Pharmacy Clinic
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Fungal Infections
Candida Albicans’ Story
Anti Mycotics:
FDA approved topical and systemic antimycotics for the treatment of fungal infections.
Griseofulvin and potassium iodide have limited clinical utility and are not utilized to treat
systemic fungal infections. Griseovulvin inhibits growth of fungal cell.
The six antifungal drugs utilized for systemic disease fall into three structural classes
that act by three mechanisms.
1- Polyene macrolid: Amphotericin B
This act by binding to ergosterol in the fungal cell membrane, creating pores in the cell
membrane, leading to depolarization of the membrane and cell leakage. Amphotericin
binds with greater affinity to ergosterol than to cholesterol. Un fortunately, amphotericin
B binds to sterols of mammalian cells(cholesterol), and this is why it is very toxic. The
alteration in the lipid content of the cell membrane may play a role in the development of
resistance.
2. 5-Flucytosine (5-FC), afluorinated cytosine analog, is believed to act principally by
inhibition of nucliec acid synthesis through active transportation into susceptible cells by
the enzyme cytocine permease, where itis metabolically transformed by the deamination
to the toxic metabolite, 5-fluorouracil.Fluorouracil, when converted to 5-fluorouridine
triphosphate, functions as an antimetabolite and is substituted for uracil in the
incorporation into fungal RNA, thus disturbing protein synthesis. Also inhibit DNA
synthesis.
3. Azole antifungals all appear to act by the same principal mechanism: inhibition of
sterol biosynthesis by interference with cytochrome P450-dependent lanosterol C14
demethylase, the critical enzyme in the biosynthesis of ergosterol.
*Azole group sub divided into:
-Triazioles (Fluconazole, itraconazole): have an improved affinity for fungal versus
mammalian enzyme, as compared to the other group imidazole.
-Imidazole (ketoconazole, miconazole)
In general, the azoles are a fungistatic in their action.
Fluconazole(fungimid®)
It is a triazole derivative which has abroad antifungal spectrum. Its use is confined to
acute or recurrent vaginal candidosis, candidosis of the mouth and oropharynx, and
some types of systemic infections. Vaginal candidosis responds to a single oral dose of
150 mg.
In uncomplicated oropharyngeal candidosis, Fluconazole is given in a dose of 50 mg
once daily for 7 to 14 days. Higher doses of 200 to 400 mg daily are reserved for
candidaemia, and cryptococcosis.
Mechanism of Action:
The antifungal activity of azole derivatives relates to their inhibition of membrane
sterol synthesis by fungal cytochrome P450 enzymes. While ketoconazole also inhibits
mammalian cytochrome P450 enzyme, supratherapeutic concentrations of Fluconazole
have a minimal effect on mammalian enzymes and, thus, Fluconazole appears to be free
of adverse effects on steroidal hormone production.
The Azole antifungal drugs interact with fungal cells to inhibit growth.
The nitrogen of the azole ring is thought to bind to the haem moiety of the fungal
cytochrome P450 enzyme lanosterol-14 alpha-demethylase, thereby halting conversion
of lanosterol to ergosterol. Because ergosterol is integral to fungal membranes, a series
of abnormalities in membrane permeability, membrane bound enzyme activity and
coordination of chitin synthesis happens. At higher concentrations azole derivatives may
increase the saturation of fatty acids in the lipid bilayer.
Fungal cells exposed to Fluconazole in vitro and in vivo typically have irregular cell wall
thickening and accumulation of intracellular lipids and membranous vesicles.
Therapeutic activity
Fluconazole is effective antifungal and produces clinical resolution in the majority of
patients. In more recent studies, Fluconazole have been effective and well tolerated in
immune-compromised and seriously ill patients.
Vaginal Candidiasis
Fluconazole antifungal agent is now indicated for treatment of vaginal candidiasis
(vaginal yeast infections caused by Candida species). The new indication represents a
major advance in treatment of vaginal candidiasis because a single, oral dose of
Fluconazole can now be given in place of treatments that require repeated vaginal
application of tablets, suppositories, or creams. Such Fluconazole rapidly relieved
symptoms and produced a favorable clinical response in 99% of patients.
In addition to reducing the number of doses of treatment required, oral Fluconazole
use can be taken at any time of day: morning, afternoon, or evening. The locally applied
remedies are generally used at bedtime, which means that women may have to wait until
late at night for symptomatic relief.
