fusarium infections in the immunocompromised host

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IDSA Treatment Guidelines for IDSA Treatment Guidelines for Candidiasis and Invasive Candidiasis and Invasive

AspergillosisAspergillosisOut with the old and in with the new!Out with the old and in with the new!

Dr. Dawn WarkentinDr. Dawn WarkentinB.Sc (Pharm), PharmDB.Sc (Pharm), PharmDPharmacotherapeutic Specialist Heme/OncPharmacotherapeutic Specialist Heme/OncCSU Pharmaceutical Sciences, VGHCSU Pharmaceutical Sciences, VGHClinical Associate Professor, Clinical Associate Professor, Faculty of Pharmaceutical Sciences, UBCFaculty of Pharmaceutical Sciences, [email protected]@vch.ca

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IDSA Treatment Guidelines for Candidiasis and IDSA Treatment Guidelines for Candidiasis and Invasive Aspergillosis: Out with the old and in with Invasive Aspergillosis: Out with the old and in with the new!the new!

Outline:Outline:Review significant changes in guidelines inReview significant changes in guidelines intreatment of invasive aspergillus and candidiasistreatment of invasive aspergillus and candidiasis

–– Supporting evidenceSupporting evidence–– Diagnostic testingDiagnostic testing–– Therapeutic drug monitoringTherapeutic drug monitoring

Review available antifungal agentsReview available antifungal agents–– Differences in spectrum of activityDifferences in spectrum of activity–– Differences in pharmacokinetics, ADRs, drug Differences in pharmacokinetics, ADRs, drug

interactions, and cost interactions, and cost

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The Old…The Old…

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Quality of EvidenceQuality of Evidence

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Incidence of Invasive MycosisIncidence of Invasive Mycosis

US National Hospital Discharge Survey statisticsCandida species is 4th leading cause of nosocomial bloodstream infections

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Mortality from Invasive MycosisMortality from Invasive Mycosis

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Expansion of Antifungal Expansion of Antifungal ArmamentariumArmamentarium

New AzolesPosaconazole (2007)

Ravuconazole

New EchinocandinsMicafungin (2007)

Anidulafungin (2007)

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2008 IDSA Guidelines: Management of 2008 IDSA Guidelines: Management of Invasive Aspergillosis (IA)Invasive Aspergillosis (IA)

Invasive pulmonary aspergillosisInvasive pulmonary aspergillosis–– DiagnosisDiagnosis–– Available antifungal agentsAvailable antifungal agents

•• Therapeutic drug monitoringTherapeutic drug monitoring–– Primary therapyPrimary therapy–– Salvage therapySalvage therapy–– ProphylaxisProphylaxis–– Combination therapyCombination therapy–– Adjunctive therapyAdjunctive therapy

•• SurgerySurgery•• ImmunomodulationImmunomodulation

Extrapulmonary aspergillosisExtrapulmonary aspergillosisChronic,saprobic, and allergic formsChronic,saprobic, and allergic forms

Walsh et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious DiseaseSociety of America. CID 2008;46:327-60.

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Advances in diagnosis of IAAdvances in diagnosis of IADiagnosis should be aggressively Diagnosis should be aggressively pursued whenever possiblepursued whenever possible

–– EORTC definition(EORTC definition(European Organization for European Organization for Research in Treatment of Cancer Research in Treatment of Cancer –– Invasive Fungal Invasive Fungal Infection Cooperative Group)Infection Cooperative Group)

–– Diagnostic imagingDiagnostic imaging•• Halo sign and airHalo sign and air--crescent sign by CTcrescent sign by CT

–– NonNon--culture based diagnosisculture based diagnosis•• Galactomannan Antigen EIAGalactomannan Antigen EIA•• Used in combination with CT findings for Used in combination with CT findings for

early initiation of therapy and to assess early initiation of therapy and to assess responseresponse

–– Not HC approvedNot HC approved–– Promising but remains investigationalPromising but remains investigational–– Surrogate markerSurrogate marker–– Be aware of false positive results (PT, Be aware of false positive results (PT, plasmalyteplasmalyte))

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Recommended approach for Recommended approach for therapeutic drug monitoring (TDM)therapeutic drug monitoring (TDM)

