Antifungal Pharmacology

Deborah Fox, Ph.D.

Children’s Hospital
3219 RIC
504-896-2766
dfox@chnola-research.org

Special thanks to:

John Perfect, MD
Andy Alspaugh, MD
Sevtap Arikan, MD
John Rex, MD
www.doctorfungus.org
 Lecture outline
• Clinical significance of fungal infection
• Fungal cell structure and targets
• Antifungal agents and mechanism of action
• Antifungal drug interactions & nephrotoxicity
• Mechanisms of antifungal resistance
• Combination antifungal therapy
 Mycology Resources

• http://www.doctorfungus.org
• http://mycology.adelaide.edu.au/mycoses
• http://mycology.cornell.edu/
• http://www.mycology.net/
 Lecture outline
• Clinical significance of fungal infection
• Fungal cell structure and targets
• Antifungal agents and mechanism of action
• Antifungal drug interactions & nephrotoxicity
• Mechanisms of antifungal resistance
• Combination antifungal therapy
Medical Problems Caused by Fungi

1) Allergic disease

2) “Mushroom” poisoning

3) Mycotoxins
Secondary metabolites
--many have industrial uses
--Fusarium mycotoxin -- USSR after WWII
--A. flavus “aflatoxin”

4) Mycoses -- infection and resulting disease cause by fungi

The Fungi

150
primary human
fungal pathogens

100,000
Validly described species
of fungi

Fungi yet to be discovered -Kwon-Chung and

Bennett, 1992
The Fungi

150
primary human
fungal pathogens

100,000
Validly described species
of fungi

Fungi yet to be discovered -Kwon-Chung and

Bennett, 1992
The Fungi

150 Candida,
Aspergillus,
primary human Crypto, Blasto, Histo,
Cocci, Dermatophytes
fungal pathogens

100,000
Validly described species
of fungi

Fungi yet to be discovered -Kwon-Chung and

Bennett, 1992
Recent events in fungal diseases
Problems of today:
a. Growing population of immunocompromised
i. Modern medical practices: transplantations, indwelling catheters,
surgeries, anti-cancer therapies, broad-spectrum antibacterials,
immunosuppressants; mycoses: especially candidiasis and aspergillosis
ii. Natural diseases: AIDS; mycoses: especially candidiasis and
cryptococcosis
iii. Mean age of population is increasing; mycoses: especially candidiasis

b. Special problems associated with immunocompromised. Candida,

Aspergillus,
i. Mycoses often are more severe, difficult to treat and diagnose. Crypto, Blasto, Histo,
ii. Number of disease-causing fungi has increased. Cocci, Dermatophytes

c. Mobile population.
i. People commonly travel through areas of endemic mycoses, which
presents diagnostic challenges.

Advances in research:
a. New antifungal agents and treatment options

b. Tremendous increase in understanding of molecular basis of pathogenesis

 Lecture outline
• Clinical significance of fungal infection
• Fungal cell structure and targets
• Antifungal agents and mechanism of action
• Antifungal drug interactions & nephrotoxicity
• Mechanisms of antifungal resistance
• Combination antifungal therapy
001
002
Fungal cell Cell membrane and cell wall

Mannoproteins

β-(1,6)-glucan
β-(1,3)-glucan

Chitin

Phospholipid bilayer
of cell membrane

β-(1,3)-glucan synthase
Ergosterol

Ergosterol
Synthesis DNA/RNA Synthesis
Pathway

Squalene
 ANTIFUNGAL DRUGS
targets
• Membrane disrupting agents • Glucan synthesis
Amphotericin B, nystatin inhibitors
• Ergosterol synthesis inhibitors Echinocandins
Azoles, allylamines, morpholine
• Nucleic acid inhibitor • Chitin synthesis
Flucytosine inhibitor
• Anti-mitotic (spindle disruption) Nikkomycin
Griseofulvin
• Protein synthesis inhibitors
Sordarins, azasordarins
 Lecture outline
• Clinical significance of fungal infection
• Fungal cell structure and targets
• Antifungal agents and mechanism of action
• Antifungal drug interactions & nephrotoxicity
• Mechanisms of antifungal resistance
• Combination antifungal therapy
 ANTIFUNGAL DRUGS
classes
• POLYENES • ECHINOCANDINS
Amphotericin B, nystatin Caspofungin,
• AZOLES
anidulafungin,
Imidazoles: Ketoconazole..
micafungin
Triazoles: Fluconazole,
itraconazole,
voriconazole, • PEPTIDE-NUCLEOSIDE
posaconazole, Nikkomycin Z
ravuconazole
• ALLYLAMINES • TETRAHYDROFURAN
Terbinafine, butenafine DERIVATIVES
• MORPHOLINE Sordarins, azasordarins
Amorolfine
• FLUORINATED PYRIMIDINE
• OTHER
Flucytosine
Griseofulvin
Polyenes
OH
OH
H3C O OH

