Anti-fungal Therapy

Anti-fungal Therapy
Janet Wong, M.D.

Spectrum of Anti-fungal Agents
Class Superficial Cutaneous Systemic
Topicals XXX
Griseofulvin XXX
Azoles
Ketoconazole
Fluconazole
Itraconazole
XXX XXX XXX
Polyenes
Nystatin XXX
Amphotericin B XXX XXX
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
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.

Topical Antifungal Agents
Agent Ringworm T. versicolor Candidiasis
Naftifine XXX XXX XXX
Clotrimazole XXX XXX XXX
Nystatin
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
representative of the azole category, and it also is useful for all
three types of superficial mycoses. Nystatin, on the other hand, is
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
. CLASS
Naftifine - allylamine derivative
Clotrimazole - imidazole
Nystatin - polyene
. METABOLISM
Naftifine renal
Clotrimazole - hepatic
Nystatin - fecal
All of these topical agents are contraindicated in the more serious
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
triazoles inhibit at a secondary step in the building of the fungal
cell wall. The imidazoles and the triazoles inhibit 14 alpha
demethylase, which mediates the conversion of lanosterol to
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: Superficial dermatophyte infections and candidiasis
. Creams, gels, solutions are used for inflamed intertriginous areas
. Powder is used for milder lesions in the identical areas
. Ointment is often times too occlusive
. Lesions on the head usually require oral therapy
Uses for the topical antifungal agents. These are useful really for
superficial dermatophyte infections as well as for superficial
candidiasis. Such things as Candida diaper rash, mild intertrigo.
The creams, the gels and solutions are very helpful in inflamed
intertriginous areas such as the toe webs, the groin and the
scrotum. Powder formulations are useful for milder lesions in the
identical areas. If it’s wet, dry it, if it’s 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 don’t 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 don’t
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
. CLASS: product of Penicillium
. ACTION: inhibition of fungal nucleic acid synthesis
. METABOLISM: hepatic
. USE: superficial fungal infections, such as tinea capitis and unguium,
especially with extensive involvement of skin, head, or nails
Griseofulvin is a product of Penicillium, so it is an antifungal
agent made by a mold and it inhibits nucleic acid synthesis at the
elongating tip of the hypha, as we would see in dermatophyte
infections. It is hepatically metabolized and it is useful particularly
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.
It’s 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. I’m going to monitor that white blood cell
count and differential on a weekly basis because the drug can
induce a neutropenia.

Griseofulvin
. Not effective in mucocutaneous candidiasis
. CONTRAINDICATIONS: porphyria, pregnancy
. SIDE EFFECTS: hepatotoxicity in porphyria, allergic reactions,
prolongation of warfarin anticoagulants
Neutropenia - Must monitor WBC/DIFF
. DOSE: Ultramicrosize: 15 mg/kg/day q 24 hrs
Absorption is augmented if one uses the Ultramicrosize. The drug
comes in two forms; a Microsize and an Ultramicrosize. Use the
Ultramicrosize form, and the dose is approximately 15 mg/kg per
day given once a day as a single dose. Griseofulvin is an oral
agent. Typically for dermatophyte infections of the head or
fingernails.

Imidazoles/triazoles
. CLASS: Imidazoles/triazoles block the conversion of lanosterol to
ergosterol and increasing membrane permeability
. EXAMPLES: (1) Ketoconazole
(2) Fluconazole
(3) Itraconazole
. METABOLISM:
Ketoconazole and itraconazole: Hepatic
Fluconazole: Renal
Imidazoles and the triazoles. The imidazoles are drugs like
clotrimazole, miconazole, ketoconazole. The triazoles are
fluconazole and itraconazole. Now these antifungals agents inhibit
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
with clinical outcome. In part that’s because many of the patients
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
. USES: Oral therapy
Severe mucocutaneous candidiasis
Deep cutaneous infections
Less severe systemic fungal infections, especially in hosts without major
immunocompromise
General uses of azoles. They can be used predominately for oral
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 host’s 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
Superficial Cutaneous Systemic
Ketoconazole XXX XXX ±
Fluconazole XXX XXX XXX
Itraconazole XXX XXX XXX
Ketoconazole is a useful agent for superficial mycoses and
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 doesn’t
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.

Ketoconazole Weaknesses
. Ketoconazole has failed to halt disseminated fungal infections (aspergillosis,
candidiasis, histoplasmosis, blastomycosis) in the immunocompromised host
(eg, neutropenia, HIV infection)
. The drug does not penetrate the CSF
Additional side effects: if you are going to use ketoconazole, be
aware that this drug will elevate the hepatic transaminases
typically to about three to four times normal. If the patient actually
gets beyond that, and we are talking about hepatic transaminases
in the 500’s 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, you’ve got to watch those white cell counts and
differentials because neutropenia can supervene.

