipophilic

­segment of the polyene antifungal and the sterol (Figure 33.4).
The pores disrupt membrane function, allowing electrolytes (par-
ticularly potassium) and small molecules to leak from the cell,
resulting in cell death.

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 II. Drugs for Subcutaneous and Systemic Mycotic Infections 567

2. Antifungal spectrum: Amphotericin B is either fungicidal or

fungistatic, depending on the organism and the concentration Amphotericin B interacts
of the drug. It is effective against a wide range of fungi, includ- 1 hydrophobically with
ergosterol in the fungal cell
ing Candida albicans, Histoplasma capsulatum, Cryptococcus membrane, forming a pore.
­neoformans, Coccidioides immitis, Blastomyces dermatitidis, and
many strains of Aspergillus. [Note: Amphotericin B is also used in K+
the treatment of the protozoal infection leishmaniasis.] Amphotericin B
A
3. Resistance: Fungal resistance to amphotericin B, although infre-
quent, is associated with decreased ergosterol content of the fun-
gal membrane. pore

Whalen7-ch033-fig005
OH

4. Pharmacokinetics: Amphotericin B is administered by slow intra-

HO

venous (IV) infusion (Figure 33.5). Amphotericin B is insoluble in FUNGAL

UNGAL CELL

water and must be coformulated with sodium deoxycholate (con- K+ and other
ventional) or artificial lipids to form liposomes. The liposomal prepa- small molecules
rations are associated with reduced renal and infusion toxicity but
are more costly. Amphotericin B is extensively bound to plasma 2 Potassium and other small
molecules are lost through
the pore, causing cell death.
proteins and is distributed throughout the body. Inflammation
favors penetration into various body fluids, but little of the drug is
found in the cerebrospinal fluid (CSF), vitreous humor, peritoneal Figure 33.4
fluid, or synovial fluid. Low levels of the drug and its metabolites
Model of a pore formed by
are excreted primarily in the urine over a long period of time.
amphotericin B in the lipid bilayer
5. Adverse effects: Amphotericin B has a low therapeutic index. membrane.
Toxic manifestations are outlined below (Figure 33.6).
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
corticosteroid 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
Minimal penetration
discontinuation of the drug, but residual damage is likely at into the CSF,
high doses. Azotemia is exacerbated by other nephrotoxic vitreous humor,
peritoneal fluid, or
drugs, such as aminoglycosides, cyclosporine, and vancomy- synovial fluid
cin, although adequate hydration can decrease its severity.
Sodium loading with infusions of normal saline prior to admin-
istration of the conventional formulation or use of the liposomal IV
amphotericin B products minimizes the risk of nephrotoxicity.
c. Hypotension: A shock-like fall in blood pressure accompa-
nied by hypokalemia may occur, requiring potassium supple-
mentation. Care must be exercised in patients taking digoxin
and other drugs that can cause potassium fluctuations.
d. Thrombophlebitis: Adding heparin to the infusion can allevi- Part of dose
ate this problem. appears in
urine over
a long period
B. Antimetabolite antifungals of time

Flucytosine [floo-SYE-toe-seen] (5-FC) is a synthetic pyrimidine anti- Amphotericin B

metabolite that is often used in combination with other antifungal agents.
1. Mechanism of action: 5-FC enters the fungal cell via a cyto- Figure 33.5
sine-specific permease, an enzyme not found in mammalian cells. Administration and fate of ampho-
It is subsequently converted to a series of compounds, including tericin B. CSF = cerebrospinal fluid.