HO O OH OH OH OH O
CH3 COOH
H
H3C

O O CH3
amphotericin B OH
NH2
OH

OH
OH
H3C O OH

HO O OH OH OH OH O
CH3 COOH

H3C

Nystatin A1 O CH3
OH

OH NH2
 Amphotericin B
Ergosterol

Cell membrane

Binding to ergosterol, Ca
Ca++
++ Ca
Ca++
++
Intercalation of cell membrane Na
Na++
Na
Na++ K
K++

K
K++

Leakage of intracellular cations

and proteins
 Amphotericin B
• Mechanism: binds sterols, preferentially ergosterol,
and disrupts osmotic integrity of cell membrane

• Complications: fever, chills, myalgia, nephrotoxicity,

thrombophlebitis

• Pharmacokinetics: poorly soluble in water

•rapid uptake by RES, then redistributed
•four formulations
• ampho B colloidal dispersion (ABCD; Amphotec)
• amphotericin B lipid complex (ABLC; Abelcet)
• liposomal amphotericin B (L-AMB; Ambisome)
• oral amphotericin B (poor absorption)

• Indications: broad range of activity, ABCD is

mainstay of antifungal therapy
Azoles, allylamines & morpholines
ergosterol synthesis inhibitors

Clin Microbiol Rev

1998; 11: 382
 N
Azoles N

O
N F
O
N
N N O O

N H3C H Cl Cl

N N
OH F
ketoconazole

fluconazole N

N
N
CH3
N O
O
H3C
N
N N N O O
N N N
H Cl Cl
N N F
OH

itraconazole
N
F CH3
N
F H3C
N
O
O
H3C

voriconazole N
N N N O
HO N
H F F

posaconazole
 Azole

Cell membrane

Ergosterol

Ergosterol
Synthesis
Pathway

Squalene

Accumulation of
toxic sterols in
cell membrane

Toxic sterols
Inhibition of
14-alpha-demethylase
 Azoles
• Mechanism: block ergosterol synthesis via inhibition
of cytochrome P450 14α-demethylase

• Complications: well-tolerated, hepatotoxicity,

hypertension, headache, visual disturbances, resistance

• Formulations: poorly soluble in water, fungistatic

• Fluconazole (Diflucan)
• Voriconazole (Vfend)
• Ravuconazole
• Itraconazole (Sporanox)
• Posaconazole
• Ketoconazole (Nizoral)

• Indications: Candida, Cryptococcus, Coccidioides, Histo,

Blasto, some Aspergillus spp.
Azoles, allylamines & morpholines
ergosterol synthesis inhibitors

Clin Microbiol Rev

1998; 11: 382
Allylamines, morpholines
CH3 C(CH3)3

terbinafine

CH3 H3C CH3

CH3
O CH3

N
H3C

butenafine
 Allylamines, morpholines
• Mechanism: block ergosterol synthesis via inhibition
of squalene epoxidase (allylamines), sterol reductase
and isomerase activity (morpholines)

• Complications: mild gastrointestinal and skin reactions

• Formulations: poorly soluble in water, oral and topical,

fungicidal
• Terbinafine (Lamisil)
• Amorolfine (Loceryl)
• Butenafine (Mentax)

• Indications: dermatophytes, Candida (Mentax)

