COMMON MYCOTIC INFECTION Dr. Awadh Al-Anazi. INTRODUCTION Last two decades witnessed marked changes in pattern of fungal infections in humans. Fungi.

COMMON MYCOTIC COMMON MYCOTIC INFECTIONINFECTION

Dr. Awadh Al-AnaziDr. Awadh Al-Anazi

INTRODUCTIONINTRODUCTION Last two decades witnessed marked changes in Last two decades witnessed marked changes in

pattern of fungal infections in humans.pattern of fungal infections in humans. Fungi are separate group of higher organisms Fungi are separate group of higher organisms

distinct from both plants and animals.distinct from both plants and animals.

- Fungal cells encased within rigid cell wall- Fungal cells encased within rigid cell wall

composed of chitin and glucan while animalscomposed of chitin and glucan while animals

have cell wall and in plants, cellulose is thehave cell wall and in plants, cellulose is the

major component of cell wall.major component of cell wall.

- Fungi cannot make their organic food as plants- Fungi cannot make their organic food as plants

can, through photosynthesis.can, through photosynthesis.

introduction(cont’d.)introduction(cont’d.)

- Fungi simpler in structure than both.- Fungi simpler in structure than both.

- No division of cell to organ or tissue.- No division of cell to organ or tissue.

Basic structure unitBasic structure unit

- Hyphae: chain of tubular, filament-like cells- Hyphae: chain of tubular, filament-like cells

- Independent single cell- Independent single cell

Classified based on appearance, rather than on Classified based on appearance, rather than on nutritional and biochemical appearancesnutritional and biochemical appearances

FUNGI AS HUMAN PATHOGENSFUNGI AS HUMAN PATHOGENS

50,000 to 250,000 fungal spp. described50,000 to 250,000 fungal spp. described 500 associated with human disease500 associated with human disease No more than 100 spp. capable of causing No more than 100 spp. capable of causing

infection in normal individual.infection in normal individual. Remainder only able to cause disease in immuno-Remainder only able to cause disease in immuno-

compromised or debilitated people.compromised or debilitated people. Fungal infection classified into broad groups Fungal infection classified into broad groups

according to initial site of infection. according to initial site of infection.

CLASSIFICATION OF FUNGAL CLASSIFICATION OF FUNGAL INFECTIONINFECTION

•• SuperficialSuperficial

•• CutaneousCutaneous

•• SubcutaneousSubcutaneous

•• SystemicSystemic

•• OpportunisticOpportunistic

Superficial mycosesSuperficial mycoses

-- Pityriasis versicolor – pigmented lesion Pityriasis versicolor – pigmented lesion on on torso.torso.

- - Tinea nigra – gray to black macular lesionTinea nigra – gray to black macular lesion

on palms.on palms.

-- Black piedra – dark gritty deposits on Black piedra – dark gritty deposits on hair.hair.

-- White piedra – soft whitish granules alongWhite piedra – soft whitish granules along

hair shaft.hair shaft.

-- All diagnosed by microscopy and easilyAll diagnosed by microscopy and easily

treated by topical preparation.treated by topical preparation.

Cutaneous infectionsCutaneous infections

Infections of skin and its appendages Infections of skin and its appendages

(nails, hair)(nails, hair) 20 spp. Of dermatophytes cause ringworm.20 spp. Of dermatophytes cause ringworm.

Subcutaneous mycosesSubcutaneous mycoses

--Subcutaneous infections, over 35 spp. produceSubcutaneous infections, over 35 spp. produce

chronic inflammatory disease of subcutaneouschronic inflammatory disease of subcutaneous

tissue & lymphatics e.g. sporotrichosis:-tissue & lymphatics e.g. sporotrichosis:-

ulcerated lesion at site of inculasion followed byulcerated lesion at site of inculasion followed by

multiple nodules, caused by dimorphic fungusmultiple nodules, caused by dimorphic fungus

sporotrix schenckii. sporotrix schenckii.

Systemic fungal infectionsSystemic fungal infections

- Uncommon- Uncommon

- Natural immunity is high- Natural immunity is high

- Physiologic barriers include:- Physiologic barriers include:

- Skin and mucus membranes- Skin and mucus membranes

- Tissue temperature: fungi grow better at- Tissue temperature: fungi grow better at

less than 37°Cless than 37°C

- Redox potential – in vivo conditions too- Redox potential – in vivo conditions too

reducing for most fungi.reducing for most fungi.