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 568 33. Antifungal Drugs

5-fluorouracil (5-FU) and 5-fluorodeoxyuridine 5′-monophosphate,

which disrupt nucleic acid and protein synthesis (Figure 33.7).
[Note: Amphotericin B increases cell permeability, allowing more
98.6
Fever 5-FC to penetrate the cell leading to synergistic effects.]
2. Antifungal spectrum: 5-FC is fungistatic. It is effective in com-
bination with itraconazole for treating chromoblastomycosis. It is
also used in combination with amphotericin B for the treatment of
systemic mycoses and for meningitis caused by C. neoformans
and C. albicans. Flucytosine can also be used for Candida uri-
Chills nary tract infections when fluconazole is not appropriate; however,
resistance can occur with repeated use.
3. Resistance: Resistance may occur due to decreased levels of
any of the enzymes in the conversion of 5-FC to 5-FU and other
metabolites. The emergence of resistant fungal cells is lower with
Kidney
a combination of 5-FC plus a second antifungal agent. Thus, 5-FC
failure is not used as a single antimycotic drug.
4. Pharmacokinetics: 5-FC is well absorbed after oral administration.
It distributes throughout the body water and penetrates well into

BP
the CSF. 5-FU is detectable in patients and is probably the result
of metabolism of 5-FC by intestinal bacteria. Excretion of both the
Hypotension parent drug and metabolites is via glomerular filtration, and the dose
must be adjusted in patients with compromised renal function.
5. Adverse effects: 5-FC causes reversible neutropenia, thrombo-
cytopenia, and dose-related bone marrow depression. Reversible
hepatic dysfunction with elevation of serum transaminases has
been observed. Nausea, vomiting, and diarrhea are common, and
Anemia severe enterocolitis may occur.

C. Azole antifungals
Azole antifungals are made up of two different classes of drugs—­
Figure 33.6
imidazoles and triazoles. Although these drugs have similar mechanisms
Adverse effects of amphotericin B.
of action and spectra of activity, their pharmacokinetics and therapeu-
tic uses vary significantly. In general, imidazoles are applied topically for
cutaneous infections, whereas triazoles are administered systemically
for the treatment or prophylaxis of cutaneous and systemic mycoses.
[Note: Imidazole antifungals are discussed in the section on agents
for cutaneous mycotic infections.] The systemic triazole antifungals
include fluconazole, itraconazole, posaconazole, voriconazole, and
isavuconazole.
1. Mechanism of action: Azoles are predominantly fungistatic. They
inhibit 14-α demethylase (a cytochrome P450 [CYP450] enzyme),
thereby blocking the demethylation of lanosterol to ergosterol
(Figure 33.8). The inhibition of ergosterol biosynthesis disrupts
fungal membrane structure and function, which, in turn, inhibits
fungal cell growth.
2. Resistance: Resistance to azole antifungals is becoming a signifi-
cant clinical problem, particularly with protracted therapy required
in immunocompromised patients, such as those who have
advanced HIV infection or bone marrow transplant. Mechanisms
of resistance include mutations in the 14-α demethylase gene that
lead to decreased azole binding and efficacy. Additionally, some

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 II. Drugs for Subcutaneous and Systemic Mycotic Infections 569

strains of fungi develop efflux pumps that pump the drug out of
the cell or have reduced ergosterol in the cell wall. NH2
F
3. Drug interactions: All azoles inhibit the hepatic CYP450 3A4 iso- N

enzyme to varying degrees. Several azoles, including itraconazole O N

H
and voriconazole, are metabolized by CYP450 3A4 and other Flucytosine
CYP450 isoenzymes except posaconazole which undergoes min- Amphotericin B

+
imal CYP metabolism; most of its metabolites are glucuronide
conjugates formed by uridine diphosphate glucuronosyltransfer- Permease
ase (UGT) pathways, mainly UGT1A4. Patients on concomitant
medications that are substrates for this isoenzyme may have FUNGAL CELL
increased concentrations and risk for toxicity. However, the clin- NH2
ical relevance of these interactions may vary upon the azole F
N
involved and upon the “target” drug including over-the-counter
O N
or alternative medicines and herbs. Therefore, concomitant use of H

potent CYP450 inhibitors (for example, ritonavir) and inducers (for Cytosine H2 O
example, rifampin and phenytoin) can lead to increased adverse deaminase
effects or clinical failure of these azoles, respectively. NH3

4. Contraindications: Azoles are considered teratogenic, and they

5-Fluorouracil
should be avoided in pregnancy unless the potential benefit out-
weighs the risk to the fetus.

