Anti-fungal Therapy

Janet Wong, M.D.

Spectrum of Anti-fungal Agents

The topical antifungal agents are only useful for superficial

mycoses. Griseofulvin is also useful for superficial mycoses and
nothing else. Azoles are really the only antifungal agents which

Class

Superficial

Cutaneous

Systemic

Topicals

XXX

Griseofulvin

XXX

Azoles

XXX

XXX

XXX

Nystatin

XXX

Amphotericin B

XXX

XXX

can go across the board and have utility in superficial, cutaneous

and systemic mycoses. Among the polyenes, nystatin is useful only
in superficial candidiasis, for example, such as thrush.
Amphotericin B is typically reserved for more serious cutaneous
disease and systemic therapy.

Ketoconazole
Fluconazole
Itraconazole
Polyenes

Topical Antifungal Agents

Topical antifungal agents. Naftifine, which is an allylamine
derivative, is quite useful in ringworm, provided it is not on the
scalp, in tinea versicolor, and in candidiasis. Clotrimazole is a

Agent

Ringworm

T. versicolor

Candidiasis

representative of the azole category, and it also is useful for all

Naftifine

XXX

XXX

XXX

three types of superficial mycoses. Nystatin, on the other hand, is

Clotrimazole

XXX

XXX

XXX

Nystatin

a polyene and of no utility in ringworm or tinea versicolor and

must be reserved for superficial candidiasis such as thrush.

Topical Anti-fungal Agents

All of these topical agents are contraindicated in the more serious

CLASS
Naftifine - allylamine derivative
Clotrimazole - imidazole
Nystatin - polyene

cutaneous mycoses. Now, here they are yet again. This is naftifine.
This is an allylamine derivative. The other allylamine that you
may encounter is terbinafine and these of course, as allylamine
derivatives, inhibit fungal metabolism very high up in the pathway
of fungal cell-wall construction. They inhibit really the first step
in the conversion of squalene to lanosterol. The imidazoles and the

METABOLISM

triazoles inhibit at a secondary step in the building of the fungal

Naftifine renal

cell wall. The imidazoles and the triazoles inhibit 14 alpha

Clotrimazole - hepatic

demethylase, which mediates the conversion of lanosterol to

Nystatin - fecal

ergosterol. The polyenes, nystatin (a topical antifungal agent) and

amphotericin as (systemic antifungal agent), inhibit the actual
synthesis of ergosterol, the major component of the fungal cell
membrane.

Topical Anti-fungal Agents

Uses for the topical antifungal agents. These are useful really for

Uses: Superficial dermatophyte infections and candidiasis

superficial dermatophyte infections as well as for superficial

Creams, gels, solutions are used for inflamed intertriginous areas

candidiasis. Such things as Candida diaper rash, mild intertrigo.

Powder is used for milder lesions in the identical areas

The creams, the gels and solutions are very helpful in inflamed

Ointment is often times too occlusive

Lesions on the head usually require oral therapy

intertriginous areas such as the toe webs, the groin and the
scrotum. Powder formulations are useful for milder lesions in the
identical areas. If its wet, dry it, if its dry, wet it - so that if this is
a wet diaper area then a powder may be very helpful. The powders,
like clotrimazole powders, the imidazole powders, are extremely
useful in stoma infections. So if you have for example a cancer
patient with a colectomy or a child with short-gut syndrome who
has a stoma and then has a bag. Those are typically very, very wet
areas. Ointments and creams really dont get the job done. The
powders are very useful in those wet areas. Ointments in particular
are typically much too occlusive and the dermatophytes and
particularly Candida love that sort of moist area. So usually I dont
use the ointment formulations of these topical antifungals. The
major exception to the use of topical antifungal agents are
dermatophyte lesions of the head. Ringworm of the scalp, tinea
capitus and kerion will require oral therapy, usually with
griseofulvin.