A number of studies have demonstrated the efficacy of single-dose Fluconazole for
treating vaginal candidiasis. In one randomized, double-blind, placebo-controlled trial,
results were evaluated from 12 women who received 200 mg Fluconazole and 10 women
who applied an 80-mg terconazole suppository once a day for 3 days. The mycological
cure rate at an early evaluation was 75% with Fluconazole and 50% with terconazole. At
a later evaluation, the cure rate was 75% with Fluconazole and 100% with terconazole.
Patients reported symptomatic relief after a mean 2.4 days with Fluconazole and 1.8
days with terconazole. Both treatment groups reported complete relief after about 6
days. No statistically significant differences in results were found between the treatment
groups.
Acute oropharyngeal candidiasis
Most studies employed a dosage of 50 mg orally once daily for 2 to 4 weeks but 100
mg once daily is advocated to prolong the disease-free interval in chronically
immunocompromised patients with AIDS; generally over half of these patients will relapse
within the first month despite apparent clinical and mucological cure of the initial episode.
The results of comparisons between Fluconazole and ketoconazole in patients with
this disease suggest that fluconazole is at least as effective as ketoconazole in this
indication. Other studies show that Fluconazole is more rapid in the resolution of oral
lesions and erythema.
Chronic Oropharengeal Candidiasis
Fluconazole 50 mg orally once daily for 14 days is superior to placebo in relieving
symptoms like erythema and inflammation, and appears effective in over 90% of those
treated. Relapse may takes place when treatment stopped.
Urinary Tract Candidiasis
Fluconazole is excreted in high conc. in the urine and it would appear to be effective
for the treatment of candidiasis of the urinary tract.
Dermatophytosis
133 patients with skin mycoses were treated for up to 6 weeks with either Fluconazole
50 mg daily or ketoconazole 200 mg daily, a comparable results for both treatments and
both treatment maintained an approximate response rate of 95% at follow up
assessment 2 to 4 weeks later.
Deep Seated Fungal infections:
-Candidiasis
Systemic infection is difficult both to diagnose and to treat and carries a poor
prognosis.
Fluconazole is useful addition to currently available antifungals. But comparable
studies are not yet available.
Cryptococcosis
Meningeal infection with C.neoformans is emerging as a major central nervous system
disease and presenting infectious syndrome in patients with AIDS.
Fluconazole is an effective alternate therapy to the more toxic amphotericin B in
treating certain cases of cryptococcal meningitis, patients with an initial episode of
cryptococcal meningitis who are at low risk for treatment failure appear to benefit from
Fluconazole. Among the 194 patients in the trial, 131 received Fluconazole and 63
received amphotericin B.
Death rates for the groups did not vary substantially-14 percent for those taking
amphotericin B and 18 percent for those taking Fluconazole. However, side effects did
differ: 73 percent of the Fluconazole recipients reported no adverse effects, compared to
37 percent of the amphotericin B group. The optimal therapy has not been determined
Fluconazole 50 mg and 400 mg, was administered once daily for 6 to 135 weeks to
patients who generally had failed therapy with amphotericin B.. Responding patient
showed a rapid resolution of such symptoms as fever, headache and neurological signs.
Dosage and Administration:
Adults:
1. vaginal candidiasis: 150 mg single oral dose.
2. Mucosal candidiasis: 50 mg once daily for 7 to 14 days. Treatment should not
normally exceed 14 days except in severely conditions.
3. Candidaemia: 400 mg on the first day followed by 200 mg once daily. Depending on a
clinical response.
4. Cryptococcal meningitis: 400 mg on the first day followed by 200-400 mg once daily.
Depending on a clinical response.
5. For the prevention of relapse of Cryptococcal meningitis in patients with AIDS, after a
patient receives full course of a primary therapy. The dose is 100 mg daily(at least).
Children:
The suggested doses for children over 4 weeks of age are 6 mg per kg body weight
initially then 3 mg per kg daily for superficial infections, and 6 to 12 mg per kg daily for
systemic infection. For infants less than 2 weeks of age, these doses should be given
every 72 hours; for children aged between 2 to 4 weeks the doses should be given every
48 hours.