▪ ▪ CoccidioidomycosisCoccidioidomycosis

▪ ▪ HistoplasmosisHistoplasmosis

▪ ▪ BlastomycosisBlastomycosis

Opportunistic MycosesOpportunistic Mycoses- Do not normally cause disease in healthy people.- Do not normally cause disease in healthy people.

- Cause disease in immunocompromised people.- Cause disease in immunocompromised people. - Weakened immune function may occue due to:- Weakened immune function may occue due to: ▪ ▪ Inherited immunodeficiency diseaseInherited immunodeficiency disease ▪ ▪ Drugs that suppress immune system:Drugs that suppress immune system: cancer chemotherapy, corticosteroids, drugscancer chemotherapy, corticosteroids, drugs to prevent organ TX. Rejection.to prevent organ TX. Rejection. ▪ ▪ Radiation therapyRadiation therapy ▪ ▪ Infection (HIV)Infection (HIV) ▪ ▪ Cancer, diabetes, advanced age and mal-Cancer, diabetes, advanced age and mal- nutrition. nutrition.

Most common opportunistic mycotic Most common opportunistic mycotic infectionsinfections::

CandidiasisCandidiasis AspergillosisAspergillosis CryptococcosisCryptococcosis Zygomycosis/mucormycosisZygomycosis/mucormycosis Pneumocystis cariniiPneumocystis carinii

CandidiasisCandidiasis C. Albicans is member of indigenous microbiol human flora:C. Albicans is member of indigenous microbiol human flora:

- Found in GIT, respiratory tract, buccal cavity & vaginal- Found in GIT, respiratory tract, buccal cavity & vaginal tracttract - Growth usually suppressed by other organisms found in- Growth usually suppressed by other organisms found in these areas.these areas. - GIT flora alteration by broad spectrum ABX or mucosal- GIT flora alteration by broad spectrum ABX or mucosal injury leads to GIT invasion.injury leads to GIT invasion. - Skin & mucus membranes are normally effective barrier - Skin & mucus membranes are normally effective barrier but damage by introduction of catheters or intravascularbut damage by introduction of catheters or intravascular devices can permit candida to enter blood stream.devices can permit candida to enter blood stream. - Vaginal candidiasis is the most common clinical infection.- Vaginal candidiasis is the most common clinical infection. - Local factors, e.g. pH & glucose conc. are of prime- Local factors, e.g. pH & glucose conc. are of prime importance in occurrence of this infection.importance in occurrence of this infection. - In mouth, normal saliva reduces adhesion.- In mouth, normal saliva reduces adhesion. - Lactofemic also protective- Lactofemic also protective

CandidiasisCandidiasis (cont’d.) (cont’d.)

Immune ResponseImmune Response Hyphae too big for phagocytosis, butHyphae too big for phagocytosis, but Damaged by PMNs and intracellular mechanismsDamaged by PMNs and intracellular mechanisms * Myeloperoxidase* Myeloperoxidase

* Glucuronidase* Glucuronidase Cytokine activated lymphocytes inhibit c. albicans growth.Cytokine activated lymphocytes inhibit c. albicans growth. Resistance to invasive candida infection is mediated by Resistance to invasive candida infection is mediated by

phagocytes, complement and antibody, althoughphagocytes, complement and antibody, although CMI plays major roleCMI plays major role Patients with defects in phagocytosis function and myelo- Patients with defects in phagocytosis function and myelo-

peroxidase deficiency are at risk for disseminated/fatalperoxidase deficiency are at risk for disseminated/fatal candidiasis.candidiasis.

Risk Factors for Candidiasis:Risk Factors for Candidiasis:

▪ ▪ Post-operative statusPost-operative status

▪ ▪ Cytotoxic cancer chemotherapyCytotoxic cancer chemotherapy

▪ ▪ Antibiotic therapyAntibiotic therapy

▪ ▪ BurnsBurns

▪ ▪ Drug abuseDrug abuse

▪ ▪ GI damageGI damage

Chronic mucocutaneous candidiasis (CMCChronic mucocutaneous candidiasis (CMC))

CNC: group of overlaping syndromes that have CNC: group of overlaping syndromes that have

in common clinical pattern of persistent, severe in common clinical pattern of persistent, severe and diffuse cutaneous candidal infection, affecting and diffuse cutaneous candidal infection, affecting skin, nails and m. membranes.skin, nails and m. membranes.

Immunologic studies of patients with CMC often Immunologic studies of patients with CMC often reveal Cmi defect, however, the defects reveal Cmi defect, however, the defects themselves vary widely.themselves vary widely.