Rationale:Rationale:–– Evidence shows patient to patient variability in Evidence shows patient to patient variability in

pharmacokinetics of triazolespharmacokinetics of triazoles–– Absorption (itra and posa), drug interactions (all), and Absorption (itra and posa), drug interactions (all), and

pharmacogenetics (vori).pharmacogenetics (vori).Not enough data to generate consensus or specific Not enough data to generate consensus or specific recommendations recommendations

Recommend TDM when evaluating reasons for Recommend TDM when evaluating reasons for therapeutic failure or toxicity (Btherapeutic failure or toxicity (B--III)III)

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Therapeutic Drug Monitoring Therapeutic Drug Monitoring (TDM)(TDM)

What the guidelines say:What the guidelines say:–– Itraconazole:Itraconazole:

•• Measure levels to document absorption (BMeasure levels to document absorption (B--II)II)•• Limited evidence but >250ng/ml Limited evidence but >250ng/ml –– more favorable more favorable

outcomeoutcome–– VoriconazoleVoriconazole

•• Measure levels especially with oral therapyMeasure levels especially with oral therapy–– Potential toxicityPotential toxicity–– Document adequate response (BDocument adequate response (B--III)III)

–– PosaconazolePosaconazole•• Limited data, one study observed an association Limited data, one study observed an association

between concentration and response in salvage between concentration and response in salvage invasive aspergillosisinvasive aspergillosis

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Other recent publications of Other recent publications of TDMTDM

Target RangeTarget Range CommentCommentItraconazoleItraconazole Trough >0.5 mcg/mLTrough >0.5 mcg/mL After 7days on therapy After 7days on therapy

to ensure absorptionto ensure absorption

VoriconazoleVoriconazole Trough >2mcg/mLTrough >2mcg/mLPeak <6mcg/mLPeak <6mcg/mLAvg. 1.25mcg/mLAvg. 1.25mcg/mL

After 7days on therapyAfter 7days on therapyEfficacy, toxicityEfficacy, toxicity

PosaconazolePosaconazole Level TBDLevel TBD Average >1.25 mcg/mL Average >1.25 mcg/mL assoc with responseassoc with response

FlucytosineFlucytosine <100 mcg/mL<100 mcg/mL Obtain 2hr after oral Obtain 2hr after oral dose; toxicity seen with dose; toxicity seen with >100mcg/mL>100mcg/mL

Dodds Ashley ES, et al. Clin Infect Dis 2006;43:S28-39. Goodwin ML, et al.J Antimicrob Chemother 2007;61:17-25.

TDM not recommended for amphotericin B, fluconazole, or echinocandins

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Voriconazole TDMVoriconazole TDMFungus Testing LaboratoryFungus Testing LaboratoryUniversity of Texas Health University of Texas Health

Science CenterScience Center7703 Floyd Curl Drive7703 Floyd Curl DriveSan Antonio, Texas 78284San Antonio, Texas 78284Contact: Gennenthel PennickContact: Gennenthel [email protected]@uthscsa.edu

Focus TechnologyFocus Technology5785 Corporate Ave.5785 Corporate Ave.Cypress, California 90630Cypress, California 90630Contact: Dr. Howard EnglerContact: Dr. Howard Englerphph--714714--220220--20652065faxfax--714714--484484--12961296email:hengler@focusanswersemail:hengler@focusanswers

.com.com

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Recommended approach for Recommended approach for primary therapy of IAprimary therapy of IA

Early initiation of therapy (AEarly initiation of therapy (A--I)I)

Voriconazole IV (AVoriconazole IV (A--1)1)

Dose: Dose: •• 6mg/kg IV q12h X 2 then 4mg/kg IV q12h6mg/kg IV q12h X 2 then 4mg/kg IV q12h•• Step down to 200mg PO BID (maximize oral dose by Step down to 200mg PO BID (maximize oral dose by

using 4mg/kg)using 4mg/kg)Consider drug interactions, ADR’s, dosing issues, Consider drug interactions, ADR’s, dosing issues,

renal function with IV renal function with IV

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Voriconazole vs Amphotericin B for Primary Voriconazole vs Amphotericin B for Primary Therapy of Invasive AspergillosisTherapy of Invasive Aspergillosis

Herbrecht R et al. N Engl J Med 2002;347:408-15.

