antifungal therapy.pdf

7/29/2019 antifungal therapy.pdf

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Anti-fungal Therapy

Janet Wong, M.D.


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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 su

mycoses. Griseofulvin is also useful for superficial my

nothing else. Azoles are really the only antifungal age

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

and systemic mycoses. Among the polyenes, nystatin is u

in superficial candidiasis, for example, such as

Amphotericin B is typically reserved for more serious c

disease and systemic therapy.


3/26

Topical Antifungal Agents

Agent Ringworm T. versicolor Candidiasis

Naftifine XXX XXX XXX

Clotrimazole XXX XXX XXX

Nystatin - -

Topical antifungal agents. Naftifine, which is an a

derivative, is quite useful in ringworm, provided it is n

scalp, in tinea versicolor, and in candidiasis. Clotrima

representative of the azole category, and it also is usef

three types of superficial mycoses. Nystatin, on the othe

a polyene and of no utility in ringworm or tinea versic

must be reserved for superficial candidiasis such as thru


4/26

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 mo

cutaneous mycoses. Now, here they are yet again. This is

This is an allylamine derivative. The other allylamine

may encounter is terbinafine and these of course, as a

derivatives, inhibit fungal metabolism very high up in the

of fungal cell-wall construction. They inhibit really the

in the conversion of squalene to lanosterol. The imidazol

triazoles inhibit at a secondary step in the building of t

cell wall. The imidazoles and the triazoles inhibit

demethylase, which mediates the conversion of lano

ergosterol. The polyenes, nystatin (a topical antifungal a

amphotericin as (systemic antifungal agent), inhibit t

synthesis of ergosterol, the major component of the fu

membrane.


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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

superficial dermatophyte infections as well as for s

candidiasis. Such things as Candida diaper rash, mild i

The creams, the gels and solutions are very helpful in

intertriginous areas such as the toe webs, the groin

scrotum. Powder formulations are useful for milder lesi

identical areas. If its wet, dry it, if its dry, wet it - so tha

a wet diaper area then a powder may be very helpful. The

like clotrimazole powders, the imidazole powders, are e

useful in stoma infections. So if you have for example

patient with a colectomy or a child with short-gut syndr

has a stoma and then has a bag. Those are typically very,

areas. Ointments and creams really dont get the job d

powders are very useful in those wet areas. Ointments in

are typically much too occlusive and the dermatoph

particularly Candida love that sort of moist area. So usua

use the ointment formulations of these topical antifun

major exception to the use of topical antifungal ag

dermatophyte lesions of the head. Ringworm of the sc

capitus and kerion will require oral therapy, usua

griseofulvin.


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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 a

agent made by a mold and it inhibits nucleic acid synth

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

infections. It is hepatically metabolized and it is useful pa

in superficial fungal infections such as tinea capitus and

(tinea infections of the fingernails). It is not, however, u

chronic candidal infection of the fingernails. But i

extensive involvement of skin, head or nails, griseofulv

orally, is the drug of choice. It will be ineffica

mucocutaneous candidiasis. So griseofulvin is active a

superficial dermatophytes, but not against Candida. It is

dicated in porphyria and should not be used orally in p

Its side effects include hepatotoxicity in porphyria

reactions such as pruritic rash, prolongation of warfarin a

lants and a very important one that we certainly ca

childhood is neutropenia. So when I am treating a child w

kerion, and I may well have to treat that child for six to

on daily griseofulvin. Im going to monitor that white b

count and differential on a weekly basis because the

induce a neutropenia.


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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.

comes in two forms; a Microsize and an Ultramicrosize

Ultramicrosize form, and the dose is approximately 15 m

day given once a day as a single dose. Griseofulvin

agent. Typically for dermatophyte infections of the

fingernails.


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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 d

clotrimazole, miconazole, ketoconazole. The triaz

fluconazole and itraconazole. Now these antifungals age

14-alpha-demethylase, blocking the conversion of lan

ergosterol and thereby increasing membrane permeabili

the antifungal agents that we are talking about have activ

fungal cell membrane. Levels of antifungal agents in

stream or even in the lesions have not been accurately c

with clinical outcome. In part thats because many of th

who acquire fungal infections have other compromise

defenses. So the antifungal agent itself may or may not

cient, depending upon the whole in-host defense, to

patient. So clinical course and level of fungal agent have

been appropriately correlated for this category of antim

The examples of the imidazoles and the triazoles are keto

fluconazole, and itraconazole. The metabolism is hepati

lism for ketoconazole and itraconazole, and renal metab

fluconazole.


