Lecturername:Dr.AhmedM.Albarrag

Lecture Title:Diversity of Fungi and Fungal Infections

(Foundation Block, Microbiology)

1. Toprovidestudentswithanoverviewofthecommonmedicallyimportantyeastsandmoldfungi.

2.Toprovidestudentswithanoverviewofthemajorfungaldiseasesthatthreatenshumanhealth.

3.Togiveafundamentalknowledgeabouttheantifungalagents,theirmechanismsofaction,andspectrum.

Lecture Objectives..

ØHypersensitivity(Allergy)

ØMycotoxicoses

ØInfections

Howtheinfectionisacquired?Ø Endogenous,Colonization(overgrowthofnormalflora)Ø Inhalation(Airborne)

Ø ContactØ Trauma

Healthyhost?ORImmunocompromised host?

(When,whichtypeofinfection)

� Superficialmycoses

� Cutaneousmycosis

� Subcutaneousmycoses

� Systemicmycoses

� Opportunisticmycoses

HealthyHost

• Superficialmycoses

• Cutaneousmycosis

• Subcutaneousmycoses

• Systemicmycoses

Immunocompromised Host

� Superficialmycoses

� Cutaneous mycosis

� Subcutaneousmycoses

� Systemicmycoses

� Opportunisticmycoses

SuperficialMycoses� Affecttheouterlayeroftheskinorhairshaft� Noimmuneresponse

CutaneousMycoses

Dermatophytosis

� Infectionoftheskin,hairornailscausedbyagroupofkeratinophilic fungi,calleddermatophytes

SubcutaneousMycoses

ØFungalinfectionsinvolvingthedermis,subcutaneoustissues,muscleandmayextendtobone.

ØUsuallytheyareinitiatedbytrauma.

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Primary Systemic Mycoses

•Causedbyprimarypathogens•Contractedbyinhalation,Startasrespiratorydisease•Geographicallyrestricted(endemic),northandsouthAmerica

Opportunisticfungalinfections

•Diseasesinimmunocompromisedhost

•RiskfactorsHIV/AIDSHematopoieticstemcelltransplant(HSCT)SolidorganstransplantationMalignanciesNeutropeniaDiabetes

Many others

A)OpportunisticFungiØNormalflora

Candidaspp.Otheryeast

ØOtherfungi

•

TheFungi

B)PrimaryPathogens§ Dermatophytes§ Endemicgeographically

restricted- Histoplasma spp.- Blastomyces spp.-Coccidioides spp.-Paracoccidioides spp

ØUbiquitousinourenvironmentAspergillusspp.Zygomycetes spp.Cryptococcusspp.

Clinicalfeatures(history,riskfactors,etc)

ImagingGoodvalueindiagnosisandtherapymonitoring

LabInvestigationsHistopathologyMicrobiologyOtherLabInvestigations

Antifungalagents

Ø Cellmembrane•Polyene• Azole

Ø Cell wall• Echinocandins

– Caspofungin– Micafungin– Anidulafungin

Ø DNA/RNA synthesis• Pyrimidine analogues

- Flucytosine

• AmphotericinB,lipidformulations• Nystatin

MechanismofActionAmphotericinB(MOA):Ø Bindstoergosterol withinthefungalcellmembraneresultinginformationof

poreswhichpermitleakageofintracellularcontents,andleadtodeath.

Ø AmphotericinBhasabroadantifungalspectrumwhichincludesmostfungithatcausehumandisease

• Fluconazole• Ketoconazole • Itraconazole• Voriconazole• Posaconazole• Miconazole, clotrimazole

• Mechanism of ActionInhibits synthesis of ergosterol, the major sterol of fungal cell

membrane.

Fluconazole Itraconazole Voriconazole Posaconazole

Yeast +++ + +++ +++Mold,e.g Aspergillus

-- ++ +++ +++

Zygomycetes - - - ++

Azoles—SpectrumofActivity

• MechanismofActionFungalRNAmiscoding

InterferingwithDNAsynthesis

• SpectrumofActivity(Restrictedspectrumofactivity)Activeagainst

Candida speciesCryptococcusneoformans

Monotherapy :nowlimited(Resistance)

mannoproteins

b1,6glucans

b1,3

chitin

ergosterol

b1,3 glucansynthase

Cellmembrane

TheFungalCellWall

IntroductiontoMedicalMycology.MerckandCo.2001

– Caspofungin– Micafungin– Anidulafungin

• MechanismofActionInhibitsB-1,3 –Dglucan synthase,theenzymecomplexthatformsglucan polymers

inthefungalcellwall.

Glucan polymersareresponsibleforprovidingrigiditytothecellwall.

• GoodactivityagainstCandidasppAspergillus spp

CommentsSpectrumofactivityAntifungalAgentsMechanismofaction

GroupTarget

Serioustoxicsideeffects(nephrotoxicity)

Broadantifungalspectrumwhichincludesmostfungi

AmphotericinB,Nystatin

Bindstoergosterolwithincellmembrane,formationofporeswhichleadtocelldeath

PolyenesCellmembrane

NoteffectiveagainstZygomycosis (exceptposaconazole)

AdverseEffects

DrugInteractions

Fluconazole hasalimitedornoactivityagainstmould fungiVoriconazol isthedrugofchoiceforAspergillosisPosaconazole hasbroaderspectrumofactivitythanotherazoles

KetoconazoleItraconazoleFluconazoleVoriconazolePosaconazoleMiconazoleclotrimazole

Inhibitthesynthesisofergosterol

Azoles

Lesstoxicity andsideeffectscomparedtoamphotericinBandazoles

GoodactivityagainstCandidaspp ,Aspergillus sppLimitedornoactivityagainstotherfungi

CaspofunginMicafunginAnidulafungin

Inhibitsglucansynthesis,(glucan polymersinthefungalcellwall)

EchinocandinsCellwall

Monotherapynowlimited(Resistance)

RestrictedspectrumofactivityCandida speciesCryptococcusneoformans

FlucytosineFungalRNAmiscodingInterferingwithDNAsynthesis

Pyrimidineanalogues

DNA/RNAsynthesis

Dr.AhmedM.Albarrag

(Foundation Block, Microbiology)

Thank You J