Mucutaneous CandidiasisMucutaneous Candidiasis::

Response to fluconazole:Response to fluconazole: Transfusion of candida-specific transfer factor Transfusion of candida-specific transfer factor

reported to be very successful (remission > 10 reported to be very successful (remission > 10 years) when combines with antifungal therapy.years) when combines with antifungal therapy.

Availability of oral agents, especially, Availability of oral agents, especially, Azole Azole anti-anti-micotics, dramatically changed life of patients with micotics, dramatically changed life of patients with CMCCMC

AspergillosisAspergillosis Contains hundred of species and occurs worldwideContains hundred of species and occurs worldwide These species form the most commonly found fungi in any These species form the most commonly found fungi in any

environment.environment. Major portal of entry: Respiratory tractMajor portal of entry: Respiratory tract Dissemination can occur from the lungs and involveDissemination can occur from the lungs and involve::

- Other areas of the lung- Other areas of the lung

- Brain- Brain- GIT- GIT- Kidneys- Kidneys

CNS and nasal-orbital – cavities can occur without lung CNS and nasal-orbital – cavities can occur without lung involvement.involvement.

Risk factors for invasive disease are:Risk factors for invasive disease are:

- - NeutropeniaNeutropenia

- High doses of corticosteroids- High doses of corticosteroids

Aspergillosis (cont’d.)Aspergillosis (cont’d.)

Most common fatal infection seen in patients with chronic Most common fatal infection seen in patients with chronic granulomatous disease of childhood.granulomatous disease of childhood.

Patients with this condition unable to form toxic oxygen Patients with this condition unable to form toxic oxygen radicals after phagocytosis.radicals after phagocytosis.

Progressive and disseminated disease can complicate neo-Progressive and disseminated disease can complicate neo-plastic diseases, esp. ac. Leukemia, BM and organ trans-plastic diseases, esp. ac. Leukemia, BM and organ trans-plantation.plantation.

In immunosuppressed host: Invasive pulmonary infection In immunosuppressed host: Invasive pulmonary infection usually with fever, cough and chest pain.usually with fever, cough and chest pain.

May disseminate to brain, bone, skin and other organs.May disseminate to brain, bone, skin and other organs. In immunocompetent host:: Localized pulmonary infection In immunocompetent host:: Localized pulmonary infection

and allergic sinusitis and allergic bronchopulmonary disease and allergic sinusitis and allergic bronchopulmonary disease (ABPA).(ABPA).

CryptococcosisCryptococcosis Cryptococcus neoformansCryptococcus neoformans

- Primary infection in lungs- Primary infection in lungs

- Cryptococcal meningitis is most common disseminated- Cryptococcal meningitis is most common disseminated

manifestation.manifestation.

- Can spread to skin, bone and prostate.- Can spread to skin, bone and prostate. Organism ubiquitous and infections occur worldwide.Organism ubiquitous and infections occur worldwide. Diagnosis: - CSF microscopic exam diagnosticDiagnosis: - CSF microscopic exam diagnostic

- India staining- India staining

- Cryptococcal antigen in CSF and serum- Cryptococcal antigen in CSF and serum

CryptococcosisCryptococcosis (cont’d.) (cont’d.)

Immune responseImmune response

- Phagocytosis by neutrophils is inhibited by presence of- Phagocytosis by neutrophils is inhibited by presence of

capsulecapsule

- CMI primary defence- CMI primary defence About 30% of cryptococcus infections occur in patients About 30% of cryptococcus infections occur in patients

with lymphoma (CNS).with lymphoma (CNS). Therapy: Ampho B & 5 FCTherapy: Ampho B & 5 FC

Fluconazole effectiveFluconazole effective

ZygomycosisZygomycosis

Due to Rhizopus, Rhizomucor, Absidia, mucor species, or Due to Rhizopus, Rhizomucor, Absidia, mucor species, or other class of zygomycetes.other class of zygomycetes.

Causes invasive sinopulmonary infectionsCauses invasive sinopulmonary infections Mucormycosis: Life-threatening form of zydomycosis known Mucormycosis: Life-threatening form of zydomycosis known

as Rhinocerebral syndrome affecting diabetics with keto-as Rhinocerebral syndrome affecting diabetics with keto-acidosis.acidosis.

Other risk factors: DKA, neutropenia, steroids Other risk factors: DKA, neutropenia, steroids

WHAT DOES EMPIRICAL OR PRE-EMPTIVE MEAN?WHAT DOES EMPIRICAL OR PRE-EMPTIVE MEAN?