 Echinocandins
HO OH

HO O
O

NH
H3C
NH

H2N N O

O N
HN OH

O O

HO NH O CH3

H2N O N
H
HO N

NH OH
OH
O OH
S O
O OH
O
HO O
NH O O

H
O
N
H
HO micafungin
H2N N
OH
O HN H3C
H3C
H
H CH3 CH3
CH3
NH O HO OH
HO
H H O
O H HO O
N
OH OH NH
H3C
NH
O
OH N O

H3C O HN OH

HO NH O CH3
HO
caspofungin O
H
N O

HO N
H3C

OH
O
OH

anidulafungin
HO
 Mannoproteins

ß(1,6)-glucan
ß(1,3)-glucan

Chitin
Phospholipid bilayer
of cell membrane

ß(1,3) glucan synthase

glucan synthase inhibitor

Depletion of ß(1,3) glucans

in cell wall

Inhibition of
ß(1,3) glucan synthase
 This AIDS patient failed fluconazole,
amphotericin B, and itraconazole…
Echinocandins: No cross-
resistance

Baseline After caspofungin

Courtesy of John Rex, MD
 Echinocandins
• Mechanism: block cell wall synthesis via β-1,3 glucan
synthesis inhibition

• Complications: well-tolerated, histamine release, no

activity against Cryptococcus, Fusarium spp.

• Formulations: poorly soluble in water, fungicidal

• Caspofungin (Cancidas)
• Micafungin
• Anidulafungin (Eraxis)

• Indications: Candida, Aspergillus spp.

 Antimetabolites

OCH3
O OCH3
H
N O

N
O
F H3CO

H3C
Cl
NH2

flucytosine griseofulvin
 Cytosine
Cytosine permease
permease

5-FC

5-FC

Cytosine
Cytosine deaminase
deaminase
5-FC

5-FU
Phosphorylation
Phosphorylation FdUMP FdUMP

Conversion
Conversion to
to FUTP
dUMP
deoxynucleosides
deoxynucleosides
dTMP

Substitution
Substitution for
for uracil
uracil

Inhibition
Inhibition of
of Protein
Protein Synthesis
Synthesis
Inhibition
Inhibition of
of thymidylate
thymidylate synthase
synthase
Inhibition
Inhibition of
of DNA
DNA synthesis
synthesis

5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine;

FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridine diphosphate;
FUTP, 5-fluorouridine triphosphate; dUMP, deoxyuridine monophosphate;
dTMP, deoxythymidine monophosphate
 Antimetabolites
• Mechanism: block fungal DNA and protein synthesis
(Flucytosine), fungal mitosis (Griseofulvin)

• Complications: GI intolerance, bone marrow suppression,

hepatotoxicity, headache, hallucinations, sedation, nausea

• Formulations: poorly soluble in water

• Flucytosine (Ancobon)
• Griseofulvin (Grifulvin V, Fulvicin U/F, Grisactin, Peninol)

• Indications: (Flucytosine): for resistant Candida,

Aspergillus spp. and in combination with Ampho B for
Cryptococcus; (Griseofulvin): dermatophytes
 A complete
Yeast in blood culture algorithm,
including moulds
as a concern

Immunocompromised
“Non-immunocompromised”
(transplant, BMT, AIDS)

Start (lipid) polyene Hemodynamically stable, Hemodynamically unstable,

and wait for ID no previous azoles previous azoles

Start echinocandin
Start fluconazole,
or (lipid) polyene, wait
Endemic mycosis Candida wait for ID and
for ID and
monitor response
monitor response

If good response
Continue (lipid) polyene
complete 14 days from first If no response
Until stable, then consider If good response No response or
negative culture, may switch to other agent
fluconazole complete 14 days from clearly resistant
Switch to fluconazole or from the
or itraconazole first negative culture isolate
voriconazole if above classes
as appropriate
stable and susceptible

Ostrosky-Zeichner & Pappas, Crit Care Med 2006

 Lecture outline
• Clinical significance of fungal infection
• Fungal cell structure and targets
• Antifungal agents and mechanism of action
• Antifungal drug interactions & nephrotoxicity
• Mechanisms of antifungal resistance
• Combination antifungal therapy
 Antifungal drug interactions
• Pharmacokinetic interactions: changes in absorption or
elimination of interacting drug and the antifungal
• Interactions of drug absorption
• Ketoconazole, itraconazole require low pH for absorption (avoid antacids, vitamin
supplements)
• Pre-systemic clearance via membrane transporters (P-gp) & metabolic enzymes.
Azoles can be both substrates and inhibitors of P-gp
• Interactions of drug metabolism
• Oxidation, reduction, hydrolysis, conjugation of lipophilic
compounds
• Interactions with cytochrome P450
• Azoles are metabolized by CYP P450 system
• Azoles are also reversible inhibitors of P450 enzymes
• Co-administered metabolites are a concern
 Azoles: Interactions
in the GI Tract
Drug-pH

