Management Of Invasive Fungal Management Of Invasive Fungal Infections In Infections In ImmunosupressedImmunosupressed HostsHosts

Dimitrios P. Kontoyiannis, MD, MS, DSc, FACP, FIDSADimitrios P. Kontoyiannis, MD, MS, DSc, FACP, FIDSAProfessor of MedicineProfessor of Medicine

Director of Mycology Research ProgramDirector of Mycology Research ProgramDepartment of Infectious Diseases and Infection Department of Infectious Diseases and Infection

ControlControlThe University of TexasThe University of Texas

M. D. Anderson Cancer CenterM. D. Anderson Cancer Center

OutlineOutline

AspergillosisAspergillosis

CandidiasisCandidiasis

Emerging mycosesEmerging mycoses

Challenges in the Management of IAChallenges in the Management of IA

Active underlying disease (e.g., leukemia, GVHD), Active underlying disease (e.g., leukemia, GVHD), pleiotropicpleiotropic immune defects following chemotherapy= poor immune defects following chemotherapy= poor host immunityhost immunityMultiple coMultiple co--morbidities, age=frequent drug toxicitiesmorbidities, age=frequent drug toxicitiesSignificant antifungal selection pressure=frequent Significant antifungal selection pressure=frequent resistanceresistanceDiagnostic tests lack specificity and Diagnostic tests lack specificity and sensitivity=empiricismsensitivity=empiricismHeterogeneous population at riskHeterogeneous population at riskMultiple interventions, either simultaneously or Multiple interventions, either simultaneously or sequentiallysequentially

Difficulties Specific to Management of Difficulties Specific to Management of Invasive Pulmonary Invasive Pulmonary AspergillosisAspergillosis

Multiple pathogens are not uncommonMultiple pathogens are not uncommonCultures have suboptimal sensitivity and Cultures have suboptimal sensitivity and specificity, timing and processing of BAL not specificity, timing and processing of BAL not standardizedstandardizedSurrogate markers: The vanishing Surrogate markers: The vanishing ““gold gold standardstandard”” (autopsy)(autopsy)Not all infiltrates in Not all infiltrates in immunosuppressedimmunosuppressedpatients with are due to IPApatients with are due to IPADissemination is not uncommonDissemination is not uncommon

1989-93 1994-98 1999-03

020

4060

8010

0

***

*P

Influence of BAL Timing on Influence of BAL Timing on Diagnosis of IPA Following HSCTDiagnosis of IPA Following HSCT

1 2 3 4 5 6 7 8 9 10 11 12 13 140

5

10

15

20

25

30

35 IPA

Day after onset of symptoms

BA

L di

agno

stic

yie

ld %

Shannon V & Kontoyiannis DP, unpublished

Controversies in the Management of IAControversies in the Management of IA--11

How to deal with voriconazole failures, the preferred How to deal with voriconazole failures, the preferred agent for IA? agent for IA? (Walsh TJ et al. IDSA guidelines. CID 2008)(Walsh TJ et al. IDSA guidelines. CID 2008)

Suboptimal VRC levels?Suboptimal VRC levels?Resistant bugs?Resistant bugs?

What is the role of posaconazole as primary or salvage What is the role of posaconazole as primary or salvage therapy?therapy?

What is the role of What is the role of azoleazole therapeutic drug monitoring?therapeutic drug monitoring?

Is there a concern about crossIs there a concern about cross--resistance and tolerance resistance and tolerance between between triazolestriazoles for for AspergillusAspergillus??

00 1414 2828 4242 5656 7070 84840.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

Global Comparative AspergillosisGlobal Comparative Aspergillosis StudyStudyComparison of MortalityComparison of Mortality

Number of Days of TherapyNumber of Days of Therapy

Prob

abili

ty o

f Sur

viva

lPr

obab

ility

of S

urvi

val

Amphotericin B Amphotericin B ±± OLATOLATVoriconazole Voriconazole ±± OLATOLAT

Hazard ratio = 0.60Hazard ratio = 0.6095% CI (0.40, 0.89)95% CI (0.40, 0.89)

OLAT = other licensed antifungal therapyOLAT = other licensed antifungal therapyHerbrechtHerbrecht et al. et al. N Engl J Med.N Engl J Med. 2002;8:4082002;8:408--415415

OLAT = other licensed antifungal therapy.OLAT = other licensed antifungal therapy.HerbrechtHerbrecht et al. et al. N Engl J Med.N Engl J Med. 2002;8:4082002;8:408--415415

Global Comparative Aspergillosis StudyGlobal Comparative Aspergillosis StudyResponses at Week 12Responses at Week 12

0

20

40

60

80

Overall Allo BMT Leuk/Lymph Pulm Extrapulm

Voriconazole ± OLAT Ampho B ± OLAT

% S

atis

fact

ory

Res

pons

e%

Sat

isfa

ctor

y R

espo

nse

Controversies in the Management of IAControversies in the Management of IA--22

What is the role of the What is the role of the echinocandinsechinocandins? ?

What is the optimal dose of lipid formulations of AMB? What is the optimal dose of lipid formulations of AMB? Are they any PD reasons to choose a certain lipid Are they any PD reasons to choose a certain lipid formulations of AMB?formulations of AMB?

What is the role of combination therapy (which drugs? What is the role of combination therapy (which drugs? when?)when?)