Griseofulvin
Griseofulvin is a product of Penicillium, so it is an antifungal

CLASS: product of Penicillium

agent made by a mold and it inhibits nucleic acid synthesis at the

ACTION: inhibition of fungal nucleic acid synthesis

elongating tip of the hypha, as we would see in dermatophyte

METABOLISM: hepatic

infections. It is hepatically metabolized and it is useful particularly

USE: superficial fungal infections, such as tinea capitis and unguium,

especially with extensive involvement of skin, head, or nails

in superficial fungal infections such as tinea capitus and unguium

(tinea infections of the fingernails). It is not, however, useful for
chronic candidal infection of the fingernails. But if there is
extensive involvement of skin, head or nails, griseofulvin, given
orally, is the drug of choice. It will be inefficacious in
mucocutaneous candidiasis. So griseofulvin is active against the
superficial dermatophytes, but not against Candida. It is contraindicated in porphyria and should not be used orally in pregnancy.
Its side effects include hepatotoxicity in porphyria, allergic
reactions such as pruritic rash, prolongation of warfarin anticoagulants and a very important one that we certainly can see in
childhood is neutropenia. So when I am treating a child who has a
kerion, and I may well have to treat that child for six to 10 weeks
on daily griseofulvin. Im going to monitor that white blood cell
count and differential on a weekly basis because the drug can
induce a neutropenia.

Griseofulvin
Absorption is augmented if one uses the Ultramicrosize. The drug

Not effective in mucocutaneous candidiasis

comes in two forms; a Microsize and an Ultramicrosize. Use the

CONTRAINDICATIONS: porphyria, pregnancy

Ultramicrosize form, and the dose is approximately 15 mg/kg per

SIDE EFFECTS: hepatotoxicity in porphyria, allergic reactions,

day given once a day as a single dose. Griseofulvin is an oral

prolongation of warfarin anticoagulants

agent. Typically for dermatophyte infections of the head or

fingernails.

Neutropenia - Must monitor WBC/DIFF

DOSE: Ultramicrosize: 15 mg/kg/day q 24 hrs

Imidazoles/triazoles
Imidazoles and the triazoles. The imidazoles are drugs like

CLASS:

Imidazoles/triazoles block the conversion of lanosterol to

clotrimazole, miconazole, ketoconazole. The triazoles are

ergosterol and increasing membrane permeability

fluconazole and itraconazole. Now these antifungals agents inhibit

EXAMPLES: (1) Ketoconazole

(2) Fluconazole
(3) Itraconazole
METABOLISM:

14-alpha-demethylase, blocking the conversion of lanosterol to

ergosterol and thereby increasing membrane permeability. So all
the antifungal agents that we are talking about have activity on the
fungal cell membrane. Levels of antifungal agents in the blood
stream or even in the lesions have not been accurately correlated

Ketoconazole and itraconazole: Hepatic

with clinical outcome. In part thats because many of the patients

Fluconazole: Renal

who acquire fungal infections have other compromises in host

defenses. So the antifungal agent itself may or may not be sufficient, depending upon the whole in-host defense, to cure the
patient. So clinical course and level of fungal agent have really not
been appropriately correlated for this category of antimicrobials.
The examples of the imidazoles and the triazoles are ketoconazole,
fluconazole, and itraconazole. The metabolism is hepatic metabolism for ketoconazole and itraconazole, and renal metabolism for
fluconazole.

Uses of Azoles
General uses of azoles. They can be used predominately for oral

USES: Oral therapy

Severe mucocutaneous candidiasis

Deep cutaneous infections

Less severe systemic fungal infections, especially in hosts without major

immunocompromise

therapy. They are especially useful in severe mucocutaneous

candidiasis, the hereditary syndromes where one sees abundant
candidal colonization at the mouth, on the skin, on the fingernails,
and, in females, in the vagina. This is a T-cell defect, although it
is thought to be a T-cell defect; the precise genetic deficit has not
been worked out. The other azoles can be useful for deep cutaneous infections such as sporotrichosis and for less severe systemic
fungal infections, especially in hosts without major
immunocompromise. The hosts degree of immunocompromise
becomes a very important factor when one is deciding whether you
are going to use an azole and go with oral therapy, or whether one
is going to use amphotericin B, the first line agent for severe fungal
infections. The azoles, with the exception that ketoconazole, have
typically failed pretty badly in the treatment of systemic mycoses,
especially in immunocompromised hosts. So if the host any degree
of immunocompromise, one is going to be unlikely to be treating
that patient with oral ketoconazole. On the other hand, fluconazole
and itraconazole have been used with good success in systemic
mycoses, but predominantly in patients who do not have severe
immune defects, such as prolonged neutropenia or pancytopenia
due to bone marrow transplants.

