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ANTIFUNGAL AGENTS I
PHARMACOLOGY IV
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Antifungal Agents: Introduction

• Human fungal infections have increased dramatically in
incidence and severity in recent years, owing mainly to
advances in surgery, cancer treatment, and bone marrow
transplantation, the HIV epidemic, and increasing use of broad-
spectrum antimicrobial therapy in critically ill patients.

• These changes have resulted in increased numbers of patients

at risk for fungal infections.
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Antifungal Agents: Introduction

• For many years, amphotericin B was the only efficacious
antifungal drug available for systemic use. While highly
effective in many serious infections, it is also quite toxic.

• In the last several decades, pharmacotherapy of fungal disease

has been revolutionized by the introduction of the relatively
nontoxic azole drugs (both oral and parenteral formulations)
and the echinocandins (only available for parenteral
administration).
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Antifungal Agents: Introduction

The new agents in these classes offer more targeted, less
toxic therapy than older agents such as amphotericin B for
patients with serious systemic fungal infections.

Combination therapy is being reconsidered, and new

formulation of old agents are becoming available.

Unfortunately, the appearance of azole-resistant organisms,

as well as the rise in the number of patients at risk for mycotic
infections, has created new challenges.
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Classification of antifungal drugs

The antifungal drugs presently available fall into several
categories:

systemic drugs (oral or parenteral) for systemic infections

oral drugs for mucocutaneous infections
topical drugs for mucocutaneous infections
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Mechanism of action of antifungal agents

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Amphotericin B
• Amphotericin B is an antifungal antibiotics produced by
Streptomyces nodosus.
• Amphotericin B is an amphoteric polyene macrolide (polyene =
containing many double bonds; macrolide = containing a large
lactone ring of 12 or more atoms).
• It is nearly insoluble in water and is therefore prepared as a
colloidal suspension of amphotericin B and sodium
desoxycholate for intravenous injection.
• Several new formulations have been developed in which
amphotericin B is packaged in a lipid-associated delivery
system.
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Amphotericin B lipid formulation

• Therapy with amphotericin B is often limited by toxicity,
especially drug-induced renal impairment.

• The advantages of delivering amphotericin encapsulate in

liposome or as a complex with lipid molecule is that a higher unit
dose can be given and there is reduction in toxic effects.

• Three such preparation are currently available:

i. Amphotericin B colloidal dispersion (AMPHOTEC)
ii. Amphotericin B lipid complex (ABELCET)
iii. Liposomal amphotericin B (BAMBISOME)
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Amphotericin B lipid formulation

• Three such formulations are now available and have differing
pharmacologic properties .
• Although clinical trials have demonstrated different renal and
infusion-related toxicities for these preparations compared with
convetional amphotericin B, there are no trials comparing the
different formulations with each other.
• Limited studies have suggested at best a moderate
improvement in the clinical efficacy of the lipid formulations
compared with conventional amphotericin B.
• Because the lipid preparations are much more expensive, their
use is usually restricted to patients intolerant to, or not
responding to, conventional amphotericin treatment.
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Liposomal amphotericin B
Liposomal amphotericin B, AMBISOME, is produced by the
incorporation of amphotericin B into a single liposomal bilayer
composed of phospholipids and cholesterol .
These liposomal preparations have the primary advantage of
reduced renal and infusion toxicity.
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Conventional amphotericin B vs.