Effect on Hepatic Enzyme Activity:
Fluconazole is a potent inhibitor of fungal lanosterol 14 alpha-demethylase but it has a
much lower affinity for the mammalian cytochrome P450 enzyme systems. The
concentration causing 50% inhibition of candida albicans C-14 demethylase.
Fluconazole would appear to be much less inhibitory towards mammalian demethylase
than ketoconazole.
In intact animals oral administration of ketoconazole 20mg/kg caused a 50% reduction
in hepatic cholesterol synthesis with a corresponding increase in the lanosterole fraction;
Fluconazole 20mg/kg had no effect.
Ketoconazole appear to interfere with androgen and adrenal steroid hormone
production at concentrations with in the therapeutic range resulting in some cases.
Plasma testosterone levels in healthy male volunteers were unaffected by 28 days of
continuous treatment with Fluconazole 25 50mg/day. Multiple doses of Fluconazole
50mg/day had no significant effect on estradiol levels in healthy female volunteers or on
the pharmacokinetics of ethinylestradiol or levonorgestrel administered in oral
contraceptives.
Renal insufficiency:
More than 90% of a Fluconazole dose is excreted in urine with about 80% as
unchanged drug and about 20% as metabolites. Since Fluconazole is excreted primarily
unchanged in the urine, doses should be adjusted in patients with renal insufficiency.
The adjustment is done according to creatinine clearance. If the creatinine clearance is 21
to 40 ml per minute, the standard dose can be given every 48 hours or half the standard
dose given every 24 hours. If the creatinine clearance is 10 to 20 ml per minute, the
standard dose can be given every 72 hours or one third the standard dose given every
24 hours. Patients on regular haemodialysis should receive a standard dose of
Fluconazole after every dialysis session.
Breast milk:
Not known if excreted in milk but no adverse effects were observed when given in
therapeutic doses to newborns and is probably safe to use during breast feeding.
Absorption and plasma concentrations:
Fluconazole is very well absorbed after oral administration with a peak plasma level
conc. reached with in 1-2 hours after administration. Greater than 90% of an oral dose
can be detected in systemic circulation. Neither food nor gastric pH modifiers had a
clinically significant effect on absorption in studies conducted in healthy volunteers. Even
in the presence of food or antacids or H2 antagonist pretreatment the absorption is not
affected and the bioavailability exceeds 90%.
Multiple dosing of Fluconazole leads to an increase in peak plasma concentration of
approximately 2.5 times that achieved after a single dose .
Steady state concentrations are generally reached with in 6 to 10 days but can be
rapidly attained by doubling the dose on the first day.
Distribution
Fluconazole is distributed to total body water and tissues including G.I.T , CNS. UN
like other azole antifungals which are highly bound, plasma protein binding of Fluconazole
is low(about 11%) most Fluconazole circulates as free drug.
In patients with oropharyngeal or esophageal candidiasis, Fluconazole produces rapid
relief and eradicate the yeast in 50 to 90%of patients. Relapse of oral infection is
common in chronically immunocompramised patients regardless of the antifungal used,
and adequate primary therapy plus long term prophylaxis appears necessary in patients
with AIDS A single oral dose of Fluconazole was comparable to standard topical azole
therapy in women with acute vaginal candidiasis.
Fluconazole is a promising treatment of cryptococcal meningitis.
The majority of clinical experience with Fluconazole has been in patients candidiasis or
cryptococcosis .Fluconazole 50 to 100mg daily produced rapid resolution of the signs
and symptoms of oropharyngeal candidiasis associated with AIDS or the treatment of
malignancy.
In large multicentre studies of acute vaginal candidiasis, Fluconazole 150 mg as a
single oral dose resolved the signs and symptoms of infection in more than 80% of
women evaluated 2 2 months post-treatment and was comparable to the efficacy of
clotrimazole I.V for 3 and 6 days, respectively, and ketoconazole orally for 5 days.
Symptomatic urinary tract infection responded well to Fluconazole, generally 50mg
daily, but urinary tract candidiasis in an ill-defined entity in controlled clinical studies are
needed to evaluate the role of Fluconazole in its management.
Very few data are available on the efficacy of Fluconazole in mycosis confined to
keratinized tissue, including hair and nails.
Fluconazole was used successfully in many patients unresponsive to or intolerant to
more established antifungal treatment. Fluconazole 100 to 300 mg/day proved useful in
the few patients treated for pulmonary candidiasis or candidaimia associated with
haematological malignancy.