5-FdUMP
D. Fluconazole
Fluconazole [floo-KON-a-zole] was the first triazole antifungal
agent. It is the least active of all triazoles, with most of its spec-
trum limited to yeasts and some dimorphic fungi. It has no role in dUMP
UMP dTMP
the treatment of aspergillosis or zygomycosis. It is highly active Thymidylate
against Cryptococcus neoformans and certain species of Candida, synthase
DNA
including C. albicans and C. parapsilosis. Resistance is a concern,
however, with other species, including C. krusei and C. glabrata. Decreased dTMP leads to
Fluconazole is used for prophylaxis against invasive fungal infections inhibition of DNA synthesis
in recipients of bone marrow transplants. It is the drug of choice for and cell division.
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 Figure 33.7
mucocutaneous candidiasis. It is commonly used as a single-dose Mode of action of flucytosine.
oral treatment for v­ ulvovaginal candidiasis. Fluconazole is available 5-FdUMP = 5-fluorodeoxyuridine
in oral and IV dosage formulations. It is well absorbed after oral 5′-monophosphate; dTMP =
administration and distributes widely to body fluids and tissues. The deoxythymidine 5′-monophosphate.
majority of the drug is excreted unchanged via the urine, and doses
must be reduced in patients with renal dysfunction. The most com-
mon adverse effects with fluconazole are nausea, vomiting, head-
ache, and skin rashes.

E. Itraconazole
Itraconazole [it-ra-KON-a-zole] is a synthetic triazole that has a
broad antifungal spectrum compared to fluconazole. Itraconazole is
a drug of choice for the treatment of blastomycosis, sporotricho-
sis, paracoccidioidomycosis, and histoplasmosis. It is rarely used
for treatment of infections due to Candida and Aspergillus species
because of the availability of more effective agents. Itraconazole
is available as a capsule, tablet, or oral solution. The capsule and
tablet should be taken with food, and ideally an acidic beverage,

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 570 33. Antifungal Drugs

to increase absorption. By contrast, the solution should be taken

Lanosterol on an empty stomach, as food decreases the absorption. The drug
Fluconazole distributes well in most tissues, including bone and adipose tis-
P450 sues. Itraconazole is extensively metabolized by the liver, and the
CH3 drug and inactive metabolites are excreted in the urine and feces.
Adverse effects include nausea, vomiting, rash (especially in immu-
Ergosterol
Ergosterol
nocompromised patients), hypokalemia, hypertension, edema, and
Ergosterol
headache. Liver toxicity can also occur, especially when given with
other hepatotoxic drugs. Itraconazole has a negative inotropic effect
and should be avoided in patients with evidence of ventricular dys-
Inhibition of ergosterol synthesis
function, such as heart failure.
disrupts membrane function and
increases permeability
F. Posaconazole
Posaconazole [poe-sa-KONE-a-zole], a synthetic triazole, is a
Figure 33.8 broad-spectrum antifungal structurally similar to itraconazole. It
Mode of action of azole antifungals. 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 immuno-
compromised patients. Because of its broad spectrum of activity,
posaconazole is used in the treatment of invasive fungal infections
caused by Scedosporium and Zygomycetes. The drug has low oral
bioavailability and should be given with food. Unlike other azoles,
posaconazole is not metabolized by CYP450, but is eliminated via
glucuronidation. Drugs that increase gastric pH (for example, pro-
ton-pump inhibitors) may decrease the absorption of oral posacon-
azole and should be avoided if possible. Due to its potent inhibition
of CYP450 3A4, concomitant use of posaconazole with a number of
agents (for example, ergot alkaloids, atorvastatin, citalopram, and
risperidone) is contraindicated.