Liposomal amphotericin B

A. Amphotericin B intercalated between the phospholipids of a

spherical liposome.
B. Outcomes of antifungal therapy in febrile, neutropenic cancer
patients treated with conventional amphotericin B and liposomal
amphotericin B
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Pharmacokinetics
• Amphotericin B is poorly absorbed from the gastrointestinal
tract.
• Amphotericin B is administered by slow, intravenous infusion.
• Amphotericin B is insoluble in water, and injectable
preparations require the addition of sodium deoxycholate,
which produces a soluble colloidal dispersion.
• The drug is more than 90% bound by serum proteins.
• The serum t1/2 is approximately 15 days.
• The drug is widely distributed in most tissues, but only 2–3% of
the blood level is reached in cerebrospinal fluid, thus
occasionally necessitating intrathecal therapy for certain types
of fungal meningitis.
• Amphotericin B does cross the placenta.
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Pharmacokinetics
• 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
compromised hepatic function, but when conventional
amphotericin B causes renal dysfunction, the total daily dose is
decreased by 50 percent.
• To minimize nephrotoxicity, alternatives including sodium
loading with infusions of normal saline and the lipid-based
amphotericin B products are used.
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Mechanism of Action
• Amphotericin B is selective in its fungicidal effect because it
exploits the difference in lipid composition of fungal and
mammalian cell membranes.
• Ergosterol, a cell membrane sterol, is found in the cell
membrane of fungi, whereas the predominant sterol of bacteria
and human cells is cholesterol.
• Several amphotericin B molecules bind to ergosterol in
the plasma membranes of sensitive fungal cells. There,
they form pores (channels) that require hydrophobic
interactions between the lipophilic segment of the polyene
antibiotic and the sterol.
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Mechanism of Action
• The pores disrupt membrane
function, allowing electrolytes
(particularly potassium) and
small molecules to leak from
the cell, resulting in cell
death.
• The polyene antibiotics bind
preferentially to ergosterol
rather than to cholesterol (the
sterol found in mammalian
membranes) a relative (but
not absolute) specificity is
conferred.
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Resistance
Resistance to amphotericin B occurs if ergosterol binding is
impaired, either by decreasing the membrane concentration of
ergosterol or by modifying the sterol target molecule to reduce its
affinity for the drug.
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Antifungal Activity
• 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.]

Some fungal organisms such as Candida lusitaniae and

Pseudallescheria boydii display intrinsic amphotericin B
resistance.
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Clinical Uses
 Owing to its broad spectrum of activity and fungicidal action,
amphotericin B remains a useful agent for nearly all life-threatening
mycotic infections, although newer less toxic agents have largely
replaced amphotericin B for most conditions.
 It is often used as the initial induction regimen in order to rapidly
reduce fungal burden and is then replaced by one of the newer
azole drugs for chronic therapy or prevention of relapse.

 Such induction therapy is especially important for

 immunosuppressed patients
 severe fungal pneumonia
 severe cryptococcal meningitis
 disseminated infections with one of the endemic mycoses such as
histoplasmosis (a severe fungal disease of the lungs ) or
coccidioidomycosis (a disease caused by inhaling spores of Coccidioides
fungi, characterized by fever, respiratory infection, and reddish bumps on the skin)
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Clinical Uses
Once a clinical response has been elicited, these patients then
often continue maintenance therapy with an azole; therapy may
be lifelong in patients at high risk for disease relapse.

• Intrathecal therapy for fungal meningitis is poorly tolerated

and fraught with difficulties related to maintaining cerebrospinal
fluid access.
• Thus, intrathecal therapy with amphotericin B is being
increasingly supplanted by other therapies but remains an
option in cases of fungal central nervous system infections that
have not responded to other agents.
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Clinical Use
• Local or topical administration of amphotericin B has been
used with success.
• Mycotic corneal ulcers and keratitis (inflammation of the cornea)
can be cured with topical drops as well as by direct
subconjunctival injection.
• Fungal arthritis has been treated with adjunctive local
injection directly into the joint.
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Adverse effects
Amphotericin B has a low therapeutic index.
A total adult daily dose should not exceed 1.5 mg/kg.
Small test doses are usually administered to assess the degree
of a patient's negative responses, such as anaphylaxis or
convulsions. Other toxic manifestations include the following:

 Fever and chills: These occur most commonly 1 to 3 hours

after starting the intravenous administration, but they usually
subside with repeated administration of the drug.
Premedication with a corticosteroid or an antipyretic helps to
prevent this problem.
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Adverse effects
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.
Nephrotoxicity may be potentiated by sodium depletion;
thus, a bolus infusion of normal saline before and after
amphotericin B infusion may reduce the incidence of drug-
induced nephrotoxicity.
Azotemia (elevated blood urea) is common and some times
sever enough to warrant dialysis. It is exacerbated by other
nephrotoxic drugs, such as aminoglycosides or cyclosporine
although adequate hydration can decrease its severity.
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Adverse effects
Hypotension: A shock-like fall in blood pressure accompanied
by hypokalemia may occur, requiring potassium
supplementation. Care must be exercised in patients taking
digoxin.
Anemia: Normochromic, normocytic anemia caused by a
reversible suppression of erythrocyte production may occur.
This may be exacerbated in patients infected with HIV who are
taking zidovudine.
Neurologic effects: Intrathecal administration can cause a
variety of serious neurologic problems.
Thrombophlebitis (Inflammation of a vein caused by or associated
with the formation of a blood clot): Adding heparin can alleviate
this problem.
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Adverse effects
Infusion-Related Toxicity
Infusion-related reactions are nearly universal and consist of
fever, chills, muscle spasms, vomiting, headache, and
hypotension. They can be ameliorated by slowing the infusion
rate or decreasing the daily dose.
Premedication with antipyretics, antihistamines, or
corticosteroids can be helpful.
When starting therapy, many clinicians administer a test dose
of 1 mg intravenously to gauge the severity of the reaction.
This can serve as a guide to an initial dosing regimen and
premedication strategy.
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Flucytosine
• Flucytosine (5-FC) was discovered in 1957 during a search for
novel antineoplastic agents. Though devoid of anticancer
properties, it became apparent that it was a potent antifungal
agent.

• Flucytosine is a water-soluble pyrimidine analog related to the

chemotherapeutic agent fluorouracil (5-FU).

• Its spectrum of action is much narrower than that of

amphotericin B.
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Pharmacokinetics
• It is poorly protein-bound and penetrates well into all body fluid
compartments, including the cerebrospinal fluid.
• It is eliminated by glomerular filtration with a half-life of 3–4
hours and is removed by hemodialysis.
• Levels rise rapidly with renal impairment and can lead to
toxicity. Toxicity is more likely to occur in AIDS patients and
those with renal insufficiency.
• Peak serum concentrations should be measured periodically in
patients with renal insufficiency and maintained between 50
and 100 mcg/mL.
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Flucytosine is taken up by fungal cells via the

Mechanism enzyme cytosine permease. It is converted
intracellularly first to 5-FU and then to 5-
of Action fluorodeoxyuridine monophosphate (FdUMP)
and fluorouridine triphosphate (FUTP), which
inhibit DNA and RNA synthesis, respectively .
Human cells are unable to convert the parent
drug to its active metabolites, resulting in
selective toxicity.
Synergy with amphotericin B has been
demonstrated in vitro and in vivo. It may be
related to enhanced penetration of the
flucytosine through amphotericin-damaged
fungal cell membranes.
In vitro synergy with azole drugs has also
been seen, although the mechanism is
unclear.
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Resistance
Resistance is thought to be mediated through altered metabolism
of flucytosine, and, though uncommon in primary isolates, it
develops rapidly in the course of flucytosine monotherapy.
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Clinical Uses
The spectrum of activity of flucytosine is restricted to:
Cneoformans, some candida species, and the dematiaceous
molds that cause chromoblastomycosis(infection of the skin and
subcutaneous tissues ).
Flucytosine is not used as a single agent because of its synergy
with other agents and to avoid the development of secondary
resistance.
Clinical use at present is confined to combination therapy,
either with amphotericin B for cryptococcal meningitis or
with itraconazole for chromoblastomycosis.
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Adverse effects
• The adverse effects of flucytosine result from metabolism
(possibly by intestinal flora) to the toxic antineoplastic
compound fluorouracil.
• Bone marrow toxicity with anemia, leukopenia, and
thrombocytopenia are the most common adverse effects.
• A form of toxic enterocolitis can occur.
• There seems to be a narrow therapeutic window, with an
increased risk of toxicity at higher drug levels and resistance
developing rapidly at sub-therapeutic concentrations.
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