Portal vein
Liver

CYP Absorption

efflux P-gp CYP

CYP
CYP Bioavailability
CYP
CYP
CYP
CYP
Metabolism CYP

To feces
Gut wall

Metabolism
 Antifungal drug interactions
• Pharmacokinetic interactions: changes in absorption or elimination of
interacting drug and the antifungal
• Interactions of drug absorption
• Ketoconazole, itraconazole require low pH for absorption (avoid antacids, vitamin
supplements)
• Pre-systemic clearance via membrane transporters (P-gp) & metabolic enzymes. Azoles can
be both substrates and inhibitors of P-gp
• Interactions of drug metabolism
• Oxidation, reduction, hydrolysis, conjugation of lipophilic compounds
• Interactions with cytochrome P450
• Azoles are metabolized by CYP P450 system
• Azoles are also reversible inhibitors of P450 enzymes
• Co-administered metabolites are a concern
Proportion of Drugs Metabolized by CYP
P450
 Antifungal drug interactions
• Pharmacokinetic interactions: changes in absorption or elimination of
interacting drug and the antifungal
• Interactions of drug absorption
• Ketoconazole, itraconazole require low pH for absorption (avoid antacids, vitamin
supplements)
• Pre-systemic clearance via membrane transporters (P-gp) & metabolic enzymes. Azoles can
be both substrates and inhibitors of P-gp
• Interactions of drug metabolism
• Oxidation, reduction, hydrolysis, conjugation of lipophilic compounds
• Interactions with cytochrome P450
• Azoles are metabolized by CYP P450 system
• Azoles are also reversible inhibitors of P450 enzymes
• Co-administered metabolites are a concern
 Inducers of CYP 3A4

Reduction in levels

Rifampin Ketoconazole (>90%)

Fluconazole (~ 50%)
Phenytoin 3A4 Itraconazole (> 90%)
Carbamezepine Voriconazole (~ 90%)
Phenobarbital

Ritonovir? 2C19 2D6 2C9

1A2 2E1 2A6 2B6 2C8

Azole Inhibition of CYP P450
Increased serum concentration of
co-administered drug or metabolite
Oral hypoglycemics
S-warfarin
R-Wafarin
Cyclosporin
Tacrolimus
Sirolimus
Phenytoin
Carbamezepine
Triazolam, alprazolam,
midazolam
Diltiazem
Lovastatin
Isoniazid
Rifabutin
Quinidine
Protease inhibitors (saquinavir,
ritonavir)
Busulfan
Vincristine
Cyclophosphamide
Digoxin
Loratidine
and others…
 Nephrotoxicity
• Primarily due to Amphotericin B
• Two mechanisms:
• Effects of ampho B on renal blood flow and
glomerular filtration
• Constriction of afferent arterioles decreases renal
blood flow and GFR
• Subsequent increase in serum creatinine and BUN
• Direct toxic effect on distal tubules via membrane
disruption
• Cholesterol target
 Proximal
tubule Distal
Efferent
arteriole tubule
Afferent
arteriole

Constriction of the afferent Direct damage of distal tubular

arterioles leading to decreased membranes leading to wasting
glomerular filtration of Na+, K+, and Mg++

Glomerulus

Tubular-glomerular feedback:
Further constriction of arterioles
 Lecture outline
• Clinical significance of fungal infection
• Fungal cell structure and targets
• Antifungal agents and mechanism of action
• Antifungal drug interactions & nephrotoxicity
• Mechanisms of antifungal resistance
• Combination antifungal therapy
 Fungal Virulence
• Fungal determinants of virulence
 Number and physical size of fungal inoculum; conditions of exposure
 Virulence factors (adhesins, proteases, toxins, interference with host
defenses)
 Morphology of fungal cells in vivo
 Regulatory and signal transduction pathways
• Host defenses, cellular & humoral immunity
 Non-specific (innate) defense
 Cell-mediated immunity
 Phagocytic and tissue response
 Predisposing factors (age, gender, heredity, pathophysiological state,
cellular immunodeficiency)
 Opportunism
 Clinical Resistance is a
Multifactorial Issue
• FUNGUS
• HOST Initial MIC
Cell type: Yeast/hyphae..
Immune status
Genomic stability
Site of infection
Biofilm production
Severity of infection Population bottlenecks
Foreign devices • DRUG
Noncompliance with drug Fungistatic nature
regimen Dosing
Pharmacokinetics
Drug-drug interactions
 Resistance to Amphotericin B