G. Voriconazole
Voriconazole [vor-i-KON-a-zole], a synthetic triazole related to fluco-
nazole, is a broad-spectrum antifungal agent that is available in both
Cyclosporine
Phenytoin Serum IV and oral dosage forms. Voriconazole has replaced amphotericin B
Triazolam concentration as the drug of choice for invasive aspergillosis. It is also approved
Warfarin increases
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. It is exten-
sively metabolized by CYP450 2C19, 2C9, and 3A4 isoenzymes, and
P450 Voriconazole the metabolites are primarily excreted via the urine. Voriconazole
displays nonlinear kinetics, which can be affected by drug inter-
actions and pharmacogenetic variability, particularly CYP450 2C19
polymorphisms. High trough concentrations have been associated
with visual and auditory hallucinations and an increased incidence
of hepatotoxicity. Voriconazole is also an inhibitor of CYP2C19, 2C9,
Metabolites and 3A4 isoenzymes. Inhibitors and inducers of these isoenzymes
may impact levels of voriconazole, leading to toxicity or clinical
failure, respectively. In addition, drugs that are substrates of these
Figure 33.9 isoenzymes are impacted by voriconazole (Figure 33.9). Because
By inhibiting cytochrome P450, of significant interactions, use of voriconazole is contraindicated
voriconazole can potentiate the with many drugs (for example, rifampin, rifabutin, carbamazepine, and
toxicities of other drugs. St. John’s wort).

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 II. Drugs for Subcutaneous and Systemic Mycotic Infections 571

H. Isavuconazole
Isavuconazole [eye-sa-voo-KON-a-zole] is a broad-spectrum antifungal
agent which is supplied as the prodrug isavuconazonium in IV and oral
dosage forms. Isavuconazonium is rapidly hydrolyzed by esterases in
the blood to isavuconazole. Isavuconazole has a spectrum of activity
similar to voriconazole and is approved for invasive aspergillosis and
invasive mucormycosis. Isavuconazonium has high bioavailability after
oral administration and distributes well into tissues. The drug is metab-
olized by CYP450 3A4/5 and uridine diphosphate-glucuronosyltrans-
ferases. Coadministration of isavuconazole with potent CYP450 3A4
inhibitors and inducers is contraindicated. Isavuconazole is also an
inhibitor of the CYP450 3A4 isoenzyme, thereby increasing the concen-
trations of drugs that are substrates of CYP450 3A4. Nausea, vomiting,
diarrhea, and hypokalemia are common adverse effects.
Figures 33.10 and 33.11 summarize the azole antifungal agents.

I. 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

FLUCONAZOLE ITRACONAZOLE ISAVUCONAZOLE VORICONAZOLE POSACONAZOLE

Spectrum of activity + ++ +++ +++ ++++

Route(s) of administration Oral, IV Oral Oral, IV Oral, IV Oral, IV

Oral bioavailability (%) 95 55 (solution) 98 96 Variable

Drug levels affected No Yes No No Yes

By food or gastric pH

Protein binding (%) 10 99 99 58 99

Primary route of elimination Renal Hepatic Hepatic Hepatic Hepatic

CYP3A4 CYP3A4, UGT CYP2C19, 2C9, 3A4 glucuronidation

Cytochrome P450 enzymes CYP3A4, 2C9, 2C19 CYP3A4, 2C9 CYP3A4 CYP2C19, 2C9, 3A4 CYP3A4
Inhibited

Half-life (t1/2) 25 hours 30–40 hours 130 hours Dose dependent 20–66 hours

CSF penetration Yes No Yes Yes Yes

Renal excretion of active > 90 <2 45 <2 <2

drug (%)

TDM recommended (Rationale) No Yes (efficacy) Unknown (therapeutic Yes (efficacy and safety) Yes (efficacy)
levels not yet
determined)

CSF = cerebrospinal fluid; TDM = therapeutic drug monitoring.

Figure 33.10
Summary of triazole antifungals.