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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 predominatel

therapy. They are especially useful in severe mucoc

candidiasis, the hereditary syndromes where one sees

candidal colonization at the mouth, on the skin, on the fi

and, in females, in the vagina. This is a T-cell defect, a

is thought to be a T-cell defect; the precise genetic defic

been worked out. The other azoles can be useful for dee

ous infections such as sporotrichosis and for less severe

fungal infections, especially in hosts withou

immunocompromise. The hosts degree of immunocom

becomes a very important factor when one is deciding wh

are going to use an azole and go with oral therapy, or wh

is going to use amphotericin B, the first line agent for seve

infections. The azoles, with the exception that ketoconaz

typically failed pretty badly in the treatment of systemic

especially in immunocompromised hosts. So if the host a

of immunocompromise, one is going to be unlikely to b

that patient with oral ketoconazole. On the other hand, flu

and itraconazole have been used with good success in

mycoses, but predominantly in patients who do not ha

immune defects, such as prolonged neutropenia or pan

due to bone marrow transplants.


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Uses of Azoles

Superficial Cutaneous Systemic

Ketoconazole XXX XXX

Fluconazole XXX XXX XXX

Itraconazole XXX XXX XXX

Ketoconazole is a useful agent for superficial myc

cutaneous mycoses. It fails badly in halting disseminat

infections such as aspergillus, candidiasis, histo, bla

immunocompromised host (i.e. neutropenic bone marr

plant patients or HIV infected patients). The other c

ketoconazole of course is that the drug does not pen

cerebrospinal fluid. Some other limitations of ketoconaz

which we need to be careful, the first is that it is a

contraindicated in patients with hepatic failure. The

hepatically excreted and therefore will accumulate to to

in patients with hepatic failures. Secondly, the high pH

would typically get in the stomach of a patient on H2 bl

patients who have achlorhydria (no HCL in the stom

prevent absorption of ketoconazole. So one has to be ve

how one uses the drug, especially in the presence of H2

One can get hypertension with long term use. Treatm

isoniazid is a relative contraindication because

ketoconazole are affected. We are not going to use this

fungal meningitis. That is a contraindication because

penetrate the CNS. Other contraindications would includ

of ketoconazole in patients who are taking certain antihi

terfenadine and astemizole. This could lead to a prolon

the Q-T interval and cardiac arrhythmias if ketoconazo

with those antihistamines. Also for those of us who

immunocompromised hosts, especially those undergo

marrow transplants, we know that ketoconazole can

elevate levels of cyclosporine, typically leading to neu

and additive renal toxicity. So the antihistamines, con

tions to the use of ketoconazole and cyclosporine - yohave to watch your cyclosporine levels very carefully if

the patient on any of the azoles.


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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 ketocon

aware that this drug will elevate the hepatic trans

typically to about three to four times normal. If the patien

gets beyond that, and we are talking about hepatic trans

in the 500s or above, most people would stop keto

Gynecomastia will occur in 20% of males tak

ketoconazole. Many would find this a very objection

effect. In addition to the gynecomastia, virtually all m

have some suppression of testosterone levels and this m

libido. It is also important to recognize that one of the maj

of ketoconazole is treatment-limiting neutropenia. Neutro

been a recognized side effect of ketoconazole. So if one i

use ketoconazole, youve got to watch those white cell c

differentials because neutropenia can supervene.