What is the impact of What is the impact of AspergillusAspergillus speciation (speciation (egeg A. A. terreusterreus))in the decisionin the decision--making?making?

What is the role of adjunctive surgery?What is the role of adjunctive surgery?Extent and timingExtent and timing

What is the role recovery from What is the role recovery from immunosupressionimmunosupression in outcome?in outcome?What is the role of immune adjunct therapy?What is the role of immune adjunct therapy?

What is the role of local drug delivery?What is the role of local drug delivery?

What is the best strategy for secondary prophylaxis?What is the best strategy for secondary prophylaxis?

Do antifungals work differently based on the Do antifungals work differently based on the immunopathologyimmunopathology of of IA (steroids IA (steroids vsvs neutropenia?)neutropenia?)

Controversies in the Management of IAControversies in the Management of IA--33

Vfend NDA Submission, www.fda.gov

Influence of CYP2C19 Genotypeon Average Steady-State Plasma Voriconazole Concentrations

Voriconazole Exhibits Significant Inter-Patient Pharmacokinetic Variability

0

1

2

3

4

5

6

7

8

HomozygousExtensive

metabolizer(n=108)

HeterozygousExtensive

metabolizer(n=39)

HomozygousPoor

metabolizer(n=8)

Toxicity?

Efficacy

80% have sub-therapeutic levels with regular oralVRC dose (200mg BID)!Bilaud et al. ISHAM 2006

MultiMulti--triazoletriazole (ITC, VRC, POSA, (ITC, VRC, POSA, RAVU)RAVU)--resistant resistant AspergillusAspergillus

Netherlands survey: 0/114 pts (170 Netherlands survey: 0/114 pts (170 A. A. fumigatusfumigatusisolates) from 1945isolates) from 1945--1998 1998 vsvs 10/81 pts (13 isolates) 10/81 pts (13 isolates) from 2002from 2002--2006 (p

Posaconazole for the Treatment of IA in Patients Posaconazole for the Treatment of IA in Patients Refractory to or Intolerant of Conventional Therapy Refractory to or Intolerant of Conventional Therapy

(mostly AMB(mostly AMB--Based)Based)

0%5%

10%15%20%25%30%35%40%45%

Glo

bal R

espo

nse

EO

TTreatment groups:Treatment groups:–– Posaconazole (107)Posaconazole (107)

HemeHeme maligmalig. 74%. 74%HSCT 51%HSCT 51%

–– Controls (86)Controls (86)HemeHeme maligmalig. 81%. 81%HSCT 44%HSCT 44%

PosaconazoleControl

OR 4.0695% CI 1.5-11.4P < 0.006

Walsh TJ et al. CID. 2006

CaspofunginCaspofungin in IAin IA

56% 56%

52%52%

42%42%

56%**56%**

44%44%

38%38%

Candoni et al. Eur J Haematol 2005*

Walsh et Al. NEJM 2004*

Betts et al. Cancer 2006*

Maertens et al. CID 2004

Kartsonis et al. J of Infection 2005

Betts et al. Cancer 2006

Monotherapy

3232

1212

1212

6666

4545

2929

% Nº Pat

Favorable Response

*First line ** >7 days of therapy

CaspofunginCaspofungin as First Line Therapy For as First Line Therapy For IFIsIFIs in in Patients with Patients with HematologicHematologic MalignancyMalignancy

Study design : OpenStudy design : Open--label, single institution study (2004label, single institution study (2004--2006)2006)–– Patients: Patients:

N =28, mean age = 46 yrs (18N =28, mean age = 46 yrs (18--66 yrs)66 yrs)HematologicHematologic malignancy (13 AML, 5 ALL, 2 MM, 8 lymphoma)malignancy (13 AML, 5 ALL, 2 MM, 8 lymphoma)Severe neutropenia in all, 22/28 possible Severe neutropenia in all, 22/28 possible IFIsIFIs, Lung infection in 27/28 , Lung infection in 27/28 HSCT 36 % ( 6 HSCT 36 % ( 6 allogeneicallogeneic + 4 + 4 autologousautologous))

–– CaspofunginCaspofungin: 50 mg/day (70 mg/day loading): 50 mg/day (70 mg/day loading)Results:Results:–– Response rate: 86% (24/28 ) w/ concomitant Response rate: 86% (24/28 ) w/ concomitant neutrophilneutrophil recovery, 2 recovery, 2 IFIsIFIs

relapsedrelapsed–– No breakthrough InfectionNo breakthrough Infection–– Mean duration of CAS treatment : 18 d (6Mean duration of CAS treatment : 18 d (6--21 d)21 d)–– No dose modification (including 6 pts receiving No dose modification (including 6 pts receiving CsACsA))–– SafetySafety

Well tolerated, no discontinuation due to AEWell tolerated, no discontinuation due to AE

Bonini A, et al. ASH 2006

ABLC vs. Liposomal Amphotericin BABLC vs. Liposomal Amphotericin BPharmacokinetic differencesPharmacokinetic differences

ABLC

L-AMB

Rapid RES uptake

Liver, spleenlung, lymphoid organs

Avoid rapid RESuptake

XX Persistent systemiccirculation

Liver, spleenlung, lymphoid organs

A Randomized, Prospective Trial of a HighA Randomized, Prospective Trial of a High--Loading Loading Regimen vs. Standard Dosing Regimen vs. Standard Dosing