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 572 33. Antifungal Drugs

EFFECT ON DRUG MAIN CLINICAL

INTERACTING DRUG AZOLE DRUG EXPOSURE CONSEQUENCE OF
INTERACTION
Amiodarone, dronedarone, citalopram, Isavuconazole, itraconazole, Exposure to QT interval prolongation
pimozide, quinidine fluconazole, voriconazole, interacting drugs with risk of torsades de
posaconazole1 pointes
Carbamazepine Isavuconazole, voriconazole Exposure to Treatment failure of
voriconazole voriconazole
Efavirenz Isavuconazole, voriconazole Exposure to Treatment failure of
voriconazole voriconazole
Exposure to Risk of efavirenz toxicity
efavirenz

Ergot alkaloids Isavuconazole, itraconazole, Exposure to ergot Ergotism

fluconazole, voriconazole, alkaloid
posaconazole1
Lovastatin, simvastatin Itraconazole, voriconazole, Exposure to HMG- Risk of rhabdomyolysis
posaconazole CoA reductase inhibitor
Midazolam, triazolam Isavuconazole, itraconazole, Exposure to Sleepiness
voriconazole, posaconazole benzodiazepine

Phenytoin Isavuconazole, voriconazole, Exposure to voriconazole, Treatment failure

posaconazole posaconazole

Exposure to Nystagmus, ataxia

phenytoin

Rifabutin Isavuconazole, voriconazole, Exposure to Treatment failure of

posaconazole voriconazole voriconazole
Exposure to Uveitis
rifabutin

Rifampicin (rifampin) Isavuconazole, voriconazole, Exposure to Treatment failure of

posaconazole voriconazole voriconazole

High-dose ritonavir (400 mg twice daily) Isavuconazole, voriconazole Exposure to Treatment failure of
voriconazole voriconazole
Vincristine, vinblastine Isavuconazole, itraconazole, Exposure to vinca Neurotoxicity
voriconazole, posaconazole alkaloids

Sirolimus Isavuconazole, voriconazole, Exposure to Risk of sirolimus toxicity

posaconazole sirolimus
1Where an interaction has been reported for one triazole, the contraindication has been extended to all others.

Figure 33.11
Major or life-threatening drug interactions of azole drugs. ↑ indicates increased; ↓ indicates decreased.

those species resistant to azoles. However, they have minimal activity

against other fungi. The most common adverse effects are fever, rash,
nausea, and phlebitis at the infusion site. They should be adminis-
tered via a slow IV infusion, as they can cause a histamine-like reac-
tion (flushing) when infused rapidly.
1. Caspofungin: Caspofungin [kas-poh-FUN-jin] 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 should be adjusted with moderate hepatic dys-
function. Concomitant administration of caspofungin with CYP450

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 III. Drugs for Cutaneous Mycotic Infections 573

enzyme inducers (for example, rifampin) may require an increase

in caspofungin dose. Caspofungin should not be coadministered
with cyclosporine due to a high incidence of elevated hepatic
transaminases with concurrent use.
2. Micafungin and anidulafungin: Micafungin [mi-ka-FUN-jin]
and anidulafungin [ay-nid-yoo-la-FUN-jin] are first-line options
for the treatment of invasive candidiasis, including candidemia.
Micafungin is also indicated for the prophylaxis of invasive
Candida infections in patients who are undergoing hematopoi-
etic stem cell transplantation. These agents are not substrates
for CYP450 enzymes and do not have any associated drug
Whalen7-ch033-fig012
interactions.

III. DRUGS FOR CUTANEOUS MYCOTIC INFECTIONS

Mold-like fungi that cause cutaneous infections are called dermatophytes

or tinea. Tinea infections are classified by the affected site (for example,
tinea pedis, which refers to an infection of the feet). Common dermatomy-
coses, such as tinea infections that appear as rings or round red patches
with clear centers, are often referred to as “ringworm.” This is a misnomer
because fungi rather than worms cause the disease. The three different
fungi that cause the majority of cutaneous infections are Trichophyton,
Microsporum, and Epidermophyton. The drugs used in the treatment of
cutaneous mycoses are listed in Figure 33.1.