Fluconazole Usage
. Prophylaxis for candidiasis in bone marrow transplant patients
. C krusei is resistant de novo to fluconazole
. Used for Candida esophagitis, peritonitis, vaginitis, but should not be use as
primary therapy for aspergillosis in the immunocompromised host
. Good CSF penetration in cryptococcal meningitis
Fluconazole is a triazole like imidazole. It is being used extensively.
We know that fluconazole has been used as prophylaxis for
candidiasis in bone marrow transplant patients. Systemic infections
due to Candida albicans were suppressed with fluconazole
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
patient’s 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.

Itraconazole Use
. 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
seen in chronic coccidioidal meningitis and cryptococcal meningitis in HIV
infection. Sustained response typically requires continuous therapy
Itraconazole is a triazole, and this one is the aspergillus drug.
Although it does have affects against other systemic fungi, it’s
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
immunocompromised host is 50-80% fatal if the neutrophils don’t
return. In many cases if those neutrophils aren’t going to come
back, you can’t put your money on an antifungal agent; whether
it’s 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.

Limitations of Ketoconazole
. Contraindications
Hepatic failure
H2 blockers or achlorhydria prevent absorption of ketoconazole
Hypertension with long-term use
Treatment with isoniazid
Not indicated for fungal meningitis
. Side Effects of Ketoconazole
Elevated hepatic transaminases
Gynecomastia
Suppression of testosterone levels
Treatment-limiting neutropenia
Side effects of the azoles. The advantage of fluconazole and
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
to ACTH impetus and decreased libido and gynecomastia in 20%
of males. None of these related side effects occur with fluconazole
or itraconazole. Neutropenia, a ketoconazole side effect, does not
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
careful about ketoconazole and elevation of the LFT’s. All three
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.

Side Effects of Imidazoles
. 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
The point is that ketoconazole is very difficult to absorb when we
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. It’s 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 we’ve 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. It’s 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 it’s 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.

Amphotericin B
. CLASS: Polyene produced by Streptomyces nodosus; binds ergosterol in the
fungal cell wall
. METABOLISM: Predominantly renal, but also biliary
. FORMULATIONS:
1. IV complexed with desoxycholate for solubility
2. liposomal-drug intercalated into the phospholipid bilayer, rather than into
the aqueous phase
. Indications for Amphotericin B: First-line therapy for disseminated fungal
infections in normal and immunocompromised hosts
Amphotericin B is a polyene. Again produced by Streptomyces
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
that haven’t been answered about amphotericin. We now have two
formulations. The standard intravenous formulation in which the
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.

Amphotericin B Warnings
. Ineffective against Aspergillosis in the immunocompromised host (50-8O%
mortality without neutrophils)
. Primary Resistance
Pseudallescheria boydii
Trichosporon beigelii
Fusaria
Non-albicans (2-3%)
Aspergillosis in the immunocompromised host is going to be a
serious and often fatal infection if the neutrophils don’t return. So
that even though one will use amphotericin B at what is considered
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
don’t return. There are, unfortunately, some additional fungi which
have primary a priori resistance to amphotericin B;
Pseudallescheria boydii, Trichosporon beigelii, and Fusarium
species. So when we see one of these fungi in an
immunocompromised host we don’t 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 that’s why it’s important to speciate the Candida that one
may grow from an immunocompromised host because we want to
make sure that if it’s Candida krusei we are not going to try to
treat with fluconazole. If it’s 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.

Side Effects of Amphotericin B
Fever and chills Anemia
Nausea and vomiting Thrombocytopenia
Hypotension Phlebitis
Nephrotoxicity Hypokalemia, hypomagnesemia
Cardiac arrhythmia Anaphylactoid reaction
Hepatotoxicity Convulsions
The most common side effect of amphotericin B: we are talking
now about the deoxycholate formulation, is nephrotoxicity.
Virtually every patient who gets amphotericin B will have an
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
is typically reversible and this is very important to remember
because aggressive treatment of fungal infections in the
immunocompromised host typically requires that one give
amphotericin B to the point of rising BUN and creatinine.

Nephrotoxicity
. Occurs in 80%
. Manifests as rising BUN and creatinine
. Progresses to cylindruria, casts, potassium wasting
. Nephrotoxicity can be prevented by sodium loading
. Typically reversible
Many of the nephrotoxic effects can be prevented by sodium
loading. A quick infusion of about 100 cc (in a large size child)
prior to the amphotericin dose has been shown to be very helpful
in preventing the nephrotoxic effects of amphotericin B.