Anti Mycotics:
FDA approved topical and systemic antimycotics for the treatment of fungal infections.
Griseofulvin and potassium iodide have limited clinical utility and are not utilized to treat
systemic fungal infections. Griseovulvin inhibits growth of fungal cell.
The six antifungal drugs utilized for systemic disease fall into three structural classes
that act by three mechanisms.
1- Polyene macrolid: Amphotericin B
This act by binding to ergosterol in the fungal cell membrane, creating pores in the cell
membrane, leading to depolarization of the membrane and cell leakage. Amphotericin
binds with greater affinity to ergosterol than to cholesterol. Un fortunately, amphotericin
B binds to sterols of mammalian cells(cholesterol), and this is why it is very toxic. The
alteration in the lipid content of the cell membrane may play a role in the development of
resistance.
2. 5-Flucytosine (5-FC), afluorinated cytosine analog, is believed to act principally by
inhibition of nucliec acid synthesis through active transportation into susceptible cells by
the enzyme cytocine permease, where itis metabolically transformed by the deamination
to the toxic metabolite, 5-fluorouracil.Fluorouracil, when converted to 5-fluorouridine
triphosphate, functions as an antimetabolite and is substituted for uracil in the
incorporation into fungal RNA, thus disturbing protein synthesis. Also inhibit DNA
synthesis.
3. Azole antifungals all appear to act by the same principal mechanism: inhibition of
sterol biosynthesis by interference with cytochrome P450-dependent lanosterol C14
demethylase, the critical enzyme in the biosynthesis of ergosterol.
*Azole group sub divided into:
-Triazioles (Fluconazole, itraconazole): have an improved affinity for fungal versus
mammalian enzyme, as compared to the other group imidazole.
-Imidazole (ketoconazole, miconazole)
In general, the azoles are a fungistatic in their action.
Fluconazole(fungimid®)
It is a triazole derivative which has abroad antifungal spectrum. Its use is confined to
acute or recurrent vaginal candidosis, candidosis of the mouth and oropharynx, and
some types of systemic infections. Vaginal candidosis responds to a single oral dose of
150 mg.
In uncomplicated oropharyngeal candidosis, Fluconazole is given in a dose of 50 mg
once daily for 7 to 14 days. Higher doses of 200 to 400 mg daily are reserved for
candidaemia, and cryptococcosis.
Mechanism of Action:
The antifungal activity of azole derivatives relates to their inhibition of membrane
sterol synthesis by fungal cytochrome P450 enzymes. While ketoconazole also inhibits
mammalian cytochrome P450 enzyme, supratherapeutic concentrations of Fluconazole
have a minimal effect on mammalian enzymes and, thus, Fluconazole appears to be free
of adverse effects on steroidal hormone production.
The Azole antifungal drugs interact with fungal cells to inhibit growth.
The nitrogen of the azole ring is thought to bind to the haem moiety of the fungal
cytochrome P450 enzyme lanosterol-14 alpha-demethylase, thereby halting conversion
of lanosterol to ergosterol. Because ergosterol is integral to fungal membranes, a series
of abnormalities in membrane permeability, membrane bound enzyme activity and
coordination of chitin synthesis happens. At higher concentrations azole derivatives may
increase the saturation of fatty acids in the lipid bilayer.
Fungal cells exposed to Fluconazole in vitro and in vivo typically have irregular cell wall
thickening and accumulation of intracellular lipids and membranous vesicles.
Therapeutic activity
Fluconazole is effective antifungal and produces clinical resolution in the majority of
patients. In more recent studies, Fluconazole have been effective and well tolerated in
immune-compromised and seriously ill patients.
Vaginal Candidiasis
Fluconazole antifungal agent is now indicated for treatment of vaginal candidiasis
(vaginal yeast infections caused by Candida species). The new indication represents a
major advance in treatment of vaginal candidiasis because a single, oral dose of
Fluconazole can now be given in place of treatments that require repeated vaginal
application of tablets, suppositories, or creams. Such Fluconazole rapidly relieved
symptoms and produced a favorable clinical response in 99% of patients.
In addition to reducing the number of doses of treatment required, oral Fluconazole
use can be taken at any time of day: morning, afternoon, or evening. The locally applied
remedies are generally used at bedtime, which means that women may have to wait until
late at night for symptomatic relief.