AmbiloadAmbiload TrialTrial

EOT response and Survival at 12 weeksCornely et al ASH 2005

Patients with proven or probable IFI(n=201)

blindedL-AMB 10 mg/kg X 14 days(n=94)

L-AMB 3 mg/kg X 14 days(n=107)

L-AMB 3 mg/kg Until EOT

SurvivalSurvivalAmbiloadAmbiload Trial Trial

Cornely et al ASH 2005

94

93

76

72

91

88

69

59

0 20 40 60 80 100

Day 14

EOT

4 weeks

12 weeks10 mg/kg3 mg/kg

% ResponseNo differences were statistically significant

PracticalPractical

ScientificScientific

Prospective clinical trialsAnimal studiesIn vitro studies

Mechanisms of synergy

Prospective clinical trialsAnimal studiesIn vitro studies

Mechanisms of synergy

Spectrum of therapyIntensity of therapySafety of therapy

Spectrum of therapyIntensity of therapySafety of therapy

Increasing net immunosuppressive state of patient

Pragmatism vs. Science andPragmatism vs. Science andDecisions to Use Combination TherapyDecisions to Use Combination Therapy

Lewis REL & Kontoyiannis DP. Br J Hematology 2005

Combination therapy for invasive aspergillosisCombination therapy for invasive aspergillosisAccumulating evidence for benefit?Accumulating evidence for benefit?

Days since diagnosis of IA

0.60.6

00 2020

Prob

abilit

y of

dea

th d

ue to

IA

1.01.0

0.40.4

0.20.2

006060 70704040

0.80.8

1010 3030 5050 8080 9090

P=.02

Marr KA. Clin Infect Dis. 2004;39:797.

VariableVariable Odds Odds ratioratio

95% C.I.95% C.I. PP--valuevalue

Treatment with VRC Treatment with VRC + CAS+ CAS

0.4190.419 0.1390.139--1.2631.263

0.120.12

Renal failureRenal failure 2.8032.803 0.9460.946--8.3048.304

0.0620.062

CMV infectionCMV infection 4.3404.340 1.4431.443--13.05713.057

0.0090.009

Singh et al. Transplantation 2006;81:320-6.

When controlled for renal failure and CMV infection, patients in the study group were 2.4 times less likely to die within 90 days compared to the control group(O.R.=0.419, 95% CI, 0.14-1.3). The difference however, was not statistically significant (p = 0.12).

0

10

20

30

40

50

60

70

80

Day 14 EOT

Ambi 10Ambi 3 + CAS

Favo

rabl

e O

vera

ll R

espo

nse P = 0.028

Caillot. et al. (Combistrat)ISHAM 2006; Abstract 0-0017

N= 30 patients

Voriconazole + CAS

Voriconazole

Retrospective salvage data of LipoAMB+ CAS in IA: ? benefit

(Alief et al. Cancer 2003, Kontoyiannis et al. Cancer 2003)

.

Maertens J et al. Cancer. 2006;107(12):2888-97

CAS-based Combination Therapy for IA

Not All Combinations are UsefulNot All Combinations are Useful

Validated neutropenic rabbit model of IAValidated neutropenic rabbit model of IASurvival rates:Survival rates:–– Control= 0%Control= 0%–– LL--AMB 1.5 mg/kg= 50%AMB 1.5 mg/kg= 50%–– RavRav 5 mg/kg= 60%5 mg/kg= 60%–– RavRav/L/L--AMB 1.5 mg/kg= 20%AMB 1.5 mg/kg= 20%–– RavRav/ L/ L--AMB 3 mg/kg= 17%AMB 3 mg/kg= 17%

Antagonism seen across all outcome markers Antagonism seen across all outcome markers ((MeletiadisMeletiadis et alet al. . JID 2006))

Itraconazole+AMBItraconazole+AMB: ? Antagonistic in IA : ? Antagonistic in IA ((KontoyiannisKontoyiannisDP et al. Cancer 2005, DP et al. Cancer 2005, ChandrasekarChandrasekar& Ito, CID 2005)& Ito, CID 2005)

The Role of Surgery in IAThe Role of Surgery in IA

Has been associated with improved outcome in Has been associated with improved outcome in uncontrolled seriesuncontrolled seriesTiming, approach varies, selected group of patientsTiming, approach varies, selected group of patientsUsually in combination with antifungals, few patients Usually in combination with antifungals, few patients treated with surgery alonetreated with surgery aloneIs delay from recovery puts patient at risk for relapse of Is delay from recovery puts patient at risk for relapse of malignancy? malignancy? Is Is ““prepre--emptiveemptive”” surgery important to prevent relapse surgery important to prevent relapse of mycosis?of mycosis?Radical excision Radical excision vsvs ““debulkingdebulking”” of a dominant lesion?of a dominant lesion?

