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Antifungal PharmacologyAntifungal PharmacologyDeborah Fox, Ph.D.Children’s Hospital3219 [email protected]
Special thanks to:John Perfect, MDAndy Alspaugh, MDSevtap Arikan, MDJohn Rex, MDwww.doctorfungus.org
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Objectives
• To recognize the clinical significance offungal infections
• To identify the antifungal agents and theirmechanisms of action
• To evaluate potential antifungal druginteractions and toxicities
• To differentiate the mechanisms ofantifungal drug resistance
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Lecture outlineLecture 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• Summary
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Mycology ResourcesMycology Resources
• http://www.doctorfungus.org• http://mycology.adelaide.edu.au/mycoses• http://mycology.cornell.edu/• http://www.mycology.net/
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Lecture outlineLecture 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• Summary
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Medical Problems Caused by FungiMedical Problems Caused by Fungi
1) Allergic disease
2) “Mushroom” poisoning
3) MycotoxinsSecondary metabolites
--many have industrial uses--Fusarium mycotoxin -- USSR after WWII--A. flavus “aflatoxin”
4) Mycoses -- infection and resulting disease cause by fungi
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100,000Validly described species
of fungi
150primary human
fungal pathogens
Fungi yet to be discovered
The FungiThe Fungi
-Kwon-Chung andBennett, 1992
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100,000Validly described species
of fungi
150primary human
fungal pathogens
Fungi yet to be discovered
The FungiThe Fungi
-Kwon-Chung andBennett, 1992
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100,000Validly described species
of fungi
150primary human
fungal pathogens
Fungi yet to be discovered
The FungiThe Fungi
-Kwon-Chung andBennett, 1992
Candida, Aspergillus,
Crypto, Blasto, Histo,Cocci, Dermatophytes
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Candida, Aspergillus,
Crypto, Blasto, Histo,Cocci, Dermatophytes
Recent events in fungal diseasesRecent events in fungal diseasesProblems 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 aspergillosisii. Natural diseases: AIDS; mycoses: especially candidiasis andcryptococcosisiii. Mean age of population is increasing; mycoses: especially candidiasis
b. Special problems associated with immunocompromised.i. Mycoses often are more severe, difficult to treat and diagnose.ii. Number of disease-causing fungi has increased.
c. Mobile population.i. People commonly travel through areas of endemic mycoses, whichpresents diagnostic challenges.
Advances in research:a. New antifungal agents and treatment options
b. Tremendous increase in understanding of molecular basis of pathogenesis
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Lecture outlineLecture 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• Summary
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001
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002
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Fungal cell
Mannoproteins
β-(1,6)-glucanβ-(1,3)-glucan
Chitin
Phospholipid bilayerof cell membrane
Cell membrane and cell wall
Ergosterolβ-(1,3)-glucan synthase
Squalene
ErgosterolSynthesisPathway
DNA/RNA Synthesis
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ANTIFUNGAL DRUGStargets
• Membrane disrupting agentsAmphotericin B, nystatin
• Ergosterol synthesis inhibitorsAzoles, allylamines, morpholine
• Nucleic acid inhibitorFlucytosine
• Anti-mitotic (spindle disruption)Griseofulvin
• Glucan synthesisinhibitorsEchinocandins
• Chitin synthesisinhibitorNikkomycin
• Protein synthesis inhibitorsSordarins, azasordarins
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Lecture outlineLecture 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• Summary
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• POLYENESAmphotericin B, nystatin
• AZOLESImidazoles: Ketoconazole..Triazoles: Fluconazole,
itraconazole, voriconazole, posaconazole, ravuconazole• ALLYLAMINES
Terbinafine, butenafine• MORPHOLINE
Amorolfine• FLUORINATED PYRIMIDINE
Flucytosine
• ECHINOCANDINSCaspofungin,
anidulafungin, micafungin
• PEPTIDE-NUCLEOSIDENikkomycin Z
• TETRAHYDROFURANDERIVATIVES
Sordarins, azasordarins
• OTHERGriseofulvin
ANTIFUNGAL DRUGSclasses
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PolyenesPolyenes
CH3O
O
OH OH OH O
H3C
HO
H3C
OHOH
COOHH
OH
OH
O CH3OH
NH2
O
OH
amphotericin B
CH3
O
O
OH OH OH OH O
H3C
HO
H3C
OHOH
OH
COOH
O CH3
OH
NH2OH
O
Nystatin A1
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Cell membrane
ErgosterolAmphotericin B
Binding to ergosterol,Intercalation of cell membrane
K+K+
Na+Na+Ca++Ca++ Ca++Ca++
Na+Na+
K+K+
Leakage of intracellular cationsand proteins
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Amphotericin BAmphotericin 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
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Azoles, allylamines & morpholinesAzoles, allylamines & morpholinesergosterol synthesis inhibitorsergosterol synthesis inhibitors
Clin Microbiol RevClin Microbiol Rev 1998; 11: 382 1998; 11: 382
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NN
H3C
O
O
OO
Cl
N
N
ClH
ketoconazole
NNNN
N
OCH3
H3CO
OO
Cl
N
NN
ClH
itraconazole
N
N
N
F
FOH
N
N N
fluconazole
N N
N N
N
CH3F
OHF
F
voriconazoleNNN
N
N
OH3C
O
O
F
N
NN
FHHO
H3C
posaconazole
AzolesAzoles
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Cell membrane
Ergosterol
Azole
Squalene
ErgosterolSynthesisPathway
Toxic sterols
Accumulation oftoxic sterols incell membrane
Inhibition of14-alpha-demethylase
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AzolesAzoles• Mechanism: block ergosterol synthesis via inhibition of cytochrome P450 dependent 14α-demethylase (Erg11)
• 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,Histoplasma, Blastomyces, some Aspergillus spp.