A. Squalene epoxidase inhibitors

These agents act by inhibiting squalene epoxidase, thereby blocking
the biosynthesis of ergosterol, an essential component of the fun-
gal cell membrane (Figure 33.12). Accumulation of toxic amounts of
squalene results in increased membrane permeability and death of
the fungal cell.
1. Terbinafine: Oral terbinafine [TER-bin-a-feen] is the drug of
choice for treating dermatophyte onychomycoses (fungal infec- Fungal cell death
tions of nails). It is better tolerated, requires a shorter duration
Toxic
of therapy, and is more effective than either itraconazole or gris- products
eofulvin for Trichophyton. Therapy is prolonged (usually about Toxic
products
3 months) but considerably shorter than that with griseofulvin.
Oral terbinafine may also be used for tinea capitis (infection of
Squalene
the scalp). [Note: Oral antifungal therapy (griseofulvin, terbinafine,
Butenafine
itraconazole) is needed for tinea capitis. Topical antifungals are Squalene Naftifine
epoxidase
ineffective.] Topical terbinafine (1% cream, gel or solution) is used Terbinafine
to treat tinea pedis, tinea corporis (ringworm), tinea cruris (infec-
tion of the groin), and tinea versicolor due to Malessezia furfur.
Ergosterol
The duration of treatment is usually 1 week. Ergosterol
Ergosterol
a. Antifungal spectrum: Terbinafine is active against
Trichophyton. It may also be effective against Candida,
Epidermophyton, and Scopulariopsis, but the efficacy in Fungal cell death
treating clinical infections due to these pathogens has not
been established. Figure 33.12
b. Pharmacokinetics: Terbinafine is available for oral and topi- Mode of action of squalene ­epoxidase
cal administration. The bioavailability after oral administration inhibitors.

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 574 33. Antifungal Drugs

is only 40% due to first-pass metabolism. Terbinafine is highly

protein bound and is deposited in the skin, nails, and adipose
tissue. 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 33.13). The drug
should be avoided in patients with moderate-to-severe renal
impairment or hepatic dysfunction. Terbinafine is an inhibi-
tor of the CYP450 2D6 isoenzyme, and concomitant use with
substrates of CYP450 2D6 may result in an increased risk of
adverse effects with those agents.
Metabolites
excreted c. Adverse effects: Common adverse effects include diarrhea,
in urine
dyspepsia, nausea, headache, and rash. Taste and visual dis-
turbances have been reported, as well as elevations in serum
Terbinafine
hepatic transaminases.
2. Naftifine: Naftifine [NAF-ti-feen] is active against Trichophyton,
Figure 33.13
Microsporum, and Epidermophyton. Naftifine cream and gel are
Administration and fate of terbinafine.
used for the topical treatment of tinea corporis, tinea cruris, and
tinea pedis. The duration of treatment is usually 2 to 4 weeks.
3. Butenafine: Butenafine [byoo-TEN-a-feen] is active against
Trichophyton rubrum, Epidermophyton, and Malassezia. Like
naftifine, butenafine cream is used for topical treatment of tinea
infections.

B. Griseofulvin
Griseofulvin [gris-ee-oh-FUL-vin] causes disruption of the mitotic
spindle and inhibition of fungal mitosis (Figure 33.14). It has been
largely replaced by oral terbinafine for the treatment of onychomyco-
sis, although it is still used for dermatophytosis of the scalp and hair.
Griseofulvin is fungistatic and requires a long duration of treatment
(for example, 6 to 12 months for onychomycosis). The duration of
therapy is dependent on the rate of replacement of healthy skin and
nails. Ultrafine crystalline preparations are absorbed adequately from
the gastrointestinal tract, and absorption is enhanced by high-fat
meals. The drug concentrates in skin, hair, nails, and adipose tissue.
Griseofulvin induces hepatic CYP450 activity, which increases the
rate of metabolism of a number of drugs, including anticoagulants.
The use of griseofulvin is contraindicated in pregnancy and patients
with porphyria.

C. Nystatin
Magnifier1-art

Nystatin [nye-STAT-in] is a polyene antifungal, and its structure,

chemistry, mechanism of action, and resistance profile resemble
those of amphotericin B. It is used for the treatment of cutaneous
and oral Candida infections. The drug is negligibly absorbed from
the gastrointestinal tract, and it is not used parenterally due to sys-
temic toxicity (acute infusion-related adverse effects and nephro-
Griseofulvin toxicity). It is administered as an oral agent (“swish and swallow”
or “swish and spit”) for the treatment of oropharyngeal candidiasis
Figure 33.14 (thrush), intravaginally for vulvovaginal candidiasis, or topically for
Inhibition of mitosis by griseofulvin. cutaneous candidiasis.

