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Optimal Prophylaxis: Case Optimal Prophylaxis: Case for for Fluconazole/ Fluconazole/

ItraconazoleItraconazole

Pranatharthi H. Chandrasekar, MDWayne State University School of MedicineKarmanos Cancer Institute

OutlineOutline

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Cancer pts & stem cell recipients

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Fungal Infection Prevention — PracticesFungal Infection Prevention — Practices

Avoidance of potted plants/contact with soil Hand Washing, ?? Masks Water: Drinking/Showering Vascular access care HEPA filtration Reduced duration of neutropenia Reduced immunosuppression CHEMOPROPHYLAXIS

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Fluconazole Prophylaxis in Hematopoietic Fluconazole Prophylaxis in Hematopoietic Stem Cell Transplant RecipientsStem Cell Transplant Recipients

*Statistical significance between fluconazole and placebo.Goodman JL, et al. N Engl J Med. 1992;326:845-851.Slavin MA, et al. J Infect Dis. 1995;171:1545-1552.

Goodman et al: 52% Allografts/48% Auto, Fluc (400 mg/d) vs Placebo Engraftment

Slavin et al: 88% Allografts/12% Auto, Fluc (400 mg/d)

vs Placebo Day 75

**

*

PlaceboFluconazole

* *

Infection Infection-related

mortality

Overallmortality

Pat

ien

ts (

%)

Infection Infection-related

mortality

Overallmortality

Pat

ien

ts (

%)

Fluconazole Prophylaxis : Acute LeukemiaFluconazole Prophylaxis : Acute Leukemia

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Flu Placebo

Overall fungal fungal infection 9% 21% P=.02

Syst fungal infection 4% 8% P=NS

Mortality ≡

Flu (400 mg/d) Placebo

Def/Probable IFI 9 32 P=.0001

Deaths from IFI 1/15 6/15 P=.04

Benefit in:• AML/induction therapy with cytarabine +anthracycline-based regimen

Winston DJ et al, Ann Intern Med 1993;118:495Rotstein C et al, Clin Infect Dis 1999; 28:331

Fluconazole : SurvivalFluconazole : Survival

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• Independent predictor of overall survival/multivar analysis(matched, unrelated donor transplant)

• Meta analysis: ↓ IFI / ↓ fungus-related death (neutropenicpatients : 16 trials)

[if inf rate > 15%]

? Optimal dose/duration ? All leukemic patients ? Non-myeloablative stem cell tx ? Allogeneic recip with Graft-versus-Host-Disease

Hansen JA et al, N Engl J Med 1998; 338:962Kanda Y et al, Cancer 2000; 89:1611

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ITRACONAZOLE : Prophylaxis in Hematopoietic ITRACONAZOLE : Prophylaxis in Hematopoietic Stem Cell Transplant RecipientsStem Cell Transplant Recipients

140 Patients

I : 200 mg q 12h x 2d IV; 200 mg sol q 12 (d + 1 to d + 100)F: 400 mg IV/PO q 24h

180d Post SCT I (%) F (%) P

Proven IFI 9 25 .01

Fungal-death 9 18 .13

Inv. Asperg. 4 12 .12

Mort NS

GI Intolerance

24 9 .02

Winston DJ, Ann Intern Med 138: 705, 2003.

304 Patients

I : 7.5 mg/kg/d sol with condition regimen

Inv. Fungal Inf

Intent to Treat I ≡ F

On Treatment I < F (P .03)

Inv. Mold I < F (P .03)

Inv. Cand I ≡ F

Hepatotoxicity / GI Intolerance

I : 36% ; F : 16%Marr KA, Blood 103: 1527, 2004.

ItraconazoleItraconazole

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vs Candida, no advantage over Fluconazole

Vs Aspergillus• ↓ low-risk patients in studies• Different formulations of Itraconazole• Inadequate # enrolled in studies

Meta analysis (Itra, Flucon, Ampho B)Itra: ↓ invasive fungal infection

48% reduction in IA (with Itra sol.)