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Azoles, allylamines & morpholinesAzoles, allylamines & morpholinesergosterol synthesis inhibitorsergosterol synthesis inhibitors
Clin Microbiol RevClin Microbiol Rev 1998; 11: 382 1998; 11: 382
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N
CH3 C(CH3)3
terbinafine
CH3
N
OCH3
CH3H3CCH3
H3C
butenafine
Allylamines, morpholinesAllylamines, morpholines
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Allylamines, morpholinesAllylamines, 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)
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HO
O
NH
O
HO
OH
HN
O
N
HO
H2N
O
H3C
HO
NH
O
HN
CH3
OH
N
O
OOH
O
NH
O
O
N
HO OH
O
H3C
S
OH
O
O
micafunginN
O
NH
OHO
HO
NH
O
OH
HN
H2N
OH
H2N
O
OH
HN
OH
HO
H
H
H HNH O
H
CH3
OH
ONH
O
H3C
CH3 CH3
caspofungin
HO
NH
O
HO
OH
HN
O
N
H3C
HO
H3C
HO
NH
O
HN
CH3
OH
N
O
OOH
O
NH
O
HO OH
O
H3C
anidulafungin
EchinocandinsEchinocandins
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Mannoproteins
ß(1,6)-glucanß(1,3)-glucan
Chitin
Phospholipid bilayerof cell membrane
ß(1,3) glucan synthaseglucan synthase inhibitor
Inhibition ofß(1,3) glucan synthase
Depletion of ß(1,3) glucansin cell wall
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EchinocandinsEchinocandins• 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.
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N
HN
F
NH2
O
flucytosine
O
O
H3C
OCH3
H3CO
Cl
O OCH3
griseofulvin
AntimetabolitesAntimetabolites
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5-FC
5-FC
5-FU
Cytosine permeaseCytosine permease
Cytosine deaminaseCytosine deaminase
PhosphorylationPhosphorylation
Inhibition of thymidylate synthaseInhibition of thymidylate synthase
FdUMP
Conversion todeoxynucleosidesConversion todeoxynucleosides
dUMP
dTMP
Inhibition of DNA synthesisInhibition of DNA synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
FdUMP
FUTP
Substitution for uracilSubstitution for uracil
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
5-FC
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AntimetabolitesAntimetabolites• 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
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Lecture outlineLecture 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• Summary
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Antifungal drug interactionsAntifungal 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, vitaminsupplements)
• 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
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Azoles: Interactionsin the GI Tract
Drug-pH
Portal vein
Gut wallTo feces
Metabolism
Metabolism
Absorption
Bioavailability
Liver
CYP
P-gpefflux
CYP CYP
CYP
CYP
CYP CYP CYP CYP
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Antifungal drug interactionsAntifungal 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) & metabolicenzymes. 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
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Proportion of Drugs Metabolized by CYPP450
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Antifungal drug interactionsAntifungal 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) & metabolicenzymes. 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
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Inducers of CYP 3A4
3A4
2C19 2D6 2C9
1A2 2E1 2A6 2B6 2C8
Ketoconazole (>90%)Fluconazole (~ 50%)Itraconazole (> 90%)Voriconazole (~ 90%)
RifampinPhenytoinCarbamezepinePhenobarbital
Ritonovir?