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 III. Drugs for Cutaneous Mycotic Infections 575

D. Imidazoles
Imidazoles are azole derivatives, which currently include buto-
conazole [byoo-toe-KON-a-zole], clotrimazole [kloe-TRIM-a-zole],
econazole [e-KONE-a-zole], ketoconazole [kee-toe-KON-a-zole],
miconazole [my-KON-a-zole], oxiconazole [oks-i-KON-a-zole], sert-
aconazole [ser-ta-KOE-na-zole], sulconazole [sul-KON-a-zole], ter-
conazole [ter-KON-a-zole], and tioconazole [tye-oh-KONE-a-zole]. As
a class of topical agents, they have a wide range of activity against
Epidermophyton, Microsporum, Trichophyton, Candida, and Malassezia,
depending on the agent. The topical imidazoles have a variety of uses,
including tinea corporis, tinea cruris, tinea pedis, and oropharyngeal and
vulvovaginal candidiasis. Topical use is associated with contact dermati-
tis, vulvar irritation, and edema. Clotrimazole is also available as a troche
(lozenge), and miconazole is available as a buccal tablet for the treat-
ment of thrush. Oral ketoconazole is rarely used today due to the risk of
severe liver injury, adrenal insufficiency, and adverse drug interactions.

E. Efinaconazole
Efinaconazole [eff-in-a-CON-a-zole] is a topical triazole antifungal
agent approved for the treatment of toenail onychomycosis caused by
Trichophyton rubrum and Trichophyton mentagrophytes. The duration
of treatment is 48 weeks. It has also shown activity against Candida
albicans.

F. Ciclopirox
Ciclopirox [sye-kloe-PEER-oks], a pyridine antimycotic, inhibits the
transport of essential elements in the fungal cell, disrupting the synthe-
sis of DNA, RNA, and proteins. Ciclopirox is active against Trichophyton,
Epidermophyton, Microsporum, Candida, and Malassezia. It is avail-
able in a number of formulations. Ciclopirox shampoo is used for the
treatment of seborrheic dermatitis. Tinea pedis, tinea corporis, tinea
cruris, cutaneous candidiasis, and tinea versicolor may be treated
with the cream, gel, or suspension. Onychomycosis can be treated
with the nail lacquer formulation.

G. Tavaborole
Tavaborole [tav-a-BOOR-ole] inhibits an aminoacyl-transfer ribonu-
cleic acid synthetase, preventing fungal protein synthesis. Tavaborole
is active against Trichophyton rubrum, Trichophyton mentagrophytes,
and Candida albicans. A topical solution is approved for the topical
treatment of toenail onychomycosis, requiring 48 weeks of treatment.

H. Tolnaftate
Tolnaftate [tole-NAF-tate], a topical thiocarbamate, 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
solution, cream, and powder.

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 576 33. Antifungal Drugs

IV. M
 ISCELLANEOUS AGENTS MEANT FOR TOPICAL
USE IN FUNGAL INFECTIONS

A. Natamycin (pimiricin)
Natamycin is a polyene amphoteric macrolide having a mechanism
similar to that of amphotericin B with wide-spectrum antifungal prop-
erties. It is a poorly water-soluble compound used as a 5% sus-
pension for topical use in eye. Upon ocular instillation, natamycin is
retained in the conjunctival fornices and reaches effective concentra-
tions in cornea for its antimycotic property.

B. Hamycin
Hamycin is an antifungal agent similar to nystatin but relatively more
water soluble. It is developed for topical application for oral thrush,
cutaneous candidiasis, trichomonas vaginitis, etc.

