antifungal therapy.pdf
TRANSCRIPT
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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.
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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
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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.
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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
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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.
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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.
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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
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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
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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.
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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
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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,
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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.
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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.
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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
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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.