Emergent Surgery for Emergent Surgery for Pulmonary BleedingPulmonary Bleeding

Active ALL, diabetes, neutropenia, pancytopenia, Aspergillus flavus+ Rhizopusspp

Lesions Suggestive of Lesions Suggestive of Aspergillosis (LISA)Aspergillosis (LISA)

Lung sequestrum, Lung sequestrum, ““halo signhalo sign””, , ““airair--crescent signcrescent sign””, , cavitationcavitationLISA have 90% positive predictive value for IPA LISA have 90% positive predictive value for IPA (25/39)(25/39)Resected LISA carry a relatively good prognosisResected LISA carry a relatively good prognosis

2 year2 year--survivalsurvivalResected LISA :Resected LISA : 36%36%Unresected LISA, culture negativeUnresected LISA, culture negative 20%20%No LISA, culture positiveNo LISA, culture positive 5%5%

YeghenYeghen, et al: CID 2000;31:859, et al: CID 2000;31:859--6868

Role of Immune EnhancementRole of Immune EnhancementNeutrophils, MC/macrophages are key effector immune cells againsNeutrophils, MC/macrophages are key effector immune cells against t molds molds ((RomaniRomani et al. Nat Rev et al. Nat Rev ImmunImmun 2004)2004)Abundant preclinical data (healthy volunteers, high infecting fuAbundant preclinical data (healthy volunteers, high infecting fungal ngal inoculum, suprainoculum, supra--physiologic doses of cytokines): ? relevancephysiologic doses of cytokines): ? relevance

Local ecology of bugs, plasticity of interactions between innateLocal ecology of bugs, plasticity of interactions between innate and and adaptive immunity, cytokine circuitry in lung environment, adaptive immunity, cytokine circuitry in lung environment, chemokineschemokinesImmunopathogenesisImmunopathogenesis is complex and dependent of underlying immune is complex and dependent of underlying immune defect (steroids Vs neutropenia, defect (steroids Vs neutropenia, BalloyBalloy et al. et al. InfInf & & ImmunImmun 2004, 2004, ChamilosChamilos et al. et al. HematologiaHematologia 20062006))FungusFungus--related immune dysfunction (related immune dysfunction (StanzaniStanzani et al. Blood 2004et al. Blood 2004))

Timing, approach varies, selected group of patientsTiming, approach varies, selected group of patients

Usually in combination with antifungals, no patients treated witUsually in combination with antifungals, no patients treated with h immune enhancement aloneimmune enhancement alone

Anecdotal evidence of beneficial adjunct use of GMAnecdotal evidence of beneficial adjunct use of GM--CSF or INFCSF or INF--gamma and or WBC transfusions in neutropenic and nongamma and or WBC transfusions in neutropenic and non--neutropenic neutropenic patients with patients with IMIsIMIs ((Segal et al. CID 2006)Segal et al. CID 2006), appears safe , appears safe ((SafdarSafdar et al. et al. Cancer 2006)Cancer 2006)

Strategies for Secondary Prevention of Strategies for Secondary Prevention of Fungal PneumoniaFungal Pneumonia

Secondary antifungal prophylaxis (new triazoles)Secondary antifungal prophylaxis (new triazoles)

GMGM--CSF elicited WBC transfusionsCSF elicited WBC transfusions

SurgerySurgery

Role of nonRole of non--culture based methods (e.g., GM) to prevent culture based methods (e.g., GM) to prevent relapse?relapse?

Adoptive ImmunotherapyAdoptive Immunotherapy ((PerrucioPerrucio et al. Blood 2005, et al. Blood 2005, ShaoShao C et al. Genes C et al. Genes ImmunImmun 20052005) ?) ?

Sipsas & Kontoyiannis. CID 2006

Local Antifungal Delivery For The Local Antifungal Delivery For The Treatment Of IPATreatment Of IPA

Aerosols, Aerosols, percutaneouspercutaneous catheter deliverycatheter deliveryPolyenesPolyenes (AMB(AMB--d, lipid AMB)d, lipid AMB)Case reports, concomitant systemic Case reports, concomitant systemic antifungals, different end points of efficacy antifungals, different end points of efficacy and safetyand safetyDrug distribution, stability, delivery devise, Drug distribution, stability, delivery devise, frequency: unclearfrequency: unclear

Arthur R et al. Expert Opin Investig Drugs 2004

Needs in Management of IANeeds in Management of IA

Improvements in Improvements in diagnosticsdiagnostics a) Culture yield, b) nona) Culture yield, b) non--cultureculture--based based early early diagnosisdiagnosis ((--> pre> pre--emptive combination therapy) and c) scorecards that emptive combination therapy) and c) scorecards that differentiate early lung infection by different mycoses, d) Studdifferentiate early lung infection by different mycoses, d) Study of y of immunopathogenesisimmunopathogenesis

Understand the specific reasons why patients with fail antifungaUnderstand the specific reasons why patients with fail antifungalsls–– Resistance, PK/PD, toxicity, host issuesResistance, PK/PD, toxicity, host issues

New antifungal drug developmentNew antifungal drug development

Innovative Innovative combinationscombinations–– Local+systemic antifungalsLocal+systemic antifungals–– Antifungals and immunotherapy (? local, e.g, inhaled GMAntifungals and immunotherapy (? local, e.g, inhaled GM--CSF)CSF)–– Antifungals +surgeryAntifungals +surgery

CandidiasisCandidiasis

Delaying the Empiric Treatment of CandidaBloodstream InfectionA Risk Factor for Hospital Mortality

0

5

10

15

20

25

30

35

24 >48

% H

ospi

tal M

orta

lity

Delay in Start of Antifungal Therapy (days)

Variable OR 95% CI P

APACHE II 1.24 (1.18-1.31)

TimeTime toto InitiationInitiation ofof FluconazoleFluconazole TherapyTherapy ImpactsImpactsMortalityMortality inin PatientsPatients withwith CandidemiaCandidemia

AA MultiMulti--InstitutionalInstitutional StudyStudy

Garey et al Clin Infect Dis 2006; 43:25-31.