EmpiricalEmpirical

- Based on observation or experience, not on theory- Based on observation or experience, not on theory

- Regarding sense-data as valid information e.g. “an- Regarding sense-data as valid information e.g. “an

empiric = a quack doctor”.empiric = a quack doctor”.

Pre-emptivePre-emptive

- To make a bid in an auction high enough to prevent- To make a bid in an auction high enough to prevent

further biddingfurther bidding

- To obtain by acting in advance of others.- To obtain by acting in advance of others.

- To occupy public land in order to lay claim to it.- To occupy public land in order to lay claim to it.

- To purchase goods before they are formally put on sale.- To purchase goods before they are formally put on sale.

- To go on the offensive in order to avert an enemy attack.- To go on the offensive in order to avert an enemy attack.

Oxford DictionaryOxford Dictionary

ARGUMENTS AGAINST LIBERALARGUMENTS AGAINST LIBERALEmpirical use of Antifungal:Empirical use of Antifungal: Introduces fake confidence by reducing the urge to Introduces fake confidence by reducing the urge to

establish a correct diagnosis.establish a correct diagnosis. Never shown to be unquestionably effective.Never shown to be unquestionably effective. Possible additional toxicity of antifungal with other Possible additional toxicity of antifungal with other

drugs.drugs. Because of toxicity and borderline indication lower Because of toxicity and borderline indication lower

dosages of antifungal might be used.dosages of antifungal might be used. Brings in emotions, not science.Brings in emotions, not science.

FDA approved drugs for empirical therapyFDA approved drugs for empirical therapyDrug Drug Dosing regimen used in controlled trialsDosing regimen used in controlled trials

Ampho BAmpho B 0.6 – 1.0 mg/kg/day (IV)0.6 – 1.0 mg/kg/day (IV)

____________________________________________________________________________________________________

LiposomalLiposomal 3 mg/kg/day (IV)3 mg/kg/day (IV)

Ampho BAmpho B

____________________________________________________________________________________________________

ItraconazoleItraconazole 400 mg/day/or two days then 200 mg/d 400 mg/day/or two days then 200 mg/d forfor

5-12 days (IV), followed by oral solution5-12 days (IV), followed by oral solution

400 mg/day for 14 days400 mg/day for 14 days

____________________________________________________________________________________________________

CaspofunginCaspofungin 70 mg day 1, then 50 mg/daily70 mg day 1, then 50 mg/daily

RD-BMT of Caspo.vs. L. Ampho B – NEJM 2004RD-BMT of Caspo.vs. L. Ampho B – NEJM 2004

The ideal empirical/pre-emptive strategyThe ideal empirical/pre-emptive strategyUSE ONLYUSE ONLY Safe and effective antifungal drugs with spectrum adapted to Safe and effective antifungal drugs with spectrum adapted to

local ecology and optimally adjusted dosage; booster host local ecology and optimally adjusted dosage; booster host defense (CSF) first.defense (CSF) first.

INCLUDE ONLY, BUT QUICKLYINCLUDE ONLY, BUT QUICKLY Patients with high probability of fungal disease, belonging to a Patients with high probability of fungal disease, belonging to a

well defined high risk categorywell defined high risk categoryEXCLUDE CERTAINLYEXCLUDE CERTAINLY Patients with low risk profile or unlikely to have fungal diseasePatients with low risk profile or unlikely to have fungal diseaseRELY EXCLUSIVELY ONRELY EXCLUSIVELY ON Optimal batteries of clinical, radiologic and laboratory testsOptimal batteries of clinical, radiologic and laboratory testsAVOID ALWAYSAVOID ALWAYS Indiscriminate primary prophylaxisIndiscriminate primary prophylaxisADOPTADOPT Early pre-emptive strategy. Secondary prophylaxisEarly pre-emptive strategy. Secondary prophylaxis

WHY DO WE STILL USE EMPIRICAL ANTIFUNGALWHY DO WE STILL USE EMPIRICAL ANTIFUNGAL THERAPY?THERAPY?Assumptions:Assumptions: Established invasive infections carry excessive Established invasive infections carry excessive

mortality rates.mortality rates. Prophylactic strategies are inefficient.Prophylactic strategies are inefficient. Colonization and disease form an obligatory Colonization and disease form an obligatory

continuum.continuum. Newer diagnostic tools yield “too little, too late”Newer diagnostic tools yield “too little, too late” The “hard” data from the published randomized The “hard” data from the published randomized

studies are reliable and form “proof of principle”studies are reliable and form “proof of principle”

Emotions and traditionsEmotions and traditions

Empirical antifungal therapyEmpirical antifungal therapy

▪▪ Optimal timingOptimal timing

▪▪ Optimal dosageOptimal dosage

▪▪ Optimal agentOptimal agent

▪▪ Optimal spectrumOptimal spectrum

▪▪ Optimal cost/benefit ratioOptimal cost/benefit ratio

ADJUNCTIVE TREATMENTADJUNCTIVE TREATMENT

White blood cells transfusionWhite blood cells transfusion CytokinesCytokines

- Gamma interferons enhances fungal hyphae- Gamma interferons enhances fungal hyphae

damage.damage.