Randomized, unblinded, MC trial

Definite or probable aspergillosis

Voriconazole 6mg/kg IV BID X1 daythen 4mg/kg IV BID X ≥7 days

then 200mg PO BID

Amphotericin B 1-1.5mg/kg/day

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Voriconazole vs Amphotericin B for Primary Voriconazole vs Amphotericin B for Primary Therapy of Invasive AspergillosisTherapy of Invasive Aspergillosis

Authors conclusions: This study shows the superiority of voriconazole over amphotericin B as initial therapy for invasive aspergillosis, in terms of response rate, survival rate, and safetyHerbrecht R et al. N Engl J Med 2002;347:408-15.

Survival at 12 wk in MITT groupVori: 70.8%AmB: 57.9%

10 d77 days

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What is an alternate agent for What is an alternate agent for primary therapy?primary therapy?

Lipid formulation of amphotericin B (ALipid formulation of amphotericin B (A--I)I)–– Dose: 3Dose: 3--5mg/kg/day IV 5mg/kg/day IV

Randomized trial looking at two doses of LRandomized trial looking at two doses of L--amphotericin Bamphotericin B–– 3 mg/kg/day was as effective and less toxic than 3 mg/kg/day was as effective and less toxic than

10mg/kg/day for first 14 days*10mg/kg/day for first 14 days*

e.g. patients where there is contraindication to voriconzolee.g. patients where there is contraindication to voriconzole

* Cornely OA, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing. Clin Infect Dis 2007;44:1289-97.

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What is an another alternate agent What is an another alternate agent for primary therapy?for primary therapy?

“Amphotericin B “Amphotericin B deoxycholate may be deoxycholate may be the only agent and the only agent and should be considered should be considered standard of care”standard of care”$53/day$53/day

ResourceResource--limited limited settingssettings

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Recommended approach for Recommended approach for salvage therapy of IAsalvage therapy of IA

Include the following:Include the following:–– Lipid formulations of Lipid formulations of

amphotericin B (LFAB)amphotericin B (LFAB)–– ItraconazoleItraconazole–– PosaconazolePosaconazole–– CaspofunginCaspofungin–– MicafuginMicafugin

Refractory to Refractory to Voriconazole?Voriconazole?–– Paucity of dataPaucity of data

Change of class of Change of class of agents and/or agents and/or combinationcombination

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Recommended approach for Recommended approach for combination therapy in IAcombination therapy in IA

Not wellNot well--controlled clinical trials for controlled clinical trials for routine administration for primary routine administration for primary therapytherapy–– potential role in salvage therapypotential role in salvage therapy

Paramount is reversal of Paramount is reversal of immunosuppression or recovery from immunosuppression or recovery from neutropenianeutropenia

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2008 Proposed IDSA Guidelines: 2008 Proposed IDSA Guidelines: Management of Candida InfectionsManagement of Candida Infections

Pappas PG et al. 2007 IDSA Annual Meeting

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Recommended approach for treatment Recommended approach for treatment of candidemia/invasive candidiasisof candidemia/invasive candidiasis

UncomplicatedUncomplicated

NonNon--neutropenicneutropenicHemodynamically stableHemodynamically stableNo recent azole exposureNo recent azole exposure

Not colonized with C. glabrata or kruseiNot colonized with C. glabrata or krusei

↓↓

Start IV fluconazoleStart IV fluconazole

800mg IV x1 800mg IV x1 →→400mg IV qday 400mg IV qday →→ POPO

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ComplicatedComplicatedNeutropenicNeutropenic

Hemodynamically unstableHemodynamically unstableRecent azole exposureRecent azole exposure

Colonized with C. glabrata or kruseiColonized with C. glabrata or krusei

↓↓

Start EchinocandinStart Echinocandin•• Caspo 70mg LD Caspo 70mg LD →→50mg IV qday or50mg IV qday or

•• Mica 100mg IV qday orMica 100mg IV qday or•• Anidula 200mg LD Anidula 200mg LD →→100mg IV qday100mg IV qday

