C H A P T E R 1 1
Antifungal agents
155
Pharmacokinetics
Anidulafungin is given as a daily IV infusion for at least
14 days. It has a rapid onset of action, is metabolised by
degradation and has a half-life of 40 to 50 hours. This
drug is excreted in the faeces.
Caspofungin is available for IV use. This drug is
slowly metabolised in the liver, with half-lives of 9 to
11 hours, then 6 to 48 hours and then 40 to 50 hours.
It is bound to protein and widely distributed throughout
the body. It is excreted through the urine.
Contraindications and cautions
Anidulafungin may cross the placenta and enter breast
milk and should not be used by pregnant or breastfeed-
ing women. Caution must be used in the presence of
hepatic impairment because it can be toxic to the liver.
Caspofungin can be toxic to the liver; therefore, reduced
doses must be used if a person has known hepatic
impairment. Caspofungin is embryotoxic in animal
studies and is known to enter breast milk; therefore, it
should be used with great caution during pregnancy and
breastfeeding.
Adverse effects
Anidulafungin and caspofungin are associated with
hepatic toxicity, and liver function should be monitored
closely when using these drugs.
Clinically important drug–drug interactions
Concurrent use of cyclosporin with caspofungin is
contraindicated unless the benefit clearly outweighs the
risk of hepatic injury.
O
ther antifungal agents
Other antifungal drugs that are available do not fit into
either of these classes. These include amphotericin B
(
Abelcet
,
AmBisome
,
Fungilin
), flucytosine (
Ancotil
),
griseofulvin (
Grisovin
) and nystatin (
Kenacomb,
Mycostatin
,
Nilstat
).
Therapeutic actions and indications
Other antifungal agents work to cause fungal cell death
or to prevent fungal cell reproduction. Amphotericin B is
a very potent drug with many unpleasant adverse effects
(see Adverse effects). The drug binds to the sterols in
the fungus cell wall, changing cell wall permeability.
This change can lead to cell death (fungicidal effect) or
prevent the fungal cells from reproducing (fungistatic
effect). (See Table 11.1 for usual indications.) Because
of the many adverse effects associated with this agent,
its use is reserved for progressive, potentially fatal
infections.
Flucytosine is a less toxic drug that alters the cell
membrane of susceptible fungi, causing cell death (see
Table 11.1 for usual indications).
Griseofulvin is an older antifungal that acts in much
the same way, changing cell membrane permeability and
causing cell death.
Nystatin binds to sterols in the cell wall, changing
membrane permeability and allowing leaking of the
cellular components, which will result in cell death.
Pharmacokinetics
Amphotericin B and flucytosine are available in IV form.
They are excreted in the urine, with an initial half-life of
24 hours and then a 15-day half-life. Their metabolism
is not fully understood. Flucytosine is well absorbed
from the GI tract, with peak levels occurring in 2 hours.
Most of the drug is excreted unchanged in the urine
and a small amount in the faeces, with a half-life of
2.4 to 4.8 hours. Griseofulvin is administered orally and
reaches peak levels in around 4 hours. It is metabolised
in the liver and excreted in the urine with a half-life of
24 hours. Nystatin is not absorbed from the GI tract and
passes unchanged in the stool.
Contraindications and cautions
Amphotericin B has been used successfully during
pregnancy, but it should be used cautiously. It crosses
into breast milk and should not be used during breast-
feeding because of the potential risk to the neonate.
Because flucytosine is excreted primarily in the urine,
extreme caution is needed in the presence of renal
impairment because drug accumulation and toxicity
can occur. Toxicity is associated with serum levels
higher than 100 mcg/mL. Because of the potential for
adverse reactions in the fetus or neonate, flucytosine
should be used during pregnancy and breastfeeding
only if the benefits clearly outweigh the risks. It is not
known whether nystatin crosses the placenta or enters
breast milk, so it should not be used during pregnancy
or breastfeeding unless the benefits clearly outweigh
the potential risks.
Adverse effects
Adverse effects of these drugs are related to their toxic
effects on the liver and kidneys. People should be moni-
tored closely for any changes in liver or kidney functions.
Bone marrow suppression has also been reported with
the use of these drugs as well as rash and dermatological
changes. Amphotericin B is associated with severe renal
impairment, bone marrow suppression, GI irritation
with nausea, vomiting and potentially severe diarrhoea,
anorexia and weight loss, and pain at the injection site
with the possibility of phlebitis or thrombophlebitis.
Adverse effects of griseofulvin are relatively mild, with