• Technical difficulties in detection of

resistance in vitro
• In vivo resistance is rare
C. lusitaniae, C. krusei
C. neoformans
Trichosporon spp.
A. terreus
S. apiospermum
Fusarium spp.
 Mechanisms of Amphotericin B
resistance
• Reduced ergosterol content (defective ERG2 or ERG3
genes)
• Alterations in sterol content (fecosterol, episterol:
reduced affinity)
• Alterations in sterol to phospholipid ratio
• Reorientation or masking of ergosterol
• Stationary growth phase
• Previous exposure to azoles
• (?)
 Resistance to Azoles
• Well-known particularly for fluconazole
• Data available also for other azoles
• A significant clinical problem

RESISTANCE TO FLUCONAZOLE
PRIMARY C. krusei
Aspergillus
C. glabrata
C. norvegensis...
SECONDARY C. albicans
C. dubliniensis...
 Mechanisms of Resistance to
Azoles
• Alteration of lanosterol (14-alpha) demethylase

• Overexpression of lanosterol demethylase

• Energy-dependent efflux systems

a. Major facilitator superfamily (MFS) proteins (BENr =MDR1 of
Candida...)
b. ATP-binding cassette (ABC) superfamily proteins (MDR, CDR
of Candida)

• Changes in sterol and/or phospholipid composition of fungal cell

membrane (decreased permeability)
 Azole Resistance
Molecular Aspects
• Single point mutation of ERG11 gene
Altered lanosterol demethylase

• Overexpression of ERG11 gene

Increased production of lanosterol demethylase

• Alterations in ERG3 or ERG5 genes

Production of low affinity sterols

• Increase in mRNA levels of CDR1 or MDR1 genes

Decreased accumulation of the azole in fungal cell
If your fungus is susceptible
to azoles..

Clin Microbiol Rev 1998; 11: 382

If it is azole-resistant..

Clin Microbiol Rev 1998; 11: 382

 Resistance to Terbinafine
• Very rare

• Primary resistance to terbinafine in a

T. rubrum strain (ICAAC 2001, abst. no. J-104)

• Mechanism: (?)
CDR1-mediated efflux (possible)
 Resistance to Flucytosine

• PRIMARY non-albicans Candida

C. neoformans
Aspergillus (highest)

• SECONDARY C. albicans
C. neoformans

Secondary resistance develops following flucytosine

MONOtherapy.
 Mechanisms of Resistance to
Flucytosine

• Loss of permease activity

• Loss of cytosine deaminase activity

• Decrease in the activity of UPRTase

 Resistance to Echinocandins
PRIMARY C. neoformans
Fusarium spp.

SECONDARY (?) Candida spp.

 Echinocandin Resistance
Molecular Aspects

• FKS1 encodes glucan synthase

• GNS1 encodes an enzyme involved in fatty acid
elongation
• Resistance is observed following laboratory
derived mutations in FKS1 or GNS1

• Other mechanisms (?)

 Lecture outline
• Clinical significance of fungal infection
• Fungal cell structure and targets
• Antifungal agents and mechanism of action
• Antifungal drug interactions & nephrotoxicity
• Mechanisms of antifungal resistance
• Combination antifungal therapy
 History lessons
• Combinations can be GOOD

• Combinations can be BAD

• Assessing all this in vitro is TRICKY

• Some interactions (e.g., metabolic) not

seen
5-Flucytosine plus various
things
Generally favorable
 5FC + Things
• Cryptococcal meningitis
• ⇑ success, ⇑ rate CSF sterilized
• ⇓ AmB dose & thus nephrotoxicity
• ⇓ relapse rates (HIV)

• Other fungi: Not obviously good or bad

• Candida: ?in vitro antag, but OK in case series
• Aspergillus et al.: OK in vitro & tiny case series
• Te Dorsthorst ICAAC ’02, M-850: +AmB is good, +ITR is bad