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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 us

sively. We know that fluconazole has been used as proph

candidiasis in bone marrow transplant patients. Systemic

due to Candida albicans were suppressed with flu

prophylaxis in adult bone marrow transplant patients bu

nately there was an eight-fold increase in systemic infec

to Candida krusei because this particular Candida s

resistant to fluconazole de novo. All Candida krusei ar

resistant to fluconazole. So although we can use fluco

prophylaxis in a bone marrow transplant patient, we h

very careful. Many places doing bone marrow transplan

surveillance cultures and see; if Candida krusei is in that

patients surveillance cultures of the stool, then I am go

very worried about using fluconazole. It does have a

utility in more defined infections such as Candida eso

Candida peritonitis, Candida vaginitis even Candid

provided there is no evidence of systemic spread from the

It should not be used as primary therapy for aspergillo

immunocompromised host. Now in contrast to keto

fluconazole has very good CSF penetration and these stu

been done largely in patients with cryptococcal mening

fluconazole has proven extremely useful as maintenance

not as initial therapy, but as maintenance therapy in HIV

patients with cryptococcal meningitis.


13/26

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 aspergil

Although it does have affects against other systemic f

greatest utility is in aspergillosis for patients who are

tolerate amphotericin B or whose disease is progressing o

(amphotericin B) therapy. With any antifungal

aspergillosis, especially pulmonary aspergillosis,

immunocompromised host is 50-80% fatal if the neutrop

return. In many cases if those neutrophils arent going

back, you cant put your money on an antifungal agent

its itraconazole or amphotericin B or even liposomal amp

B in order to cure that patient. So curing aspergillus

normal neutrophils. Itraconazole has been useful, how

prophylaxis for chronic granulomatous disease. These pa

get systemic fungi. Typically aspergillus in unusual locat

as the vertebrae; and itraconazole does indeed seem to h

these fungal infections. With itraconazole, in co

fluconazole, has never been found in the CSF but respo

been seen in chronic coccidioidal meningitis and in cry

meningitis in HIV infections. But a sustained response

requires continuous therapy. So as we will see when

reviewing first line antifungal agents, most people wo

coccidioidal meningitis or cryptococcal meningitis init

amphotericin B and then when they are moving to a ma

phase are going to have long-term disease such as HIV

patients, switch to oral itraconazole.


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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 flucona

itraconazole is that their side effects are substantially

particular GI upset, which can be a major side ef

ketoconazole, is much reduced with oral flucon

itraconazole. Ketoconazole can have a decreased cortiso

to ACTH impetus and decreased libido and gynecomast

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

or itraconazole. Neutropenia, a ketoconazole side effect

occur with fluconazole or itraconazole. With those tw

although the GI upset is reduced, we will see transient in

transaminases. With ketoconazole we will typically see

in transaminases that may continue to rise. So we ha

careful about ketoconazole and elevation of the LFTs.

of these drugs will increase cyclosporine levels. So if you

these azoles in a bone marrow transplant patient on cyc

those levels are going to go up; perhaps with toxic side e


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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

are in an achlorhydric situation or when the pH of the st

not acid. In terms of tissue penetration we get very good

tion of ketoconazole into the sputum, into the skin, but

into the CNS. Metabolism is hepatic. Dilantin, INH and

will all affect ketoconazole levels. The half life of ketoco

the shortest among the azoles. Its 6-8 hours and the do

mg/kg given q.12-24 h.

Fluconazole does not have the same difficulties of abso

does ketoconazole. And in contrast to ketoconazole, flu

gives excellent levels weve said into the CNS and into

of other sites. So this is the drug that penetrates. This is

that gets into the CSF. Its metabolism is divided betwee

and renal. Renal is the predominant site of excre

fluconazole will inhibit the metabolism of antico

cyclosporine and digoxin. The half-life is about 18-24 h

the dose is thought to be more efficacious if given as

loading dose of 10 mg/kg and then 4-6 mg/kg q.12-24 ho

people will give a single daily dose of fluconazole after th

dose has been attained.