05

1015202530354045

Culture day Day 1 Day 2 Day >= 3

Mor

talit

y (%

)

Difficulties in Establishing a Difficulties in Establishing a Diagnosis for CandidemiaDiagnosis for Candidemia

No disease Cultures/AntigenSigns andsymptoms

Cultures/histopathology

Sequelae

Prophylaxis Preemptive Empirical

Crude Mortality40%

Dise

ase

burd

enTreatment Morbidity/

Mortality

Mortality doubles if antifungals are not started within 12 hrs of a positive blood culture*

* Morrell et al. Antimicrob Agent Chemother 2005;49:3640.

Antigentest orPCR?

(1(1→→3) 3) ßß--DD--Glucan as a Marker for Glucan as a Marker for Invasive MycosesInvasive Mycoses

Cell wall component of yeast and filamentous Cell wall component of yeast and filamentous fungifungi

AmebocyteAmebocyte lysate assay lysate assay

Does detect:Does detect:–– Aspergillus, Candida, FusariumAspergillus, Candida, Fusarium, , TrichosporonTrichosporon, , SaccharomycesSaccharomyces, ,

and and AcremoniumAcremonium

Does not detect:Does not detect:–– Cryptococcus, Cryptococcus, ZygomycetesZygomycetes

1. Yoshida M, et al. J Med Vet Mycol. 1997;35:371-374; 2. Obayashi T, et al. Lancet.1995;345:17-20; 3. Mori T, et al. EJCCCB. 1997;35:553-560.

Wilson DA, et al. J Clin Microbiol. 2005;43:2909-2912.

Diagnostic MethodsDiagnostic MethodsRapid Culture/IdentificationRapid Culture/Identification

Peptide nucleic acid fluorescence in situ hybridization assay Peptide nucleic acid fluorescence in situ hybridization assay (PNA (PNA FISH)FISH)–– Utilizes fluorescentUtilizes fluorescent--labeledlabeled peptide nucleic acid probes targeting the peptide nucleic acid probes targeting the

specific specific rRNArRNA sequencessequences of of Candida albicansCandida albicans

Can reduce the medianCan reduce the median time required for the identification of time required for the identification of C. C. albicansalbicans to 9.5 hto 9.5 h (range, 3 to 17 h) vs. standard culture median(range, 3 to 17 h) vs. standard culture median time time of 44 h (range, 36 to 92 h) (of 44 h (range, 36 to 92 h) (PP < 0.001)< 0.001)–– Non C. albicansNon C. albicans by culture was even longer (61 h; range, 36 to 124by culture was even longer (61 h; range, 36 to 124 h).h).

EchinocandinsEchinocandins: The preferred Drugs in The : The preferred Drugs in The Treatment of Invasive CandidiasisTreatment of Invasive Candidiasis

End of IV Therapy (ITT/MITT Analysis)End of IV Therapy (ITT/MITT Analysis)

0102030405060708090

100

Ampho-d 0.6 mg/kg

Fluconazole 800/400

Vori 6mg/3mgCaspo 70/50Mica 100Mica 150Anid 200/100

% R

espo

nse

Mora-Duarte et al. N Eng J Med 2002;347:2020.Kullberg et al. Lancet 2005;366:1435.Reboli et al. ICAAC 2005; LB Abstract M-718.Betts et al ICAAC 2006; LB Abstract M-1308a

73.4% 73.9% 75.6%70.3%

CandidemiaCandidemia--Initial TherapyInitial Therapy

AI-Recommendation

• Caspofungin 70 mg d#1, 50 mg/d• Fluconazole 400-800 mg/day• Amphotericin B 0.7 mg/kg/d• Amphotericin B (5-6 days) +

Fluconazole 800 mg/day

C-III

Liposomal AMB 3 mg/kg/dAmphotericin B + 5-FC

IDSA Guidelines for Treatment of Candidiasis. Clin Infect Dis 2004;38:161-189.

C. glabrata

• Caspofungin 70d#1, 50mg/d (A-I)• Amphotericin B 0.7mg/kg/d (B-III)• Fluconazole 12mg/kg/d(C-III)

C. krusei

• Caspofungin 70d#1, 50mg/d(A-I)• Voriconazole 4 mg/kg q12h(B-III) • Amphotericin B 1mg/kg/d(C-III)

Limitations of modern Limitations of modern candidiasiscandidiasistrialstrials

No No neutropenicneutropenic patientspatientsRelatively stable, most with Relatively stable, most with APACHEII

Caspofungin Use in a “Real-World”Setting

Caspofungin Use in aCaspofungin Use in a ““RealReal--WorldWorld””SettingSetting

Clinical Cure rates 55/66 (83%)– 23/26 (88%) intra-

abdominal infections

Attributable mortality to candidiasis (13%)Adverse events (rare)

Clinical Cure rates Clinical Cure rates 55/66 (83%)55/66 (83%)–– 23/26 (88%) intra23/26 (88%) intra--

abdominal abdominal infectionsinfections

Attributable Attributable mortality to mortality to candidiasis (13%)candidiasis (13%)Adverse events Adverse events (rare)(rare)