- Growth factors reduce IFI in leukemia patients- Growth factors reduce IFI in leukemia patients

- GMCSF hepatosplenic candidiasis in patients- GMCSF hepatosplenic candidiasis in patients

with acute leukemia.with acute leukemia.

**Organism (n=52Organism (n=52) ) GMCSFGMCSF Placebo (n=47)Placebo (n=47)

ASP ¼ (25) 5/7 (71)ASP ¼ (25) 5/7 (71)

CandidaCandida 0/3 0/3 ¾ (75)¾ (75)

OtherOther 0/1 0/1 1/1 (100)1/1 (100)

TotalTotal 1/8 (13) 9/12 (75%) 1/8 (13) 9/12 (75%)

(P = 0.02)(P = 0.02)

Hyperbaric oxygenHyperbaric oxygen

Enhances cell-mediated fungal killingEnhances cell-mediated fungal killing Optimises tissue oxygenationOptimises tissue oxygenation Reduces edema and acidosisReduces edema and acidosis Promotes tissue survivalPromotes tissue survival

SURGICAL MANAGEMENTSURGICAL MANAGEMENTExcision of well-defined fungal lesion associated withExcision of well-defined fungal lesion associated withsuperior outcome over medical therapy alone for:superior outcome over medical therapy alone for: Fungal endocarditis valve replacement & antifungals better Fungal endocarditis valve replacement & antifungals better

survival than med. therapy alone.survival than med. therapy alone. Endophthalmitis, bone & joint diseaseEndophthalmitis, bone & joint disease Early bleeding from mycotic lung sequestrum (primary Early bleeding from mycotic lung sequestrum (primary

aspergilloma)aspergilloma) Invasic fungal sinusitisInvasic fungal sinusitisROLE OF SURGERY LESS CLEARLY DEFINED FOR:ROLE OF SURGERY LESS CLEARLY DEFINED FOR: Preventing bleeding in well-circumscribed mycotic lung Preventing bleeding in well-circumscribed mycotic lung

sequestrum.sequestrum. Cases refractory to medical therapyCases refractory to medical therapy Prevention of future relapses in patients initially survived I.A. Prevention of future relapses in patients initially survived I.A.

who undergo further immunosuppression of their underlying who undergo further immunosuppression of their underlying disease.disease.

NEWER/NOVEL ANTIFUNGAL AGENTSNEWER/NOVEL ANTIFUNGAL AGENTS TriazolesTriazoles

- Voriconazole- Voriconazole- Posaconazole- Posaconazole- Ravuconazole- Ravuconazole

EchinocardinsEchinocardins- Caspofungin- Caspofungin- Anidulafungin- Anidulafungin- Micafungin- Micafungin

PneumocardinsPneumocardins PradimicinsPradimicins BenanomycinsBenanomycins NikkomycinsNikkomycins Allylamines (e.g. terbinafine)Allylamines (e.g. terbinafine) ThiocarbamatesThiocarbamates

CandinsCandins

Good activity against Aspergillus and Good activity against Aspergillus and Candida Candida

FungicidalFungicidal in vitroin vitro

Novel mechanism of activityNovel mechanism of activity

Low potential for developing resistanceLow potential for developing resistance

Well tolerated in humansWell tolerated in humans

Potential for drug interactionsPotential for drug interactions

Average daily cost of AntifungalsAverage daily cost of Antifungals

AntifungalsAntifungals DoseDose EurosEuros

Conv. AmphoB Conv. AmphoB 1 mg/kg1 mg/kg 88

Liposomal AmphoBLiposomal AmphoB 3 mg/kg3 mg/kg 629629

Lipid complex AmphoBLipid complex AmphoB 5 mg/kg5 mg/kg 405405

FluconazoleFluconazole 400 mg IV400 mg IV 6060

FluconazoleFluconazole 200 mg PO200 mg PO 1111

ItraconazoleItraconazole 40 mg PO40 mg PO 4040

VoriconazoleVoriconazole 40 mg IV40 mg IV 407407

VoriconazoleVoriconazole 40 mg PO40 mg PO 8484

CaspofunginCaspofungin 70 mg IV70 mg IV 644644

MAJOR ISSUESMAJOR ISSUES Unacceptable case fatality ratesUnacceptable case fatality rates When to start treatment?When to start treatment?