Itraconazole. It gives us very good levels in the sputum

nails, but again poor CNS levels. Here is its metabolism

largely hepatic and its important to point out here that b

the pH-dependent effects of itraconazole absorption, w

give itraconazole separately from DDI when we are trea

infected patients. In addition, like fluconazole, itracona

inhibit the metabolism of anticonvulsants, anticoagulantand cyclosporine. It has the longest half-life; at least 24 h

its dose is 5-10 mg/kg typically given as a single daily d


16/26

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 Strep

nodosus, and it binds ergosterol. Renal excretion is the

nant mechanism of excretion but you will also g

amphotericin B into the biliary tract and about 40% of

of amphotericin B is not known how it is excreted. So

although it has tremendous utility, there are still a lot of

that havent been answered about amphotericin. We now

formulations. The standard intravenous formulation in

drug is complexed with the deoxycholate for solubility.

new liposomal formulations in which the drug has bee

lated into the phospholipid bilayer rather than into the

phase. This is thought not only to increase uptake by fat

but also to decrease side effects, particularly the nephr

Amphotericin B is first-line therapy for disseminate

infections in normal and immunocompromised hosts. An

gold-standard for antifungal therapy.


17/26

Amphotericin BWarnings

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 goin

serious and often fatal infection if the neutrophils dont

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

the standard dose for aspergillosis, which is 1.5 mg/kg

you are still going to lose 50-80% of the time if those ne

dont return. There are, unfortunately, some additional fu

have primary a priori resistance to amphote

Pseudallescheria boydii, Trichosporon beigelii, and

species. So when we see one of these fung

immunocompromised host we dont have much to go

albicans Candida species, 2-3% of these will also be re

amphotericin B. Resistance among Candida albicans is e

low. So thats why its important to speciate the Candid

may grow from an immunocompromised host because w

make sure that if its Candida krusei we are not going

treat with fluconazole. If its a non-albicans species we

bit of a worry about amphotericin B resistance as well.

Side effects of amphotericin B. Fever and chills, na

vomiting, hypotension, nephrotoxicity, cardiac ar

hepatotoxicity, anemia, thrombocytopenia, phlebitis, re

of potassium and magnesium, anaphylactoid react

convulsions. In children we may see some fever and chill

see some nausea and vomiting, a little bit of anemia and

renal losses and nephrotoxicity, but by and large many

other side effects such as hypotension, arrhythmias, hepat

convulsions, are very rare in childhood. Children

amphotericin B much better than do adults; and neona

premature neonates, tolerate amphotericin much bettechildren. Many of these side effects can be abated o

markedly decreased by pre-infusion with Benadryl and hy

sone to decrease fever and chills, nausea and vomiting or

In patients in whom nausea and vomiting or severe hea

particularly bad side effect, then the Meperidine (Demer

given intravenously and that also will be very helpful in

the side effects. In patients who have more severe side ef

as decreased blood pressure etc., amphotericin B

although typically given as one daily dose, can be div

three daily doses with equal efficacy, and that can help t

rate some of the side effects such as hypotension.


18/26

Side Effects of Amphotericin B

ever and chills Anemia

ausea and vomiting Thrombocytopenia

ypotension Phlebitis

ephrotoxicity Hypokalemia, hypomagnesemia

ardiac arrhythmia Anaphylactoid reaction

epatotoxicity Convulsions

The most common side effect of amphotericin B: we a

now about the deoxycholate formulation, is nephr

Virtually every patient who gets amphotericin B will

elevation of their BUN and creatinine. And this in

progress to cylindruria, casts, potassium and magnesium

from tubular disease. However, the nephrotoxicity of amp

is typically reversible and this is very important to r

because aggressive treatment of fungal infection

immunocompromised host typically requires that

amphotericin B to the point of rising BUN and creatinin


19/26

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 b

loading. A quick infusion of about 100 cc (in a large s

prior to the amphotericin dose has been shown to be ver

in preventing the nephrotoxic effects of amphotericin B


20/26

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 administratio

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

protocols. Where we give a 1 mg test dose, typically a

approximately four hours. It doesnt need to go in over si

giving that test dose to look for severe side effects

hypotension or convulsions. Then we are going to wait f

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

dose of amphotericin at the initial level of therapeusis is

mg/kg. There are no reasons to stay at 0.3 mg/kg if one i

systemic fungal infections, but most MICs of most

species for example are down about 0.1. So if you ar

about 0.3 mg/kg you are above the MIC of most Candida

species. After this first dose at the therapeutic level you

24 hours and then immediately jump to the therapeutic d

people would say that for systemic fungal disease, especi

immunocompromised host, although the dosage range fo

roughly 0.5 - 0.7 mg/kg, in young children we have no

going to 1.0 mg/kg. For systemic candidal infections tha

you want to be. About 1 mg/kg for neonate, in toddl

children. Adults typically use 0.7 or 0.75 mg/kg.