Uses of Azoles
Ketoconazole is a useful agent for superficial mycoses and

Superficial

Cutaneous

Systemic

Ketoconazole

XXX

XXX

Fluconazole

XXX

XXX

XXX

Itraconazole

XXX

XXX

XXX

cutaneous mycoses. It fails badly in halting disseminated fungal

infections such as aspergillus, candidiasis, histo, blasto in the
immunocompromised host (i.e. neutropenic bone marrow transplant patients or HIV infected patients). The other caveat for
ketoconazole of course is that the drug does not penetrate the
cerebrospinal fluid. Some other limitations of ketoconazole about
which we need to be careful, the first is that it is absolutely
contraindicated in patients with hepatic failure. The drug is
hepatically excreted and therefore will accumulate to toxic levels
in patients with hepatic failures. Secondly, the high pH that one
would typically get in the stomach of a patient on H2 blockers or
patients who have achlorhydria (no HCL in the stomach) will
prevent absorption of ketoconazole. So one has to be very careful
how one uses the drug, especially in the presence of H2 blockers.
One can get hypertension with long term use. Treatment with
isoniazid is a relative contraindication because levels of
ketoconazole are affected. We are not going to use this drug for
fungal meningitis. That is a contraindication because it doesnt
penetrate the CNS. Other contraindications would include the use
of ketoconazole in patients who are taking certain antihistamines,
terfenadine and astemizole. This could lead to a prolongation of
the Q-T interval and cardiac arrhythmias if ketoconazole is used
with those antihistamines. Also for those of us who deal with
immunocompromised hosts, especially those undergoing bone
marrow transplants, we know that ketoconazole can markedly
elevate levels of cyclosporine, typically leading to neurotoxicity
and additive renal toxicity. So the antihistamines, contraindications to the use of ketoconazole and cyclosporine - you simply
have to watch your cyclosporine levels very carefully if you have
the patient on any of the azoles.

10

Ketoconazole Weaknesses
Additional side effects: if you are going to use ketoconazole, be

Ketoconazole has failed to halt disseminated fungal infections (aspergillosis,

aware that this drug will elevate the hepatic transaminases

candidiasis, histoplasmosis, blastomycosis) in the immunocompromised host

typically to about three to four times normal. If the patient actually

(eg, neutropenia, HIV infection)

The drug does not penetrate the CSF

gets beyond that, and we are talking about hepatic transaminases

in the 500s or above, most people would stop ketoconazole.
Gynecomastia

will occur in 20% of males taking oral

ketoconazole. Many would find this a very objectionable side

effect. In addition to the gynecomastia, virtually all males will
have some suppression of testosterone levels and this may affect
libido. It is also important to recognize that one of the major effects
of ketoconazole is treatment-limiting neutropenia. Neutropenia has
been a recognized side effect of ketoconazole. So if one is going to
use ketoconazole, youve got to watch those white cell counts and
differentials because neutropenia can supervene.

11

Fluconazole Usage
Fluconazole is a triazole like imidazole. It is being used exten-