- Emperical or- Emperical or

- Diagnosis-guided- Diagnosis-guided Will higher doses of existing antifungals improve Will higher doses of existing antifungals improve

survival?survival? Definition of proven invasive fungal infectionDefinition of proven invasive fungal infection How will the clinical response be monitors?How will the clinical response be monitors?

Mode of action of antifungalsMode of action of antifungals

ergosterolergosterol

polyeneseg amphotericin Bpolyeneseg amphotericin B

azoleseg fluconazoleazoleseg fluconazole

squalenessqualenes

lanosterollanosterolKK++

Mg Mg 2+2+

KK++

Mg Mg 2+2+

allylamineseg terbinafineallylamineseg terbinafine

acetyl-Co-Aacetyl-Co-A

nucleosideseg 5-flucytosinenucleosideseg 5-flucytosine

nucleic acid synthesis

nucleic acid synthesis

pneumocandinseg caspofunginpneumocandinseg caspofungin

glucan synthesis synthesisglucan synthesis synthesis

nikkomycinsnikkomycinschitin chitin synthesischitin chitin synthesis

azasordarinsazasordarinsprotein synthesisprotein synthesis

Definite invasive fungal diseaseDefinite invasive fungal disease

Host factor

Clinical Clinical featuresfeatures

MycologyMycologyTissueTissue++ ++ ++

Do higher doses of Lipid AMB result Do higher doses of Lipid AMB result in greater survival?in greater survival? Animal studies reveal non-parallelismAnimal studies reveal non-parallelism

Higher doses: mouse models:Higher doses: mouse models: Invasive aspergillosis: Invasive aspergillosis:

Less survival : AbelcetLess survival : Abelcet Greater survival: AmbisomeGreater survival: Ambisome

Systemic candidosis: greater survival (100%)Systemic candidosis: greater survival (100%) Other factors impact on survivalOther factors impact on survival Clinical studies: greater survival with higher doses Clinical studies: greater survival with higher doses

1 mg vs. 4 mg (Ellis CID 1998)1 mg vs. 4 mg (Ellis CID 1998) Mean daily dose: 4.4 mg/kg; cumulative: 5.7 g Mean daily dose: 4.4 mg/kg; cumulative: 5.7 g

Lung tissue concentrationsLung tissue concentrations 1 mg/kg: 1.8 mg/kg1 mg/kg: 1.8 mg/kg 5 mg/kg: 10.3 mg/kg5 mg/kg: 10.3 mg/kg

Ellis J Med Micro. 2002; 51: 95-97

FungusFungus AMB FCZ ITZ VZ PCZ RCZ CF MF AFAMB FCZ ITZ VZ PCZ RCZ CF MF AF

Candida albicansCandida albicansCandida tropicalisCandida tropicalisCandida parapsilosisCandida parapsilosisCandida kruseiCandida kruseiCandida glabrataCandida glabrataCryptococcus neoformansCryptococcus neoformansHistoplasma capsulatumHistoplasma capsulatumBlastomyces dermatitidisBlastomyces dermatitidisCoccidiodes immitisCoccidiodes immitisParacocci brasiliensisParacocci brasiliensisPneumocystis cariniiPneumocystis cariniiAspergillus fumigatusAspergillus fumigatusMucor sppMucor sppRhizopusRhizopus spp sppFusariumFusarium spp spp

FungusFungus AMB FCZ ITZ VZ PCZ RCZ CF MF AFAMB FCZ ITZ VZ PCZ RCZ CF MF AF

Candida albicansCandida albicansCandida tropicalisCandida tropicalisCandida parapsilosisCandida parapsilosisCandida kruseiCandida kruseiCandida glabrataCandida glabrataCryptococcus neoformansCryptococcus neoformansHistoplasma capsulatumHistoplasma capsulatumBlastomyces dermatitidisBlastomyces dermatitidisCoccidiodes immitisCoccidiodes immitisParacocci brasiliensisParacocci brasiliensisPneumocystis cariniiPneumocystis cariniiAspergillus fumigatusAspergillus fumigatusMucor sppMucor sppRhizopusRhizopus spp sppFusariumFusarium spp spp