Protocols for Administration
. Rapid Initiation
1. Give 1 mg test dose
2. Wait 4 hours
3. Initiate 0.3-0.5 mg/kg/day
4. Wait 24 hours
5. Increase to 0.5-1.0 mg/kg/day
There are at least a couple of protocols for administration. First a
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 doesn’t need to go in over six. We are
giving that test dose to look for severe side effects; such as
hypotension or convulsions. Then we are going to wait four hours
and then we are going to start a therapeutic dose. The therapeutic
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 MIC’s 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 that’s 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.

Amphotericin B in Renal Compromise
. Decrease dosage: 0.5-1.0 mg/kg/day (1.5 for aspergillosis)
. Sodium loading
. When creatinine doubles or exceeds 3.5 gm/dL, reduce dose to 50% of daily
dose for 2-5 days
. Return to standard dose
Amphotericin B in patients with renal compromise. In children 1.0
mg/kg per day. If you are treating aspergillosis, 1.5 mg/kg per day.
Sodium loading can help to decrease the incidence of
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 don’t take out the line
we are not going to be able to clear the candidal infection.

Common Reasons for Amphotericin B Treatment
Failure
. Failure to remove an infected line
. Failure to recognize an intravascular focus
• Fungus ball in atrium
• Infected cardiac graft or patch
. Lesion requires surgical approach
. Dosage too low (#0.5 mg/kg/day)
. Inadequate length of therapy (ie, <7 days for line infection)
. Resistant organism
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
has an intravascular fungus ball, or a clot. Sometimes occurring in
the atrium or sometimes occurring in the IVC. There may be an
infected cardiac graft or patch. So if I have removed the line and
I’m adequately treating that patient with amphotericin B and
fungemia is continuing, I’m going to have them echo this patient
looking for intravascular foci that require either removal or a
surgical approach. The other problems include too low a dose.
Less than 0.5 mg/kg per day is much too low. In children we really
don’t 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.

Drug Resistance in Candidal Infections
. 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
Increasing for C albicans
Can occur in HIV positive patients without previous exposure
Drug resistance in candidal infections. There’s primary resistance
to amphotericin B. That’s defined as an MIC greater than 2 µ/ml.
It is rare. It occurs only 2-3 % of Candida, and these are typically
non-albicans species. Unfortunately there’s 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 resistance
to fluconazole, which is the emergence of a resistant species
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. It’s 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.

Fluconazole vs. Amphotericin B
. Fluconazole is the drug of choice for fungal prophylaxis in the neutropenic host
. Fluconazole is of equal efficacy for treatment of disseminated candidiasis in
adults without neutropenia
So, fluconazole is the drug of choice for fungal prophylaxis in the
bone marrow transplant patient who is neutropenic. Fluconazole
is of equal efficacy with amphotericin B for treatment of disseminated
candidiasis in adults without neutropenia.

First-line Drugs for Fungal Infections
Indication Drug of Choice Alternate
Candidiasis (systemic)
Amphotericin B ± 5FC
Histoplasmosis
Mild/moderate Itraconazole Amphotericin B
Severe ICH CNS Amphotericin B
AIDS: acute Amphotericin B
AIDS: maintenance Itraconazole Fluconazole
Cryptococcosis
Meningeal Amphotericin B ± 5FC Fluconazole
other sites Amphotericin B Fluconazole
AIDS: acute Amphotericin B
AIDS: maintenance Fluconazole Amphotericin B
Coccidiomycosis
meningeal Amphotericin B (IV, IT)
other sites Amphotericin B
AIDS: initial Amphotericin B (IV, IT)
AIDS: maintenance Amphotericin B
Blastomycosis
mild, moderate Ketoconazole Amphotericin B
severe: CNS, GU, ICH Amphotericin B
Aspergillosis Amphotericin B (+5FC
or rifabutin
Itraconazole
Mucormycosis Amphotericin B
Sporotrichosis
lymphocutaneous Itraconazole Potassium iodide
deep-seated Amphotericin B Itraconazole
First line drugs for fungal infections. For systemic candidiasis the
drug of choice is still amphotericin B. We’ve 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
immunocompromised with CNS disease, amphotericin B is the
drug of choice. In acute histoplasmosis and HIV infections,
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
same is true for other sites of Coccidioidomycosis. There’s really
no other drug than amphotericin for Coccidioidomycosis. For
blastomycosis, this is the one area where ketoconazole may have
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
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.
Mucormycosis, the choice is amphotericin B. For sporotrichosis,
lymphocutaneous disease can actually be treated orally with
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 doesn’t need
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.

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.