Prophylaxis for candidiasis in bone marrow transplant patients

sively. We know that fluconazole has been used as prophylaxis for

C krusei is resistant de novo to fluconazole

candidiasis in bone marrow transplant patients. Systemic infections

Used for Candida esophagitis, peritonitis, vaginitis, but should not be use as

due to Candida albicans were suppressed with fluconazole

primary therapy for aspergillosis in the immunocompromised host

Good CSF penetration in cryptococcal meningitis

prophylaxis in adult bone marrow transplant patients but unfortunately there was an eight-fold increase in systemic infections due
to Candida krusei because this particular Candida species is
resistant to fluconazole de novo. All Candida krusei are a priori
resistant to fluconazole. So although we can use fluconazole as
prophylaxis in a bone marrow transplant patient, we have to be
very careful. Many places doing bone marrow transplants will do
surveillance cultures and see; if Candida krusei is in that particular
patients surveillance cultures of the stool, then I am going to be
very worried about using fluconazole. It does have additional
utility in more defined infections such as Candida esophagitis,
Candida peritonitis, Candida vaginitis even Candida cystitis
provided there is no evidence of systemic spread from the kidneys.
It should not be used as primary therapy for aspergillosis in the
immunocompromised host. Now in contrast to ketoconazole,
fluconazole has very good CSF penetration and these studies have
been done largely in patients with cryptococcal meningitis where
fluconazole has proven extremely useful as maintenance therapy,
not as initial therapy, but as maintenance therapy in HIV infected
patients with cryptococcal meningitis.

12

Itraconazole Use
Itraconazole is a triazole, and this one is the aspergillus drug.

Greatest utility is for aspergillosis in patients who are unable to tolerate

amphotericin B or who are progressing while on amphotericin B
Prophylaxis for chronic granulomatous disease
Detectable drug has not been found in the CSF, but responses have been

Although it does have affects against other systemic fungi, its

greatest utility is in aspergillosis for patients who are unable to
tolerate amphotericin B or whose disease is progressing on polyene
(amphotericin B) therapy. With any antifungal agent in
aspergillosis, especially pulmonary aspergillosis, in the

seen in chronic coccidioidal meningitis and cryptococcal meningitis in HIV

immunocompromised host is 50-80% fatal if the neutrophils dont

infection. Sustained response typically requires continuous therapy

return. In many cases if those neutrophils arent going to come

back, you cant put your money on an antifungal agent; whether
its itraconazole or amphotericin B or even liposomal amphotericin
B in order to cure that patient. So curing aspergillus requires
normal neutrophils. Itraconazole has been useful, however, for
prophylaxis for chronic granulomatous disease. These patients can
get systemic fungi. Typically aspergillus in unusual locations, such
as the vertebrae; and itraconazole does indeed seem to help avoid
these fungal infections. With itraconazole, in contrast to
fluconazole, has never been found in the CSF but responses have
been seen in chronic coccidioidal meningitis and in cryptococcal
meningitis in HIV infections. But a sustained response typically
requires continuous therapy. So as we will see when we start
reviewing first line antifungal agents, most people would treat
coccidioidal meningitis or cryptococcal meningitis initially with
amphotericin B and then when they are moving to a maintenance
phase are going to have long-term disease such as HIV infected
patients, switch to oral itraconazole.

13

Limitations of Ketoconazole
Side effects of the azoles. The advantage of fluconazole and

Contraindications
Hepatic failure
H2 blockers or achlorhydria prevent absorption of ketoconazole

itraconazole is that their side effects are substantially fewer. In

particular GI upset, which can be a major side effect with
ketoconazole, is much reduced with oral fluconazole or
itraconazole. Ketoconazole can have a decreased cortisol response

Hypertension with long-term use

to ACTH impetus and decreased libido and gynecomastia in 20%

Treatment with isoniazid

of males. None of these related side effects occur with fluconazole

Not indicated for fungal meningitis

or itraconazole. Neutropenia, a ketoconazole side effect, does not

Side Effects of Ketoconazole

Elevated hepatic transaminases
Gynecomastia

occur with fluconazole or itraconazole. With those two agents,

although the GI upset is reduced, we will see transient increases in
transaminases. With ketoconazole we will typically see increases
in transaminases that may continue to rise. So we have to be

Suppression of testosterone levels

careful about ketoconazole and elevation of the LFTs. All three

Treatment-limiting neutropenia

of these drugs will increase cyclosporine levels. So if you are using

these azoles in a bone marrow transplant patient on cyclosporine,
those levels are going to go up; perhaps with toxic side effects.

14

Side Effects of Imidazoles

The point is that ketoconazole is very difficult to absorb when we

Ketoconazole: GI upset, impotence and decreased libido, decreased cortisol

response to ACTH, gynecomastia in 20%, neutropenia
Fluconazole: less GI upset, transient increase in transaminases
Itraconazole: less GI upset, transient increase in transaminases

are in an achlorhydric situation or when the pH of the stomach is

not acid. In terms of tissue penetration we get very good penetration of ketoconazole into the sputum, into the skin, but very poor
into the CNS. Metabolism is hepatic. Dilantin, INH and rifampin
will all affect ketoconazole levels. The half life of ketoconazole is
the shortest among the azoles. Its 6-8 hours and the dose is 5-10
mg/kg given q.12-24 h.