0

5

10

15

20

25

30

2001 2002 2003

Invasive candidiasis failure rates

Zaas E et al. AJM 2006

10

20

30

40

5060

70

80

90

100

Day 7 Day 14 Clinical Mycological

Caspofungin monotherapyCaspofungin monotherapytreatment outcome at MDACC, 2001treatment outcome at MDACC, 2001--2006 2006

(n=64 patients)(n=64 patients)

% R

espo

nse

5

10

15

20

25

30

Day 7 Day 14 AttributableDay 30

% M

orta

lity

Sipsas & Kontoyiannis. ECCMID 2007

Day 30

CaspofunginCaspofungin For For Other Invasive Other Invasive Candida Candida InfectionsInfectionsNoncomparative study to evaluate caspofungin in Noncomparative study to evaluate caspofungin in less common cases of invasive candidiasis:less common cases of invasive candidiasis:–– Osteomyelitis, meningitis, & endocarditisOsteomyelitis, meningitis, & endocarditis–– Chronic disseminated candidiasis (CDC)Chronic disseminated candidiasis (CDC)–– Candida Candida intraintra--abdominal infections (peritonitis & abdominal infections (peritonitis &

abscesses) abscesses)

Diagnostic criteria: Clinical & microbiological Diagnostic criteria: Clinical & microbiological evidence of infectionevidence of infection

Caspofungin dosing at 50 or 100 mg/day Caspofungin dosing at 50 or 100 mg/day –– UpdosingUpdosing of caspofungin (to 100 or 150 mg daily) of caspofungin (to 100 or 150 mg daily)

allowed in patients not responding allowed in patients not responding Cornely O et al, ICAAC 2006

CaspofunginCaspofungin For Other Invasive For Other Invasive Candida Candida Infections (cont.)Infections (cont.)

Total of 40+ sites in 13 countriesTotal of 40+ sites in 13 countries–– Enrollment at 17 sites in 10 countries, including US (4), Enrollment at 17 sites in 10 countries, including US (4),

Central or Latin America (6), Europe (5), & Australia (2)Central or Latin America (6), Europe (5), & Australia (2)

Target enrollment ~50 patientsTarget enrollment ~50 patients

Enrollment August 2004 to February 2006Enrollment August 2004 to February 2006–– Since June 2005, enrollment limited to certain types of Since June 2005, enrollment limited to certain types of

infections (i.e., endocarditis, meningitis, osteomyelitis, infections (i.e., endocarditis, meningitis, osteomyelitis, septic arthritis, endophthalmitis)septic arthritis, endophthalmitis)

–– Final data available on all 48 patientsFinal data available on all 48 patients

Cornely O et al, ICAAC 2006

n/mEndpoint

Success at the End of Caspofungin Therapy (MITT)

Relapse out to 12 weeks posttherapy in patients with a favorable response

Mortality (to 12 weeks posttherapy)

39/48 (81)

2/39 (5)

(%)

Efficacy Results Efficacy Results

MITT defined as any patient with a confirmed diagnosis of invasive candidiasis who received at least 1 dose of caspofungin

11/48 (23)

Cornely O et al, ICAAC 2006

Efficacy by Site of Efficacy by Site of Candida Candida InfectionInfection

0102030405060708090

100

Peritonitis Endocarditis, Osteomyelitis, or Septic Arthritis

50%

Suc

cess

(%)

10/13

77%

Abscess CDC Multiple/Other

Success at the End of Caspofungin Therapy

9/10

90%

7/888%

5/771% 8/10

80%

Cornely et al, Cancer 2007

Controversies about treatment of Controversies about treatment of candidiasiscandidiasis

Antifungal activity in Antifungal activity in biofilmbiofilm--associated associated CandidaCandidaCatheter managementCatheter managementActivity in Activity in neutropenicneutropenic and critically ill patientsand critically ill patientsIs there any role of in vitro Is there any role of in vitro echinocandinechinocandin MICsMICs??What is the potential of What is the potential of echinocandinechinocandin resistance in resistance in CandidaCandida? ? Value of short term Value of short term echinocandinechinocandin therapy followed by therapy followed by

azolesazolesAre they any meaningful differences among the Are they any meaningful differences among the echinocandinsechinocandins??

Echinocandins are fungicidal versus Echinocandins are fungicidal versus CandidaCandida species and exhibit activity species and exhibit activity against against biofilmbiofilm--embedded organismsembedded organisms

FIG. 3. CSLM of planktonic C. albicans cells treated with antifungal agents. Images utilize CAAF and FUN-1 staining, a 63x oil immersion objective, and 2xmagnification. Green CAAF staining highlights blastospore cell walls.

Control CAS

Kuhn et al. Antimicrob Agent Chemother. 2002;46:1773-80

Echinocandin Activity vs. Echinocandin Activity vs. BiofilmBiofilm--Embedded Embedded CandidaCandida

Ramage et al. Antimicrob Agent Chemother 2002;46:3634

Antifungal Killing vs. Biofilm-EmbeddedCandida spp.

Echinocandin response in azole-refractory esophagitis

10 days after echinocandin therapy10 days after echinocandin therapy

0.5 2 160

25

50

75

100CASAMBFLU

Drug Conc (µg/mL)

% V

iabi

lity

(XTT

Ass

ay)

Removal of Infected CathetersRemoval of Infected Catheters

Rex et al Clin Infect Dis 1995:21;994-6.