OR LFAB 3mg/kg/dayOR LFAB 3mg/kg/day

Transition to PO fluco/vori only if sensitivities Transition to PO fluco/vori only if sensitivities knownknown

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Which agent to use for invasive Which agent to use for invasive candida candida -- EchinocandinsEchinocandins

–– MIC and pharmacokinetic differences smallMIC and pharmacokinetic differences small–– More experience with CaspofunginMore experience with Caspofungin–– Micafungin dose is determined (100mg)Micafungin dose is determined (100mg)–– Caspo/mica equivalentCaspo/mica equivalent–– No future studies likelyNo future studies likely

–– Consider all three therapeutically equivalentConsider all three therapeutically equivalent

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What is about in resourceWhat is about in resource--limited limited settings when echinocandins or settings when echinocandins or

LFAB are unavailable?LFAB are unavailable?

“Amphotericin B “Amphotericin B deoxycholate 0.5deoxycholate 0.5--1.0mg/kg/day should 1.0mg/kg/day should be considered standard be considered standard of care”of care”Transition to Transition to fluconazole when you fluconazole when you have an isolate with have an isolate with predictable sensitivitiespredictable sensitivities

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VoriconazoleVoriconazole–– Offers little advantage over fluconazole as Offers little advantage over fluconazole as

primary therapyprimary therapy–– Limited to transition to PO in selected cases Limited to transition to PO in selected cases

(e.g.. (e.g.. C. kruseiC. krusei))Intravenous catheter removal recommendedIntravenous catheter removal recommendedDuration or therapyDuration or therapy–– Candidemia: at least 2 weeks after last positive Candidemia: at least 2 weeks after last positive

culture and resolution of symptomsculture and resolution of symptoms–– Candidiasis: not studiedCandidiasis: not studied

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When are the echinocandins NOT When are the echinocandins NOT the drug of first choice?the drug of first choice?

Sanctuary SitesSanctuary Sites–– Endophthalmitis?Endophthalmitis?–– Endocarditis?Endocarditis?–– CNS infections?CNS infections?–– CandiduriaCandiduria

C. Parapsilosis in C. Parapsilosis in complicated situations complicated situations such as endocarditis or such as endocarditis or osteomyelitisosteomyelitis

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Quality Improvement MeasuresQuality Improvement Measures

Fundoscopic exam on all patients with Fundoscopic exam on all patients with proven invasive candidiasisproven invasive candidiasisStart antifungal agents within 24 hours of Start antifungal agents within 24 hours of positive culturepositive cultureConfirmatory negative cultures (i.e.. get Confirmatory negative cultures (i.e.. get follow up cultures to document clearance)follow up cultures to document clearance)

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Major changes from 2004Major changes from 2004

–– EmphasisEmphasis on fluconazole and echinocandins as the on fluconazole and echinocandins as the “preferred choices” for proven/suspected cases“preferred choices” for proven/suspected cases

–– DeDe--emphasisemphasis on AmB and LFAB under most on AmB and LFAB under most circumstancescircumstances

–– Concept of Concept of stepstep--downdown therapy is strongly encouragedtherapy is strongly encouraged–– Voriconazole generally advised as stepVoriconazole generally advised as step--down therapy for down therapy for

selected isolated (e.g. selected isolated (e.g. c. krusei c. krusei and other isolates with and other isolates with known susceptibility dataknown susceptibility data))

–– More emphasis on species identification and More emphasis on species identification and susceptibilitysusceptibility

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Major changes from 2004Major changes from 2004

–– Little distinction made between echinocandinsLittle distinction made between echinocandins–– Fluconazole prophylaxis in neonatal units limited to high Fluconazole prophylaxis in neonatal units limited to high

risk sitesrisk sites–– Consideration of resourceConsideration of resource--limited environmentslimited environments

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Review of currently available Review of currently available antifungal agentsantifungal agents

AvailabilityAvailability POPO IVIVAzolesAzoles

itra, fluco, voriitra, fluco, vori ++ ++

posaconazoleposaconazole ++ --PolyenesPolyenes

amphotericin B deoxycholate amphotericin B deoxycholate and lipid formulations of and lipid formulations of amphotericin B (LFAB)amphotericin B (LFAB)

-- ++

EchinocandinsEchinocandins

caspofungin, micafungin, caspofungin, micafungin, anidulafunginanidulafungin -- ++

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Recent advances in susceptibility Recent advances in susceptibility testing for testing for AspergillusAspergillus sp.sp.