Fluconazole does not have the same difficulties of absorption as

does ketoconazole. And in contrast to ketoconazole, fluconazole
gives excellent levels weve said into the CNS and into a number
of other sites. So this is the drug that penetrates. This is the azole
that gets into the CSF. Its metabolism is divided between hepatic
and renal. Renal is the predominant site of excretion and
fluconazole will inhibit the metabolism of anticoagulants,
cyclosporine and digoxin. The half-life is about 18-24 hours, and
the dose is thought to be more efficacious if given as an initial
loading dose of 10 mg/kg and then 4-6 mg/kg q.12-24 hours. Most
people will give a single daily dose of fluconazole after the loading
dose has been attained.

Itraconazole. It gives us very good levels in the sputum and the

nails, but again poor CNS levels. Here is its metabolism which is
largely hepatic and its important to point out here that because of
the pH-dependent effects of itraconazole absorption, we like to
give itraconazole separately from DDI when we are treating HIV
infected patients. In addition, like fluconazole, itraconazole will
inhibit the metabolism of anticonvulsants, anticoagulants, digoxin
and cyclosporine. It has the longest half-life; at least 24 hours and
its dose is 5-10 mg/kg typically given as a single daily dose.

15

Amphotericin B
Amphotericin B is a polyene. Again produced by Streptomyces

CLASS: Polyene produced by Streptomyces nodosus; binds ergosterol in the

fungal cell wall
METABOLISM: Predominantly renal, but also biliary
FORMULATIONS:

nodosus, and it binds ergosterol. Renal excretion is the predominant mechanism of excretion but you will also get some
amphotericin B into the biliary tract and about 40% of excretion
of amphotericin B is not known how it is excreted. So this drug,
although it has tremendous utility, there are still a lot of questions

1. IV complexed with desoxycholate for solubility

that havent been answered about amphotericin. We now have two

2. liposomal-drug intercalated into the phospholipid bilayer, rather than into

formulations. The standard intravenous formulation in which the

the aqueous phase

Indications for Amphotericin B: First-line therapy for disseminated fungal
infections in normal and immunocompromised hosts

drug is complexed with the deoxycholate for solubility. Then the

new liposomal formulations in which the drug has been intercalated into the phospholipid bilayer rather than into the aqueous
phase. This is thought not only to increase uptake by fatty tissues
but also to decrease side effects, particularly the nephrotoxicity.
Amphotericin B is first-line therapy for disseminated fungal
infections in normal and immunocompromised hosts. And it is the
gold-standard for antifungal therapy.

16

Amphotericin B Warnings
Aspergillosis in the immunocompromised host is going to be a

Ineffective against Aspergillosis in the immunocompromised host (50-8O%

serious and often fatal infection if the neutrophils dont return. So

mortality without neutrophils)

that even though one will use amphotericin B at what is considered

Primary Resistance

the standard dose for aspergillosis, which is 1.5 mg/kg per day,
you are still going to lose 50-80% of the time if those neutrophils

Pseudallescheria boydii

dont return. There are, unfortunately, some additional fungi which

Trichosporon beigelii

have primary a priori

Fusaria

Pseudallescheria boydii, Trichosporon beigelii, and Fusarium

Non-albicans (2-3%)

species. So when we see one of these fungi in an

resistance to amphotericin B;

immunocompromised host we dont have much to go on. Nonalbicans Candida species, 2-3% of these will also be resistant to
amphotericin B. Resistance among Candida albicans is extremely
low. So thats why its important to speciate the Candida that one
may grow from an immunocompromised host because we want to
make sure that if its Candida krusei we are not going to try to
treat with fluconazole. If its a non-albicans species we do have a
bit of a worry about amphotericin B resistance as well.