Block Proc Soc Exp Biol Med 142;476, ’73; Te Dorsthorst AAC 46:2982, ’02; Bennett NEJM 301:126, 1979; van der Horst
NEJM 337:15, ’97; Saag CID 28:291, ’99; Saag CID 30:710, ’00; Te Dorsthorst AAC 46:2982, ’02; Martin AAC 38:1331,
’94; Barbaro Chest 110:1507, ’96; Polak Chemotherapy 33:381, ’87; Verweij Infection 22:81, ’94; Sllling Mycoses 42
(S2):101, ’99; Denning RID 12:1147, ‘90
 Useful lesson: Dose matters
Ding AAC 41:1589, ’97; Allendoerfer AAC 35:726, ’91; Barchiesi AAC 44:2435, ‘00

• Murine models of cryptococcal meningitis

• FLU + 5FC is generally quite favorable

100+ There is a zone

CFU/g of optimal
brain interaction

The place to be!

Candins plus various things

A hot topic at present!

 Aspergillus: Not quite dead
• Rabbit model, persistent neutropenia
• Anidulafungin (AFG), intratracheal inoculation
AmB, 1 mg/kg/d
~1.5 log ↓ CFU/g

Dead

Control lung section AFG, 10 mg/kg/d

6.5 d survival No ↓ CFU/g

Petraitis et al., AAC 42:2898, 1998

Not quite
 For Aspergillus:
• Echinocandins alone do not completely kill
• Persistent neutropenia: tissue may not clear
• Transient neutropenia: tissue is cleared
• So, the candin needs a helping hand
• Second agent could be a neutrophil
• Or a drug!
 Other Fungi
• Cryptococcus
• Candins alone have minimal effects
• CFG + AmB:
• Favorable in vitro, but no obvious in vivo advantage
• Candida
• In vitro: candins are very potent, combos additive
• Bachman ICAAC ’02, M-1813: FLU+CAS bad in biofilm?
• CFG + AmB: Favorable in vivo effect
• Also reported with cilofungin + AmB

Franzot AAC 41:331, ’97; Flattery ICAAC #J-61, ’98; Smith EJCMID 10:588, ’91; unpublished data (Rex);
Sugar AAC 35:2128, ’91; Roling DMID 43:13, ‘02
Polyenes plus azoles

The really confusing one

 Azoles + AmB: In vitro
• In theory
• Azole depletes ergosterol, AmB needs ergosterol
• Thought experiment Valley of
• If azole works, who cares? antagonism

• Always at least azole effect? MIC

• In practice… A
• AmB first? No negative effect
• Together? Negative at [sub-MIC] MIC
• Azole first? Often negative, especially w/ ITR, KETO

Scheven AAC 39:1779, ’95, Scheven Mycoses 38 (S1):14, ‘95

 Aspergillus: Any answer you
want…
• KETO first, AmB second: Bad in rat model
• ITR and AmB together
• Series of murine disseminated disease
models
• Mostly no interaction, occasionally slightly negative
• POS+AmB: neutral (Najvar, ICAAC ’02, M-1818)
• Murine CNS aspergillosis model
• Combination trended towards better survival then
either alone. Not negative, for sure!
• Key: Result is model-, drug-, site-specific
Schaffner JID 151:902, ’85; Polak Chemotherapy 33:381, ’97; Chiller ICAAC #J-1615, ’01.
 Continued variation
• Cryptococcus: GOOD
• Murine model: FLU + AmB gave best results!
• But, FLU first was bad

• Histoplasma: BAD
• Higher lung & spleen CFU with FLU + AmB

• Trichosporon: GOOD
• FLU + AmB was better than AmB alone

Barchiesi AAC 44:2435, ’00; LeMonte JID 182;545, ’00; Louie ICAAC J-1619, ‘01
 AmB + Azoles: Bottom Line
• Very confusing
• Many negative trends, but many surprises
• Cryptococcus: Combination often positive
• Candida: A wild range of results
• The one human trial was NOT negative
• Can do if needed. This strategy pursued to get better
spectrum. Candins should render moot.
• Aspergillus
• Start w/AmB, switch to azole, may overlap
 Clinical Implications
• Cryptococcus
• Adding 5FC is generally good. +FLU is better?
• Candida
• Can combine fluconazole with AmB
• But, probably should avoid in endocarditis
• Candins may render this idea moot
• Aspergillus
• Candin-based combos look like the way to go
 Future Directions to Avoid
Development of Resistance
• Proper dosing strategies
• Combination therapies
• Restricted and well-defined indications for
prophylaxis with azoles

 Fungi will continue to develop NEW

resistance mechanisms!..