A number of studies have demonstrated the efficacy of single-dose Fluconazole for
treating vaginal candidiasis. In one randomized, double-blind, placebo-controlled trial,
results were evaluated from 12 women who received 200 mg Fluconazole and 10 women
who applied an 80-mg terconazole suppository once a day for 3 days. The mycological
cure rate at an early evaluation was 75% with Fluconazole and 50% with terconazole. At
a later evaluation, the cure rate was 75% with Fluconazole and 100% with terconazole.
Patients reported symptomatic relief after a mean 2.4 days with Fluconazole and 1.8
days with terconazole. Both treatment groups reported complete relief after about 6
days. No statistically significant differences in results were found between the treatment
groups.
Acute oropharyngeal candidiasis
Most studies employed a dosage of 50 mg orally once daily for 2 to 4 weeks but 100
mg once daily is advocated to prolong the disease-free interval in chronically
immunocompromised patients with AIDS; generally over half of these patients will relapse
within the first month despite apparent clinical and mucological cure of the initial episode.
The results of comparisons between Fluconazole and ketoconazole in patients with
this disease suggest that fluconazole is at least as effective as ketoconazole in this
indication. Other studies show that Fluconazole is more rapid in the resolution of oral
lesions and erythema.
Chronic Oropharengeal Candidiasis
Fluconazole 50 mg orally once daily for 14 days is superior to placebo in relieving
symptoms like erythema and inflammation, and appears effective in over 90% of those
treated. Relapse may takes place when treatment stopped.
Urinary Tract Candidiasis
Fluconazole is excreted in high conc. in the urine and it would appear to be effective
for the treatment of candidiasis of the urinary tract.
Dermatophytosis
133 patients with skin mycoses were treated for up to 6 weeks with either Fluconazole
50 mg daily or ketoconazole 200 mg daily, a comparable results for both treatments and
both treatment maintained an approximate response rate of 95% at follow up
assessment 2 to 4 weeks later.
Deep Seated Fungal infections:
-Candidiasis
Systemic infection is difficult both to diagnose and to treat and carries a poor
prognosis.
Fluconazole is useful addition to currently available antifungals. But comparable
studies are not yet available.
Cryptococcosis
Meningeal infection with C.neoformans is emerging as a major central nervous system
disease and presenting infectious syndrome in patients with AIDS.
Fluconazole is an effective alternate therapy to the more toxic amphotericin B in
treating certain cases of cryptococcal meningitis, patients with an initial episode of
cryptococcal meningitis who are at low risk for treatment failure appear to benefit from
Fluconazole. Among the 194 patients in the trial, 131 received Fluconazole and 63
received amphotericin B.
Death rates for the groups did not vary substantially-14 percent for those taking
amphotericin B and 18 percent for those taking Fluconazole. However, side effects did
differ: 73 percent of the Fluconazole recipients reported no adverse effects, compared to
37 percent of the amphotericin B group. The optimal therapy has not been determined
Fluconazole 50 mg and 400 mg, was administered once daily for 6 to 135 weeks to
patients who generally had failed therapy with amphotericin B.. Responding patient
showed a rapid resolution of such symptoms as fever, headache and neurological signs.
Dosage and Administration:
Adults:
1. vaginal candidiasis: 150 mg single oral dose.
2. Mucosal candidiasis: 50 mg once daily for 7 to 14 days. Treatment should not
normally exceed 14 days except in severely conditions.
3. Candidaemia: 400 mg on the first day followed by 200 mg once daily. Depending on a
clinical response.
4. Cryptococcal meningitis: 400 mg on the first day followed by 200-400 mg once daily.
Depending on a clinical response.
5. For the prevention of relapse of Cryptococcal meningitis in patients with AIDS, after a
patient receives full course of a primary therapy. The dose is 100 mg daily(at least).
Children:
The suggested doses for children over 4 weeks of age are 6 mg per kg body weight
initially then 3 mg per kg daily for superficial infections, and 6 to 12 mg per kg daily for
systemic infection. For infants less than 2 weeks of age, these doses should be given
every 72 hours; for children aged between 2 to 4 weeks the doses should be given every
48 hours.
Effect on Hepatic Enzyme Activity:
Fluconazole is a potent inhibitor of fungal lanosterol 14 alpha-demethylase but it has a
much lower affinity for the mammalian cytochrome P450 enzyme systems. The
concentration causing 50% inhibition of candida albicans C-14 demethylase.