Side effects of amphotericin B. Fever and chills, nausea and

vomiting, hypotension, nephrotoxicity, cardiac arrhythmia,
hepatotoxicity, anemia, thrombocytopenia, phlebitis, renal losses
of potassium and magnesium, anaphylactoid reactions and
convulsions. In children we may see some fever and chills; we may
see some nausea and vomiting, a little bit of anemia and of course
renal losses and nephrotoxicity, but by and large many of these
other side effects such as hypotension, arrhythmias, hepatotoxicity,
convulsions, are very rare in childhood. Children tolerate
amphotericin B much better than do adults; and neonates, even
premature neonates, tolerate amphotericin much better than do
children. Many of these side effects can be abated or at least
markedly decreased by pre-infusion with Benadryl and hydrocortisone to decrease fever and chills, nausea and vomiting or phlebitis.
In patients in whom nausea and vomiting or severe headache is a
particularly bad side effect, then the Meperidine (Demerol) can be
given intravenously and that also will be very helpful in reducing
the side effects. In patients who have more severe side effects such
as decreased blood pressure etc., amphotericin B infusions,
although typically given as one daily dose, can be divided into
three daily doses with equal efficacy, and that can help to ameliorate some of the side effects such as hypotension.

17

Side Effects of Amphotericin B

The most common side effect of amphotericin B: we are talking

Fever and chills

Anemia

now about the deoxycholate formulation, is nephrotoxicity.

Nausea and vomiting

Thrombocytopenia

Virtually every patient who gets amphotericin B will have an

Hypotension

Phlebitis

Nephrotoxicity

Hypokalemia, hypomagnesemia

Cardiac arrhythmia

Anaphylactoid reaction

is typically reversible and this is very important to remember

Hepatotoxicity

Convulsions

because aggressive treatment of fungal infections in the

elevation of their BUN and creatinine. And this indeed can

progress to cylindruria, casts, potassium and magnesium wasting
from tubular disease. However, the nephrotoxicity of amphotericin

immunocompromised host typically requires that one give

amphotericin B to the point of rising BUN and creatinine.

18

Nephrotoxicity
Many of the nephrotoxic effects can be prevented by sodium

Occurs in 80%

loading. A quick infusion of about 100 cc (in a large size child)

Manifests as rising BUN and creatinine

prior to the amphotericin dose has been shown to be very helpful

Progresses to cylindruria, casts, potassium wasting

in preventing the nephrotoxic effects of amphotericin B.

Nephrotoxicity can be prevented by sodium loading

Typically reversible

19

Protocols for Administration

There are at least a couple of protocols for administration. First a

Rapid Initiation
1. Give 1 mg test dose
2. Wait 4 hours

test dose of 1 mg, Many of us have now moved to rapid initiation

protocols. Where we give a 1 mg test dose, typically again over
approximately four hours. It doesnt need to go in over six. We are
giving that test dose to look for severe side effects; such as

3. Initiate 0.3-0.5 mg/kg/day

hypotension or convulsions. Then we are going to wait four hours

4. Wait 24 hours

and then we are going to start a therapeutic dose. The therapeutic

5. Increase to 0.5-1.0 mg/kg/day

dose of amphotericin at the initial level of therapeusis is about 0.3

mg/kg. There are no reasons to stay at 0.3 mg/kg if one is treating
systemic fungal infections, but most MICs of most Candida
species for example are down about 0.1. So if you are here at
about 0.3 mg/kg you are above the MIC of most Candida albicans
species. After this first dose at the therapeutic level you then wait
24 hours and then immediately jump to the therapeutic dose. Most
people would say that for systemic fungal disease, especially in the
immunocompromised host, although the dosage range for adults is
roughly 0.5 - 0.7 mg/kg, in young children we have no difficulty
going to 1.0 mg/kg. For systemic candidal infections thats where
you want to be. About 1 mg/kg for neonate, in toddler and in
children. Adults typically use 0.7 or 0.75 mg/kg.

20

Amphotericin B in Renal Compromise

Decrease dosage: 0.5-1.0 mg/kg/day (1.5 for aspergillosis)

Amphotericin B in patients with renal compromise. In children 1.0

Sodium loading

mg/kg per day. If you are treating aspergillosis, 1.5 mg/kg per day.