Therapy started

0255075

100

% C

andi

dem

ic

-5 5 15Day of Last +BC

25

Changed

Not changed

Mortality 3 months after the initial positive blood cultureamong adults with candidemia, according to Candida species

and APACHE II score

Pappas et al. Clin Infect Dis. 2003;37:634-643

Does CAS Work in NeutropenicPatients?

Does CAS Work in Does CAS Work in NeutropenicNeutropenicPatients?Patients?

Casn/

pofungm (%

in)

L-An/m (

MB%)

Overall* 14/27 (51.9) 7/27 (25.9)

Aspergillus spp. 5/12 (41.7) 1/12 (8.3)

Candida spp. 8/12 (66.7) 5/12 (41.7)

Other 1/3 (33.3) 1/3 (33.3)

* p = 0.043

Walsh et al. N Eng J Med 2004;351:1391-1402

C. C. glabrataglabrata FungemiaFungemia in Patients in Patients

With CancerWith Cancer

0102030405060708090

AMB (n=35) FLU (n=72)

C. albicansC. glabrata

0102030405060708090

AMB (n=16) FLU(n=3)

% R

espo

nded

Not neutropenic Persistently neutropenic

Bodey et al. Am J Med 2002;112:380-386.

Comparing tComparing thehe echinechinocandinsocandinsAre MIC differences clinically important? Are MIC differences clinically important?

MIC data MIC data ((unstandardizedunstandardized, mixed results, differences not consistent , mixed results, differences not consistent with with animal data)animal data)–– Pharmacokinetics Pharmacokinetics (Serum (Serum eexposures xposures MICA, CAS, > MICA, CAS, > AnidulAnidul))–– Clinical outcome Clinical outcome (no correlation with outcomes in (no correlation with outcomes in candidemiacandidemia))

Is there a difference in the potential to select or treat echinoIs there a difference in the potential to select or treat echinocandin candin resistant resistant CandidaCandida species? species? NoNo

PPharmacokinetic differences, drug interactions, and hepatic harmacokinetic differences, drug interactions, and hepatic toxicity? toxicity? Some, uSome, unclear clinical significancenclear clinical significance

Important differences in pivotal clinical trials and indicationsImportant differences in pivotal clinical trials and indications? ? Probably notProbably not

Formulary considerations: Formulary considerations: Complex, costComplex, cost

Comparison of Comparison of MicafunginMicafungin and and CaspofunginCaspofungin for for CandidemiaCandidemia or Invasive or Invasive CandidiasisCandidiasis

Phase 3, 1:1:1 randomized doublePhase 3, 1:1:1 randomized double--blind nonblind non--inferiority study in adults:inferiority study in adults:–– MicafunginMicafungin 150 mg/day150 mg/day–– MicafunginMicafungin 100 mg/day100 mg/day–– CaspofunginCaspofungin 70/50 mg/day70/50 mg/day

Primary endpoint:Primary endpoint:–– Clinical and mycological response at end of IV Clinical and mycological response at end of IV

therapy with a pretherapy with a pre--specified specified ΔΔ -- 15%15%

Betts et al. ICAAC 2006. Abstract M-1308a

C. albicans C. glabrata C. tropicalis C. krusei C. parapsilosis0

102030405060708090

MICA 100 CAS 70/50

Comparison of Comparison of MicafunginMicafungin and and CaspofunginCaspofungin for for CandidemiaCandidemia or Invasive or Invasive CandidiasisCandidiasis

MICA 100 MICA 150 CAS 70/500

25

50

75

100

Per

cent

N=199 202 192

71/93 62/84

24/28

22/33 21/31 24/32 6/8 3/4 23/30

27/42

Overall Success Success by Baseline Pathogen

Betts et al. ICAAC 2006. Abstract M-1308a

Invasive candidiasisInvasive candidiasisWhere weWhere we’’ve been, where weve been, where we’’re goingre going……..

SuccessesSuccesses–– Improved prevention/treatment of Improved prevention/treatment of seriousserious CandidaCandida infectionsinfections–– Less toxic alternatives to Less toxic alternatives to AmBAmB--based therapybased therapy–– Resistance remains relatively uncommon overallResistance remains relatively uncommon overall

ChallengesChallenges: F: Further reductions in mortality!urther reductions in mortality!–– Improved prevention strategies for high risk ptsImproved prevention strategies for high risk pts–– Early initiation of therapy with the best drug, at an effective Early initiation of therapy with the best drug, at an effective

dosedose–– Improved nonImproved non--culture based diagnosisculture based diagnosis–– Better laboratory support for management and detection of Better laboratory support for management and detection of

antifungal resistanceantifungal resistance

Changing Epidemiology of Invasive Changing Epidemiology of Invasive Moulds Era of Voriconazole?Moulds Era of Voriconazole?