21/26

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 ch

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

Sodium loading can help to decrease the incid

nephrotoxicity in patients whose kidneys are normal, but

creatinine doubles (if we are talking about a very young

example a neonate with a creatinine of 0.4) or when the c

in an older child (with a typical creatinine of 0.9) or an a

exceeds 3.5 gm/dl, cut back to about 50% of the daily do

5 days, the creatinine will drift down. Not to a totally nor

but to a midway value and then you can return to your

dose.

Another issue that we confront frequently is treatment fa

amphotericin B. Often there are real reasons for treatme

which are not the fault of the drug. The biggest one is

remove the line in systemic candidal infection in pati

Hickman or other intravascular catheters. These plasti

are a wonderful adhesive site for Candida. Candid

adhesions find plastic very appetizing. If we dont take o

we are not going to be able to clear the candidal infectio


22/26

Common Reasons for Amphotericin B Treat-

ment 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,


23/26

Drug Resistance in CandidalInfections

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. Theres primary r

to amphotericin B. Thats defined as an MIC greater tha

It is rare. It occurs only 2-3 % of Candida, and these are

non-albicans species. Unfortunately theres both prim

secondary resistance if we are using fluconazole for

infections. Primary resistance to fluconazole occurs w

species, non-albicans species, especially Candida krusei

with Candida glabrata and Candida tropicalis. Second

tance to fluconazole, which is the emergence of a resistan

while the patient is under treatment with fluconazole

increasing for Candida albicans and it will occur in HIV

patients who are on therapy with the azoles, and it

reported rarely to occur in patients without previous exp

these patients when cultured, for example for thrush, w

Candida albicans. Its originally sensitive to fluconazole.

not get any azoles, but over time they will develop s

resistance to fluconazole and subsequent cultures wi

resistant albicans species. So the problem of Candida res

fluconazole is probably just beginning. This drug ma

effective for more than another two to three years.


24/26

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 prophyla

bone marrow transplant patient who is neutropenic. Flu

is of equal efficacy with amphotericin B for treatment o

nated candidiasis in adults without neutropenia.


25/26

First-line Drugs for FungalInfections

Indication Drug of Choice Alternate

Candidiasis (sys-

temic)

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 candi

drug of choice is still amphotericin B. Weve not talked

addition of5 FC. For histoplasmosis of mild to moderate

mild, say pneumonitis with symptoms of more that thr

weeks - one can use oral itraconazole. But if the

immunocompromised with CNS disease, amphotericin

drug of choice. In acute histoplasmosis and HIV in

amphotericin B. Maintenance therapy with itracon

Cryptococcus, in meningeal disease amphotericin B is th

choice, but one can use maintenance therapy with fluc

Other sites of Cryptococcus and acute disease in HIV

patients will require amphotericin B.

Coccidioidomycosis meningeal disease is very seriou

requires amphotericin B, both intravenously and intrathe

same is true for other sites of Coccidioidomycosis. Ther

no other drug than amphotericin for Coccidioidomyc

blastomycosis, this is the one area where ketoconazole

some utility, but frankly even if I have mild to modera

with blastomycosis I greatly prefer amphotericin B to gai

For severe CNS disease, genitourinary disease,

immunocompromised host with blastomycosis, there is no

amphotericin B.

For aspergillus we are talking amphotericin B, itracona

alternative. The two may be given together in seve

Mucormycosis, the choice is amphotericin B. For sporo

lymphocutaneous disease can actually be treated or

itraconazole. Deep seated sporotrichosis will require ampB. Then we have several of these agents, such as Pseuda

boydii: resistant to amphotericin B. Miconazole has be

cious in some cases, but they have also been helped by

of neutrophils. Malassezia furfur by and large does

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

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

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


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References

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.

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.

Evans TG, Mayer JM, Cohen S,. Cassen D, Carroll K. Fluconazole in the treatment

of invasive mycoses, I Infect Dis 164:1232-1235, 1991.

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

42:66.5-685, 1995.

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