When creatinine doubles or exceeds 3.5 gm/dL, reduce dose to 50% of daily

Sodium loading can help to decrease the incidence of

dose for 2-5 days

Return to standard dose

nephrotoxicity in patients whose kidneys are normal, but when the

creatinine doubles (if we are talking about a very young child, for
example a neonate with a creatinine of 0.4) or when the creatinine
in an older child (with a typical creatinine of 0.9) or an adolescent
exceeds 3.5 gm/dl, cut back to about 50% of the daily dose for 2 5 days, the creatinine will drift down. Not to a totally normal level
but to a midway value and then you can return to your standard
dose.

Another issue that we confront frequently is treatment failure with

amphotericin B. Often there are real reasons for treatment failure,
which are not the fault of the drug. The biggest one is failure to
remove the line in systemic candidal infection in patients with
Hickman or other intravascular catheters. These plastic sources
are a wonderful adhesive site for Candida. Candida surface
adhesions find plastic very appetizing. If we dont take out the line
we are not going to be able to clear the candidal infection.

21

Common Reasons for Amphotericin B Treatment Failure

The second issue is continued fungemia while on adequate doses

of amphotericin B ascribable to failure to recognize an
intravascular focus. So the neonate who had a line in place, who

Failure to remove an infected line

has an intravascular fungus ball, or a clot. Sometimes occurring in

Failure to recognize an intravascular focus

the atrium or sometimes occurring in the IVC. There may be an

Fungus ball in atrium

Infected cardiac graft or patch
Lesion requires surgical approach

infected cardiac graft or patch. So if I have removed the line and

Im adequately treating that patient with amphotericin B and
fungemia is continuing, Im going to have them echo this patient
looking for intravascular foci that require either removal or a

Dosage too low (#0.5 mg/kg/day)

surgical approach. The other problems include too low a dose.

Inadequate length of therapy (ie, <7 days for line infection)

Less than 0.5 mg/kg per day is much too low. In children we really

Resistant organism

dont like to drop below 0.75 mg/kg per day. Ideally we would
like to be at about 1.00 mg/kg per day for most systemic fungal
infections, and 1.5 for aspergillus. Too short a course. For
example, less that 7 days for a line infection because of a rising
creatinine. And lastly, we have to think of a resistance organism.
So when I have continued fungemia in a patient on adequate doses
of amphotericin B, I run the list because almost assuredly something in here has been omitted.

22

Drug Resistance in Candidal Infections

Drug resistance in candidal infections. Theres primary resistance

Primary resistance to amphotericin B (MIC>2.0 ug/mL)

Rare: 2-3%

Non-albicans species are resistant

Primary resistance to fluconazole (MIC>1.2 Fs/mL)

C krusei, C glabrata, tropicalis

Secondary resistance to fluconazole

to amphotericin B. Thats defined as an MIC greater than 2 /ml.

It is rare. It occurs only 2-3 % of Candida, and these are typically
non-albicans species. Unfortunately theres both primary and
secondary resistance if we are using fluconazole for Candida
infections. Primary resistance to fluconazole occurs with those
species, non-albicans species, especially Candida krusei, but also
with Candida glabrata and Candida tropicalis. Secondary resis-

Increasing for C albicans

tance to fluconazole, which is the emergence of a resistant species

Can occur in HIV positive patients without previous exposure

while the patient is under treatment with fluconazole, is now

increasing for Candida albicans and it will occur in HIV-positive
patients who are on therapy with the azoles, and it has been
reported rarely to occur in patients without previous exposure. So
these patients when cultured, for example for thrush, will show a
Candida albicans. Its originally sensitive to fluconazole. They will
not get any azoles, but over time they will develop secondary
resistance to fluconazole and subsequent cultures will show a
resistant albicans species. So the problem of Candida resistance to
fluconazole is probably just beginning. This drug may not be
effective for more than another two to three years.

23

Fluconazole vs. Amphotericin B

So, fluconazole is the drug of choice for fungal prophylaxis in the

Fluconazole is the drug of choice for fungal prophylaxis in the neutropenic host

bone marrow transplant patient who is neutropenic. Fluconazole

Fluconazole is of equal efficacy for treatment of disseminated candidiasis in

is of equal efficacy with amphotericin B for treatment of dissemi-

adults without neutropenia

nated candidiasis in adults without neutropenia.