In untreated patients, In untreated patients, currently considered firstcurrently considered first--line therapy for invasive line therapy for invasive aspergillosisaspergillosisHas activity against many Has activity against many AMBAMB--resistant speciesresistant species–– Aspergillus terreusAspergillus terreus–– Aspergillus flavusAspergillus flavus–– FusariumFusarium sppspp..–– ScedosporiumScedosporium apiospermumapiospermum

2000 2001 2002 20030.0

0.10.2

0.3

0.40.5

0.60.7

Aspergillus

Zygomycetes

0.00

0.030.06

0.09

0.120.15

0.180.21

Year

Kontoyiannis et al. J Infect Dis 2005: 191:1350

Inci

denc

e /1

000

pt d

ay

0

2

4

6

8

10

12

14

16

19891990199119921993199419951996199719981999200020012002200320042005

All inpatientsAllo-HSCT

Zygomycosis at MDACC (1989-2005)A review of 100 cases

Cas

es P

er 1

00,0

00 In

patie

nt D

ays

Chamilos G, et al. ICAAC 2006 Abstract A-2156

Case 1Case 1

Persistent fever on day 4 of neutropenia in a patient with leukemia during remission induction chemotherapy on fluconazoleprophylaxis

All are false but one:A. Empiric antifungal therapy is not justified B. Fluconazole is appropriateC. Viruses are common cause of fever in that settingD. Caspofungin, lipid AMB formulations,

voriconazole are appropriate choices

Case 2Case 2

Development of fever, positive cultures for yeasts in a febrile critically patient with in ICU while on fluconazole prophylaxis.

The most common yeasts in that setting is:

A. C. glabrataB. C. parapsilosisC. C. albicansD. C. tropicalis

Case 3Case 3

Development of fever, increased alkaline phosphatase, and multiple lucent lesions in liver and spleen on CT scan after engraftment post-HSCT is most likely due to:

A. Fusarium sppB. Aspergillus fumigatusC. Candida sppD. Staphylococcus sppE. Zygomycetes

Case 4Case 4

In the late postengraftment period after HSCT a pulmonary cavitary nodule seen on chest CT would most likely be due to:

A. Candida tropicalisB. Invasive moulds, most likely Aspergillus sppC. Candida glabrataD. Pseudomonas aeruginosaE. Staphylococcus aureus

Case 5Case 5

A non-neutropenic patient with AML developed postnasal drainage and left maxillary sinus pain 52 days after allogeneic BMT while receiving voriconazole prophylaxis (400 mg/day) since transplantation. The patient had been receiving high-dose methylprednisolone (total dose> 600 mg in the month prior) for GvHD

What is a major consideration here?A) CandidaB) FusariumC) AspergillusD) Zygomycetes

Case 6Case 6

A profoundly neutropenic patient with refractory AML develops sepsis, acute pneumonia and multiple necrotic skin lesions

What is a major consideration here?A) CandidaB) FusariumC) AspergillusD) Zygomycetes

Thank you!Thank you!

Management Of Invasive Fungal Infections In Immunosupressed HostsOutlineChallenges in the Management of IADifficulties Specific to Management of Invasive Pulmonary AspergillosisWe increasingly do not know the cause �of death in patients with IA �Autopsy Rate (Autopsies/deaths) at MDAAC (1015 Autopsies,Influence of BAL Timing on Diagnosis of IPA Following HSCT Global Comparative Aspergillosis Study �Comparison of MortalityGlobal Comparative Aspergillosis Study Responses at Week 12Controversies in the Management of IA-3Multi-triazole (ITC, VRC, POSA, RAVU)-resistant AspergillusPosaconazole for the Treatment of IA in Patients Refractory to or Intolerant of Conventional Therapy (mostly AMB-Based)Caspofungin in IACaspofungin as First Line Therapy For IFIs in Patients with Hematologic MalignancyABLC vs. Liposomal Amphotericin B�Pharmacokinetic differencesA Randomized, Prospective Trial of a High-Loading Regimen vs. Standard Dosing �Ambiload Trial Survival�Ambiload Trial Pragmatism vs. Science and�Decisions to Use Combination TherapyCombination therapy for invasive aspergillosis�Accumulating evidence for benefit?Not All Combinations are UsefulThe Role of Surgery in IALesions Suggestive of �Aspergillosis (LISA)Role of Immune EnhancementStrategies for Secondary Prevention of Fungal PneumoniaLocal Antifungal Delivery For The Treatment Of IPANeeds in Management of IACandidiasisDifficulties in Establishing a �Diagnosis for Candidemia(13) ß-D-Glucan as a Marker for �Invasive MycosesDiagnostic Methods�Rapid Culture/IdentificationEchinocandins: The preferred Drugs in The Treatment of Invasive Candidiasis�End of IV Therapy (ITT/MITT Analysis)Candidemia-Initial TherapyLimitations of modern candidiasis trialsCaspofungin Use in a “Real-World” SettingCaspofungin monotherapy� treatment outcome at MDACC, 2001-2006 �(n=64 patients)Caspofungin For �Other Invasive Candida InfectionsCaspofungin For Other Invasive Candida Infections (cont.)Efficacy Results Efficacy by Site of Candida InfectionControversies about treatment of candidiasis Echinocandins are fungicidal versus Candida species and exhibit activity against biofilm-embedded organismsEchinocandin Activity vs. �Biofilm-Embedded CandidaRemoval of Infected CathetersDoes CAS Work in Neutropenic Patients?�C. glabrata Fungemia in Patients �With Cancer Comparing the echinocandinsComparison of Micafungin and Caspofungin for Candidemia or Invasive CandidiasisComparison of Micafungin and Caspofungin for Candidemia or Invasive CandidiasisInvasive candidiasis�Where we’ve been, where we’re going….Changing Epidemiology of Invasive Moulds Era of Voriconazole?