Development of standardized susceptibility testing Development of standardized susceptibility testing for for AspergillusAspergillus species. species. AspergillusAspergillus spp. sent to reference lab in Edmontonspp. sent to reference lab in Edmonton–– Some clinical correlation with azoles and amphotericinSome clinical correlation with azoles and amphotericin

Interpretive breakpoints not established for any Interpretive breakpoints not established for any antifungal agents against filamentous fungi.antifungal agents against filamentous fungi.NonNon--aspergillus molds difficult to interpret MIC dataaspergillus molds difficult to interpret MIC dataOften data from animal models do not correlate Often data from animal models do not correlate clinicallyclinically

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Recent advances in susceptibility Recent advances in susceptibility testing for testing for CandidaCandida sp.sp.

Clinical and Laboratory Standards Institute (CLSI) Clinical and Laboratory Standards Institute (CLSI) has developed reproducible standardized testing of has developed reproducible standardized testing of azoles against azoles against CandidaCandida spp.spp.–– Clinical correlation best for patients with Clinical correlation best for patients with

oropharyngeal/esophageal candidiasis and C. oropharyngeal/esophageal candidiasis and C. albicansalbicans–– Not as good correlation with systemic infections and Not as good correlation with systemic infections and

other yeastsother yeastsCLSI developed standardized testing and CLSI developed standardized testing and determined MIC’s for echinocandins but poor determined MIC’s for echinocandins but poor clinical correlationclinical correlation

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Spectrum of Activity: Spectrum of Activity: EchinocandinsEchinocandins

ActivityActivity SpeciesSpeciesHighly ActiveHighly ActiveLow MIC, fungicidalLow MIC, fungicidal

C. albicans, glabrata, tropicalis, C. albicans, glabrata, tropicalis, krusei, kefyrkrusei, kefyrP. jeroviciP. jerovici

Very ActiveVery ActiveLow MIC without fungicidal Low MIC without fungicidal activity mostlyactivity mostly

C. parapsilosis, guilliermondii, C. parapsilosis, guilliermondii, lusitaniaelusitaniaeA. fumigatus, flavus, terreusA. fumigatus, flavus, terreus

Some ActivitySome ActivityMight have therapeutic Might have therapeutic potential (?combination)potential (?combination)

Coccidioides immitis, B. dermatitidis, Coccidioides immitis, B. dermatitidis, Scedosporium spp, P. variotii, H. Scedosporium spp, P. variotii, H. capsulatumcapsulatum

InactiveInactive Zygomycetes, Cryptococcus Zygomycetes, Cryptococcus neoformans, Fusarium, neoformans, Fusarium, TrichosporonTrichosporon

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Echinocandin’s spectrum of Echinocandin’s spectrum of activity activity -- summarysummary

No consistent relevant differences between No consistent relevant differences between echinocandinsechinocandinsMIC’s in vitro studies vary depending on MIC’s in vitro studies vary depending on center and mediumcenter and mediumC. parapsilosis C. parapsilosis -- MIC in all 3 but ? clinical MIC in all 3 but ? clinical relevance relevance For candida and aspergillus infections: For candida and aspergillus infections: choice of agent is not species drivenchoice of agent is not species driven

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Pharmacokinetic considerationsPharmacokinetic considerations

http://images.google.ca/imgres?imgurl=http://www.genomenewsnetwork.org/gnn_images/news_content/12_03/yeast/saccharomyces.jpg&imgrefurl=http://www.genomenewsnetwork.org/articles/12_03/yeast_screen.shtml&h=200&w=200&sz=10&tbnid=s5LULtJrfwLJ1M:&tbnh=104&tbnw=104&prev=/images%3Fq%3Dyeast&start=1&sa=X&oi=images&ct=image&cd=1

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Drug Interactions Drug Interactions -- EchinocandinsEchinocandins