C. Ciclopirox olamine
Ciclopirox olamine is a broad-spectrum antifungal agent which also
shows anti-inflammatory and antibacterial activity. It is reported to
penetrate the skin to the level of dermis, hair follicles, and sebaceous
glands. The lotion and cream formulations of ciclopirox are effec-
tive in many types of infection, including tinea corporis/cruris, tinea
pedis, tinea mentagrophytes, tinea rubrum, cutaneous candidiasis,
pityriasis (tinea) versicolor, and seborrheic dermatitis and in infec-
tions caused by Epidermophyton floccosum and Microsporum canis.
It is used as a topical formulation (0.77% cream) for the treatment of
seborrheic dermatitis of the scalp, interdigital tinea pedis, and tinea
corporis. It is used as 8% nail lacquer for onychomycosis. It has been
reported to have high cure rates up to 90% for dermatomycoses and
candidal infections, and no significant topical toxicity has been reported.

D. Undecylenic acid
Undecylenic acid is a semisynthetic fatty acid isolated from ricinoleic
acid of castor oil by pyrolysis. It is a yellow-colored liquid with a typical
rancid odor. It is fungistatic and upon usage for longer duration at
higher concentration, it becomes fungicidal. It is used along with zinc
for the treatment of dermatomycoses caused due to tinea pedis, tinea
cruris, and Candida. Some clinical studies show that topical unde-
cylenic acid is equivalent to topical tolnaftate in the treatment of
cutaneous fungal infections. It has also been reported to be effective
against tinea pedis when used as a topical dusting powder. However,
its efficacy is lower than that of imidazole and tolnaftate. Undecylenic
acid is commonly used for the treatment of diaper rash, tinea cruris,
and other milder forms of fungal infections.

E. Benzoic acid
Benzoic acid is one of the old remedies for topical antifungal therapy.
The combination of benzoic acid with salicylic acid (in the ratio of 2:1)
is called Whitfield’s ointment. This combination associates fungistatic

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 Study Questions 577

activity of benzoic acid with keratolytic activity of salicylic acid that

causes the infected stratum corneum to shed. It is used for treating
tinea pedis and tinea capitis; a prolonged treatment is required to get
the desired result. It causes mild irritation upon application.

F. Quiniodochlor
Quiniodochlor is an antiamoebic compound used by the oral route. It
has also been reported to exhibit antifungal and antibacterial activity
on topical application. It has been used for treating dermatophytosis
seborrhoeic dermatitis, pityriasis versicolor, mycosis barbae, athlete’s
foot, impetigo, infected eczema, and furunculosis. It is used as vag-
inal creams for the treatment of monilial and trichomonas vaginitis.
Upon topical application (3% to 8%), it can cause itching, redness,
peeling, dryness, swelling, and irritation of the skin.

G. Sodium thiosulfate
Sodium thiosulfate is used topically as a solution at a concentrations
of 20% to 25% for the treatment of pityriasis (tinea) versicolor. It takes
3 to 4 weeks to exhibit its effectiveness but repigmentation of skin will
take a longer time. It is a weak fungistatic agent which is also used
for treating Malassezia furfur infection. Its application is safe during
pregnancy. It is generally well tolerated but occasionally it can cause
mild irritation.

Study Questions

Choose the ONE best answer.

33.1 Which antifungal agent is MOST likely to cause
Correct answer = B. Amphotericin B is the best choice
renal insufficiency?
since nephrotoxicity is commonly associated with
A. Fluconazole this medication. Although the dose of fluconazole
B. Amphotericin B must be adjusted for renal insufficiency, it is not asso-
C. Itraconazole ciated with causing nephrotoxicity. Itraconazole and
posaconazole are metabolized by the liver and are
D. Posaconazole
not associated with nephrotoxicity.

33.2 A 55-year-old woman presents to the hospital with

Correct answer = A. Voriconazole is the drug of
shortness of breath, fever, and malaise. She has a
choice for aspergillosis. Studies have found it to be
history of breast cancer and is receiving chemo-
superior to other regimens including amphotericin B.
therapy. Her chest x-ray shows pneumonia, and
Fluconazole, flucytosine, and ketoconazole do not
respiratory cultures are positive for Aspergillus
have reliable in vitro activity and are therefore not
fumigatus. Which is the MOST appropriate choice
recommended.
for treatment?
A. Voriconazole
B. Fluconazole
C. Flucytosine
D. Ketoconazole

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