Comparative spectrum of activityComparative spectrum of activity

Sentry Antimicrobial SurveillanceSentry Antimicrobial SurveillanceProgramme 2000Programme 2000

Aspergillus Aspergillus spp. and other filamentous fungispp. and other filamentous fungiMIC MIC 1 1 g/mlg/ml

PosaconazolePosaconazole 94%94%VoriconazoleVoriconazole 91%91%Amphotericin BAmphotericin B 89%89%RavuconazoleRavuconazole 88%88%ItraconazoleItraconazole 70%70%

Pfaller AAC April 2002; 46: 1032-1037

Before we start some observationsBefore we start some observations

““Fluconazole and itraconazole represented fast Fluconazole and itraconazole represented fast and useful progress along the azole learning and useful progress along the azole learning curve towards ideal compounds i.e.curve towards ideal compounds i.e.

Broad spectrum of activityBroad spectrum of activity Low toxicityLow toxicity Ease of administrationEase of administration

Subsequent triazoles have emerged more slowly Subsequent triazoles have emerged more slowly and suggest the law of diminishing returns may and suggest the law of diminishing returns may be operating against major advances in triazole be operating against major advances in triazole agents”agents”

Odds ICAAC 2000

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CultureCultureCultureCulture + TissueTissueTissueTissue +GalactomannanGalactomannanGalactomannanGalactomannan +

PCRPCRPCRPCR +

Treatment

Disease likelihood

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ProphylaxisProphylaxis

RemoteRemote

SpecificSpecific

ProvenProven

Pre-emptivePre-emptive

Probable diseaseProbable disease

When to treat with the new antifungals?

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WeeksWeeksTransplantTransplant

ENGRAFTMENTENGRAFTMENTPRE-TRANSPLANTPRE-TRANSPLANT

EARLY POST-ENGRAFTMENTEARLY POST-

ENGRAFTMENTLATE POST-ENGRAFTMENTLATE POST-ENGRAFTMENT

Treatment

Disease likelihood

ProphylaxisProphylaxis

RemoteRemote

High riskHost factorsHigh riskHost factors

EmpiricalEmpirical

PossiblePossible

Persistent feverMucositis

Persistent feverMucositis

Pre-emptivePre-emptive

Probable diseaseProbable disease

Clinicalfeatures Clinical

features

Mycologicalevidence features

Mycologicalevidence features

SpecificSpecific

ProvenProven

Tissueevidence

Tissueevidence

How will the new antifungals be used?How will the new antifungals be used?G

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ENGRAFTMENTENGRAFTMENTPRE-TRANSPLANTPRE-TRANSPLANT

EARLY POST-ENGRAFTMENTEARLY POST-ENGRAFTMENT LATE POST-ENGRAFTMENTLATE POST-ENGRAFTMENT

IIVV

oraorall

oraorall

itraconazolevoriconazoleposaconazole

itraconazolevoriconazoleposaconazole

Ambisomeitraconazolecaspofunginvoriconazoleposaconazole

How will the clinical response to new How will the clinical response to new antifungals be monitored?antifungals be monitored?

Antigen levelsAntigen levels Reduction in Aspergillus GM levelsReduction in Aspergillus GM levels Persistence of high GM levels: poor Persistence of high GM levels: poor

prognosisprognosis Suggests modification of antifungal Suggests modification of antifungal

treatmenttreatment Glucan (Glucatell)Glucan (Glucatell) Mannan/anti-mannan (Platelia Candida)Mannan/anti-mannan (Platelia Candida) Molecular methods: point-of-care-testsMolecular methods: point-of-care-tests

Combination therapyCombination therapy

Additive or synergisticAdditive or synergistic Very poor clinical evidence (IDSA Guidelines, Very poor clinical evidence (IDSA Guidelines,

2000) 2000) Good animal dataGood animal data New targetsNew targets New drug combinationsNew drug combinations

AmBisome + caspofunginAmBisome + caspofungin AmBisome + anidulafungin (invasive aspergillosis)AmBisome + anidulafungin (invasive aspergillosis)

Invasive aspergillosis in allogeneic Invasive aspergillosis in allogeneic stem cell transplant recipients: stem cell transplant recipients: increasing antigenemia is associated increasing antigenemia is associated with progressive diseasewith progressive disease

37 allogeneic SCT recipients37 allogeneic SCT recipients CAMB/LAMB/ITRA/VORICAMB/LAMB/ITRA/VORI 58 response episodes evaluated58 response episodes evaluated

42 treatment failures42 treatment failures 16 complete or partial responses16 complete or partial responses