Fluconazole would appear to be much less inhibitory towards mammalian demethylase
than ketoconazole.
In intact animals oral administration of ketoconazole 20mg/kg caused a 50% reduction
in hepatic cholesterol synthesis with a corresponding increase in the lanosterole fraction;
Fluconazole 20mg/kg had no effect.
Ketoconazole appear to interfere with androgen and adrenal steroid hormone
production at concentrations with in the therapeutic range resulting in some cases.
Plasma testosterone levels in healthy male volunteers were unaffected by 28 days of
continuous treatment with Fluconazole 25 50mg/day. Multiple doses of Fluconazole
50mg/day had no significant effect on estradiol levels in healthy female volunteers or on
the pharmacokinetics of ethinylestradiol or levonorgestrel administered in oral
contraceptives.
Renal insufficiency:
More than 90% of a Fluconazole dose is excreted in urine with about 80% as
unchanged drug and about 20% as metabolites. Since Fluconazole is excreted primarily
unchanged in the urine, doses should be adjusted in patients with renal insufficiency.
The adjustment is done according to creatinine clearance. If the creatinine clearance is 21
to 40 ml per minute, the standard dose can be given every 48 hours or half the standard
dose given every 24 hours. If the creatinine clearance is 10 to 20 ml per minute, the
standard dose can be given every 72 hours or one third the standard dose given every
24 hours. Patients on regular haemodialysis should receive a standard dose of
Fluconazole after every dialysis session.
Breast milk:
Not known if excreted in milk but no adverse effects were observed when given in
therapeutic doses to newborns and is probably safe to use during breast feeding.
Absorption and plasma concentrations:
Fluconazole is very well absorbed after oral administration with a peak plasma level
conc. reached with in 1-2 hours after administration. Greater than 90% of an oral dose
can be detected in systemic circulation. Neither food nor gastric pH modifiers had a
clinically significant effect on absorption in studies conducted in healthy volunteers. Even
in the presence of food or antacids or H2 antagonist pretreatment the absorption is not
affected and the bioavailability exceeds 90%.
Multiple dosing of Fluconazole leads to an increase in peak plasma concentration of
approximately 2.5 times that achieved after a single dose .
Steady state concentrations are generally reached with in 6 to 10 days but can be
rapidly attained by doubling the dose on the first day.
Distribution
Fluconazole is distributed to total body water and tissues including G.I.T , CNS. UN
like other azole antifungals which are highly bound, plasma protein binding of Fluconazole
is low(about 11%) most Fluconazole circulates as free drug.
In patients with oropharyngeal or esophageal candidiasis, Fluconazole produces rapid
relief and eradicate the yeast in 50 to 90%of patients. Relapse of oral infection is
common in chronically immunocompramised patients regardless of the antifungal used,
and adequate primary therapy plus long term prophylaxis appears necessary in patients
with AIDS A single oral dose of Fluconazole was comparable to standard topical azole
therapy in women with acute vaginal candidiasis.
Fluconazole is a promising treatment of cryptococcal meningitis.
The majority of clinical experience with Fluconazole has been in patients candidiasis or
cryptococcosis .Fluconazole 50 to 100mg daily produced rapid resolution of the signs
and symptoms of oropharyngeal candidiasis associated with AIDS or the treatment of
malignancy.
In large multicentre studies of acute vaginal candidiasis, Fluconazole 150 mg as a
single oral dose resolved the signs and symptoms of infection in more than 80% of
women evaluated 2 2 months post-treatment and was comparable to the efficacy of
clotrimazole I.V for 3 and 6 days, respectively, and ketoconazole orally for 5 days.
Symptomatic urinary tract infection responded well to Fluconazole, generally 50mg
daily, but urinary tract candidiasis in an ill-defined entity in controlled clinical studies are
needed to evaluate the role of Fluconazole in its management.
Very few data are available on the efficacy of Fluconazole in mycosis confined to
keratinized tissue, including hair and nails.
Fluconazole was used successfully in many patients unresponsive to or intolerant to
more established antifungal treatment. Fluconazole 100 to 300 mg/day proved useful in
the few patients treated for pulmonary candidiasis or candidaimia associated with
haematological malignancy.