CaspofunginCaspofungin–– ↑↑ Caspo by Caspo by CSACSA (33%) (33%) –– controversialcontroversial–– ↓↓ AUC AUC tacrolimustacrolimus by 20%by 20%–– ↓↓ Caspo by P450 inducers such as Caspo by P450 inducers such as rifampin, rifampin,

phenytoin, carbamezapime, nelfinavir, efavirenzphenytoin, carbamezapime, nelfinavir, efavirenz•• ((↑↑ dose from 50 mg to 70mg/day)dose from 50 mg to 70mg/day)

MicafunginMicafungin–– ↑↑ AUC of AUC of nifedipinenifedipine and and sirolimussirolimus

Anidulafungin Anidulafungin –– No interactions reportedNo interactions reported

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Common Drug ToxicitiesCommon Drug Toxicities

Amphotericin B and LFABAmphotericin B and LFAB–– NephrotoxicityNephrotoxicity–– Electrolyte abnormalitiesElectrolyte abnormalities–– InfusionInfusion--related reactionsrelated reactions

AzolesAzoles–– LFT elevations, rashLFT elevations, rash–– Itra: GI disturbanceItra: GI disturbance–– Vori: visual changes and hallucinationsVori: visual changes and hallucinations

EchinocandinsEchinocandins–– Generally well toleratedGenerally well tolerated–– No major or significant difference between three No major or significant difference between three

drugsdrugs

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Relative “Econotoxicities”Relative “Econotoxicities”

2186 77

220180 201

420

95

188

735

0

100

200

300

400

500

600

700

800FlucoPOFlucoIVAmpho B CaspoMicaAnidulaVori IVVori POPosa POLamB

Daily acquisition cost ($) for treatment of invasive fungal infections

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In conclusion…..In conclusion…..

IDSA Primary treatment of IAIDSA Primary treatment of IA–– Voriconazole or LFABVoriconazole or LFAB–– Resource limited: Amphotericin B deoxycholateResource limited: Amphotericin B deoxycholateIDSA Primary treatment of IC or candidemiaIDSA Primary treatment of IC or candidemia–– Stable patient: fluconazoleStable patient: fluconazole–– Unstable patient: echinocandin or LFABUnstable patient: echinocandin or LFAB

•• Resource limited: Amphotericin B deoxycholateResource limited: Amphotericin B deoxycholate

Consider: species and location of infection, Consider: species and location of infection, organ function, pharmacokinetics, ADR’s organ function, pharmacokinetics, ADR’s and drug interactionsand drug interactions

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Treatment Protocol for Probable/Proven Treatment Protocol for Probable/Proven Invasive Invasive Aspergillosis (IA)Aspergillosis (IA) InfectionInfection

Proven/Probable Aspergillosis

Low risk for developing renal dysfunctionAmphotericin B Deoxycholate

CrCL>50mL/min and high risk for developing renal dysfunction(e.g. allogeneic HSCT and MM, ICU with↓ urine output)Voriconazole (PO if possible)

Consider potential drug interactions with VoriconazoleStep down to PO Voriconazole as soon as safely possible

In Amphotericin B resistant organism (Aspergillus terreus) use Voriconazole or Caspofungin

Marked infusion-related toxicity OR renal dysfunction

CrCL<50mL/min AND 1. Able to take POVoriconzole PO

2. Unable to take POAmbisome

Voriconazole (PO if possible)

Walsh et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Disease Society of America. CID 2008;46:327-60

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Treatment Protocol for Probable/Proven Treatment Protocol for Probable/Proven Invasive Invasive Candida (IC)Candida (IC) InfectionInfection

Yeast in blood (species unknown)

Uncomplicated patient(all of the following)Non neutropenicHemodynamically stableNo recent azole exposureNot colonized with C. glabrata or kruseiFluconazole

Complicated patient(any of the following)Neutropenic or major immunodeficiencyHemodynamically unstableRecent azole exposureColonized with C. glabrata or krusei

CaspofunginAmphotericin Bdeoxycholate

Low risk for developing renal dysfunction

CrCL<50mL/min OR high risk for developing renal dysfunction (e.g.allogeneic HSCT and MM, ICUwith↓ urine output)

Pappas PG et al. 2007 IDSA Annual Meeting

Once species identified and sensitivities determined, tailor therapy.See table on next page

fusarium infections in the immunocompromised host

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