Reduction in levels
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Azole Inhibition of CYP P450Increased serum concentration ofco-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…
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NephrotoxicityNephrotoxicity
• Primarily due to Amphotericin B• Two mechanisms:
• Effects of ampho B on renal blood flow andglomerular filtration
• Constriction of afferent arterioles decreases renalblood flow and GFR
• Subsequent increase in serum creatinine and BUN• Direct toxic effect on distal tubules via membrane
disruption• Cholesterol target
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Afferent arteriole
Efferent arteriole
Proximaltubule Distal
tubule
Glomerulus
Direct damage of distal tubularmembranes leading to wastingof Na+, K+, and Mg++
Constriction of the afferentarterioles leading to decreasedglomerular filtration
Tubular-glomerular feedback:Further constriction of arterioles
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Lecture outlineLecture 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• Summary
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Clinical Resistance is aClinical Resistance is aMultifactorial IssueMultifactorial Issue
• FUNGUSInitial MICCell type: Yeast/hyphae..Genomic stabilityBiofilm productionPopulation bottlenecks
• DRUGFungistatic natureDosingPharmacokineticsDrug-drug interactions
• HOSTImmune statusSite of infectionSeverity of infectionForeign devicesNoncompliance with drug
regimen
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Anderson JA. (2005) Nature Reviews. 3:547-556
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Resistance to Amphotericin BResistance to Amphotericin B
• Technical difficulties in detection ofresistance in vitro
• In vivo resistance is rareC. lusitaniae, C. kruseiC. neoformansTrichosporon spp.A. terreusS. apiospermumFusarium spp.
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Mechanisms of Amphotericin BMechanisms of Amphotericin Bresistanceresistance
• Reduced ergosterol content (defective ERG2 or ERG3genes)
• 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• (?)
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Resistance to AzolesResistance to Azoles• Well-known particularly for fluconazole• Data available also for other azoles• A significant clinical problem
RESISTANCE TO FLUCONAZOLEPRIMARY C. krusei
AspergillusC. glabrataC. norvegensis...
SECONDARY C. albicans
C. dubliniensis...
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Azole ResistanceAzole Resistance• 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
• Changes in sterol and/or phospholipid composition offungal cell membrane (decreased permeability)
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If your fungus is susceptibleIf your fungus is susceptibleto azoles..to azoles..
Clin Microbiol Rev 1998; 11: 382
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If it is azole-resistant..If it is azole-resistant..
Clin Microbiol Rev 1998; 11: 382
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Resistance to FlucytosineResistance to Flucytosine
• PRIMARY non-albicans CandidaC. neoformansAspergillus (highest)
• SECONDARY C. albicansC. neoformans
Secondary resistance develops following flucytosineMONOtherapy.
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Mechanisms of Resistance toMechanisms of Resistance toFlucytosineFlucytosine
• Loss of permease activity
• Loss of cytosine deaminase activity
• Decrease in the activity of UPRTase
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Resistance to EchinocandinsResistance to Echinocandins
PRIMARY C. neoformansFusarium spp.
SECONDARY (?) Candida spp.
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Echinocandin ResistanceEchinocandin ResistanceMolecular AspectsMolecular 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 (?)
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Future Directions to AvoidFuture Directions to AvoidDevelopment of ResistanceDevelopment of Resistance
• Proper dosing strategies• Combination therapies• Restricted and well-defined indications for
prophylaxis with azoles
Fungi will continue to develop NEWresistance mechanisms!..
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Lecture outlineLecture 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• Summary
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Yeast in blood culture
Immunocompromised(transplant, BMT, AIDS) “Non-immunocompromised”
Start (lipid) polyene and wait for ID
Endemic mycosis Candida
Continue (lipid) polyene Until stable, then consider
fluconazole or itraconazole as appropriate
Hemodynamically stable, no previous azoles
Hemodynamically unstable,previous azoles
Start fluconazole, wait for ID and
monitor response
Start echinocandin or (lipid) polyene, wait
for ID and monitor response
If good response complete 14 days from
first negative culture
No response or clearly resistant
isolate
If good response complete 14 days from first
negative culture, may Switch to fluconazole or
voriconazole if stable and susceptible
If no response switch to other agent
from the above classes
Ostrosky-Zeichner & Pappas, Crit Care Med 2006
Acompletealgorithm,includingmouldsasaconcern
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Baseline After caspofungin
This AIDS patient failed fluconazole,amphotericin B, and itraconazole…
Courtesy of John Rex, MD
Echinocandins: No cross-resistance
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RecommendationsRecommendations
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Ideal antifungal?Ideal antifungal?Not yetNot yet……
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The future ofThe future of antifungals antifungals
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Sample Exam Question
The effectiveness of the azole class ofantifungals is based upon what structuralfeature of the fungus?
A. the chitin composition of the cell wallB. the cholesterol composition of the cell membraneC. the protein components of the cell membraneD. the ergosterol composition of the cell membrane
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