24

First-line Drugs for Fungal Infections

First line drugs for fungal infections. For systemic candidiasis the

Indication

Drug of Choice

Alternate

Candidiasis (sys-

Amphotericin B 5FC

--

drug of choice is still amphotericin B. Weve not talked about the

addition of 5 FC. For histoplasmosis of mild to moderate disease mild, say pneumonitis with symptoms of more that three or four
weeks - one can use oral itraconazole. But if the host is

temic)

immunocompromised with CNS disease, amphotericin B is the

Histoplasmosis

drug of choice. In acute histoplasmosis and HIV infections,

Mild/moderate

Itraconazole

Amphotericin B

Severe ICH CNS

Amphotericin B

--

AIDS: acute

Amphotericin B

--

AIDS: maintenance

Itraconazole

Fluconazole

Cryptococcosis

amphotericin B. Maintenance therapy with itraconazole. In

Cryptococcus, in meningeal disease amphotericin B is the drug of
choice, but one can use maintenance therapy with fluconazole.
Other sites of Cryptococcus and acute disease in HIV-infected
patients will require amphotericin B.

Coccidioidomycosis meningeal disease is very serious and it

requires amphotericin B, both intravenously and intrathecally. The

Meningeal

Amphotericin B 5FC

Fluconazole

other sites

Amphotericin B

Fluconazole

no other drug than amphotericin for Coccidioidomycosis. For

AIDS: acute

Amphotericin B

--

blastomycosis, this is the one area where ketoconazole may have

AIDS: maintenance

Fluconazole

Amphotericin B

same is true for other sites of Coccidioidomycosis. Theres really

Coccidiomycosis

some utility, but frankly even if I have mild to moderate disease

with blastomycosis I greatly prefer amphotericin B to gain control.
For severe CNS disease, genitourinary disease, or the

meningeal

Amphotericin B (IV, IT)

--

other sites

Amphotericin B

--

AIDS: initial

Amphotericin B (IV, IT)

--

AIDS: maintenance

Amphotericin B

--

immunocompromised host with blastomycosis, there is nothing but

amphotericin B.

For aspergillus we are talking amphotericin B, itraconazole as an

alternative. The two may be given together in severe cases.

Blastomycosis

lymphocutaneous disease can actually be treated orally with

mild, moderate

Ketoconazole

Amphotericin B

severe: CNS, GU, ICH

Amphotericin B

--

Aspergillosis

Amphotericin B (+5FC

Itraconazole

Amphotericin B

itraconazole. Deep seated sporotrichosis will require amphotericin

B. Then we have several of these agents, such as Pseudallescheria
boydii: resistant to amphotericin B. Miconazole has been efficacious in some cases, but they have also been helped by the return
of neutrophils. Malassezia furfur by and large doesnt need

or rifabutin
Mucormycosis

Mucormycosis, the choice is amphotericin B. For sporotrichosis,

treatment when we see it in the neonatal nursery as a consequence

--

of intralipid infusion. But if one does need to treat it, miconazole

is the drug of choice. For Fusarium we actually have no treatment.

Sporotrichosis
lymphocutaneous

Itraconazole

Potassium iodide

deep-seated

Amphotericin B

Itraconazole

25

References
1. Wingard JR, Merz WG, Rinaldi MG, Johnson TR, Karp JE, Saral R. Increase in
Candida krusei infection among patients with bone marrow transplantation and
neutropenia treated prophylactically with fluconazole. N Engl I Med 325:1274-1277,
1994.
2. Rex JH, Bennett JE, Sugar AM, Pappas PG, et al. A randomized trial comparing
fluconazole with Amphotericin B for the treatment of candidemia in patients without
neutropenia. N Engl l Med 331:1325-1330, 1994.
3.

Evans TG, Mayer JM, Cohen S,. Cassen D, Carroll K. Fluconazole in the treatment
of invasive mycoses, I Infect Dis 164:1232-1235, 1991.

4.

DeMuri GP, Hostetter MK. Resistance to antifungal agents. Ped Clin NA

42:66.5-685, 1995.

26