Treatment failures: Treatment failures: galactomannan (GM)galactomannan (GM) GM level 1.0 over baseline: predictive of treatment failureGM level 1.0 over baseline: predictive of treatment failure

Conclusion: serial determination of serum GM a useful tool for Conclusion: serial determination of serum GM a useful tool for assessing prognosis of IA in allogeneic SCT during treatmentassessing prognosis of IA in allogeneic SCT during treatment

Boutboul et al. CID 2002 (April 15th); 34: 939-943

The future of empiric antifungal

Major critical issues for future Major critical issues for future antifungalsantifungals

Spectrum of activitySpectrum of activity BioavailabilityBioavailability PharmacokineticsPharmacokinetics Side effectsSide effects Will prophylaxis with new azoles Will prophylaxis with new azoles

induce amphotericin B resistance?induce amphotericin B resistance? InteractionsInteractions Combinations Combinations

Why do we still use empirical Why do we still use empirical antifungal therapy?antifungal therapy?

Assumptions:Assumptions: Established invasive infections carry excessive Established invasive infections carry excessive

mortality ratesmortality rates Prophylactic strategies are inefficientProphylactic strategies are inefficient Colonization and disease form an obligatory Colonization and disease form an obligatory

continuumcontinuum Newer diagnostic tools yield "too little, too late"Newer diagnostic tools yield "too little, too late" The "hard" data from the published randomized The "hard" data from the published randomized

studies are reliable and form "proof of principle"studies are reliable and form "proof of principle"

Emotions and traditionsEmotions and traditions

HEM/20283M

EmpiricEmpiricalal antifungal antifungal therapytherapy

Optimal timingOptimal timing

Optimal dosageOptimal dosage

Optimal agentOptimal agent

Optimal spectrumOptimal spectrum

Optimal cost/benefit ratioOptimal cost/benefit ratio

HEM/90326M

Start empirical

antibiotics

Add empirical

antibiotics

Add growth factors

Think about

antifungals

Add empirical

antifungals

Realize cost of

strategyEmotional activity of physician

Duration of neutropenic fever

24 hr 72 hr 96 hr

Breakthrough infections

Fewer in voriconazole arm than Fewer in voriconazole arm than ambisome armambisome arm

VoriconazoleVoriconazole AmbisomeAmbisome

1.9%1.9% 5.0%5.0%

Adjusted for death – FDA analysisAdjusted for death – FDA analysisVoriconazoleVoriconazole AmbisomeAmbisome

9.2% (38/415)%9.2% (38/415)% 9.2% (39/422)%9.2% (39/422)%Walsh et al, 2002

Newer antifungal agentsNewer antifungal agents

EchinoEchinocandincandinss*caspo,anidula,mika *caspo,anidula,mika

PneumocandinsPneumocandins PradimicinsPradimicins BenanomycinsBenanomycins NikkomycinsNikkomycins AllylaminesAllylamines ThiocarbamateThiocarbamatess

HEM/80652M

The ideal empirical/pre-emptive strategy

USE ONLY safe and effective antifungal drugs with spectrum adapted to

local ecology and optimally adjusted dosage; booster host defense (CSF) first

INCLUDE ONLY, BUT QUICKLY patients with high probability of fungal disease , belonging to a

well defined high risk category

EXCLUDE CERTAINLY patients with low risk profile or unlikely to have fungal disease

RELY EXCLUSIVELY ON optimal batteries of clinical, radiologic and laboratory tests

AVOID ALWAYS indiscriminate primary prophylaxis

ADOPT early pre-emptive strategy, secondary prophylaxis

HEM/90593M

ConclusionsConclusions Potent in vitro activity: fungistatic vs. fungicidalPotent in vitro activity: fungistatic vs. fungicidal Greater tissue penetrationGreater tissue penetration More appropriate pharmacokineticsMore appropriate pharmacokinetics Flexibility of dosing and formulationsFlexibility of dosing and formulations Induction of resistance: Should we be concerned?Induction of resistance: Should we be concerned? Longer treatment periods: define end pointsLonger treatment periods: define end points Activity to be shown in all clinically relevant Activity to be shown in all clinically relevant

infectionsinfections Earlier diagnosisEarlier diagnosis

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PREVENTION IS BETTER THAN CUREPREVENTION IS BETTER THAN CURE

The essence of wisdom is the ability The essence of wisdom is the ability to make the right decision on the to make the right decision on the basis of inadequate evidence.basis of inadequate evidence.

Alan GreggAlan Gregg