Oren I et al, Bone Marrow Transplant 2006; 38:127Vardakas KZ et al, Br J Hematol 2005:131:22Glassmacher A et al, J Clin Oncol 2003:21:4615

Itraconazole : DrawbacksItraconazole : Drawbacks

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Marr K et al, Blood 2004;103:1527Maertins J et al, J Antimicrob Chemother 2005;56:33De Beule KL, Int J Antimicrob Agents Chemother 1996:6:175Winston DJ et al, Ann Intern Med 2003;138:705

IDSA Guidelines: ProphylaxisIDSA Guidelines: Prophylaxis Candidiasis Candidiasis

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• Chemo-induced Neutropenia

Flucon, Itracon, Posacon (A-I)

Caspof (B-II)• Stem Cell Transpl (Neutropenia)

Flucon, Posacon, Micaf (A-I)

• Solid Organ Transpl (Hi-risk Liver, Pancrease, Sm Bowel

Flucon• ICU

Hi-risk units with ↑ freq. candidiasis

FluconPappas PG et al, Clin Inf Dis 2009;48:509

What is Changed/Known Now?What is Changed/Known Now?

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• Treatment Practices

• Epidemiology of IFI/heme Ca, SCT

• Resistance in Aspergillus

Frequency of IFI : Influencing FactorsFrequency of IFI : Influencing Factors

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Cancer/Stem Cell Recipient Population

• Ac leukemia/status Salvage for relapse/refr Highest RiskInduction for newly diagnosed High RiskConsolidation Low Risk

• Duration of NeutropeniaPeriph blood vs bone marrowNon-myeloablative vs myeloablative

• Mucositis – Non-myeloablative regimen•GVHD & its therapy• Antifungal Prophylaxis

Impact of Flucon Prophy : Stem Cell PopulationImpact of Flucon Prophy : Stem Cell Population

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Marr KA et al J Infect Dis  2000;181:309.

• ‘80-’86 vs. ‘94-’97 (585 pts)

• Comm. Colonizer : C. alb.

• C. alb.: Flu Res. 5%

• Mort : 39% → 20%

□ 1980-1986

■ 1994-1997

Candidemia : 2004 – 2008 Candidemia : 2004 – 2008 (N. America)(N. America)

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Prospective Antifungal Therapy (PATH) Alliance (Registry)

Non albicans cand 54%

C. albicans 46%

Distribution of NAC:

C. glab.* > C. parap. > C. trop. > C. krusei* (*Prior Flucon use.)

Overall mort (12-wk) 35%

with C. krusei 53%

Risks for C.krusei : Prior Af use; Heme Ca/SCT; Steroids; Neutropenia

Horn et al, Clin Infect Dis 2009; 48:1695

Candidemia : Karmanos Cancer InstituteCandidemia : Karmanos Cancer Institute6/05 → 6/09

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Prior to Flucon Prophylaxis ~ 15/year

Fluconazole Prophy. Since 1994

Ac myelog leukemia (Neutropenia)

Stem Cell recip (Pre-engraftment)

# Pts with Candidemia 19

C. albicans 9

Non alb Cand 9

C. glab 5

C. parap 3

C. trop 1

C. krusei 1

Invasive Fungal Infections/Stem Cell Recipients: 2004-2007Invasive Fungal Infections/Stem Cell Recipients: 2004-2007PATH Registry (16 N Am Centers)PATH Registry (16 N Am Centers)

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234 Adult SCT / 250 IFI

Inv Asp 59%

Inv Can 25%

Mortality (6 wk), IA 22%

Survival with IA > Survival with Cand/other

*Candida remains a significant pathogenNeofytos D et al, Clin Infect Dis 2009; 48:265

Aspergillus : Azole ResistanceAspergillus : Azole Resistance

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Global Antifungal Surveillance Program (‘01-’06)

771 Asp:A. fum 553, A. fl 76, A. niger 59, A. terr 35

A. versicolor 24

MIC Vori./Posa. > 2 mg/L : < 1% isolates

MICs of Vori/Ravu & Posa/Itra correlated in A.fum, A.fl

Pfaller MA et al, J Clin Microbiol 2008, 46:2568

Azole Resistance : Aspergillus fumigatusAzole Resistance : Aspergillus fumigatus1992 – 2008 (611 isol.)

Azole R ‘92-’97 5% (20/400)

’08 11% (5/63)

Mechanisms of Resistance

Multiple

Harrison E et al. ICAAC 2009, (#M-1720)

Regional Mycology Lab, Manchester, UK(519 isol, 1992 – 2007)

Resist to Itra 34 (5%)

Cross Resist to Vori 65%

Posa 74%

Patient Data (14)

•Prior Azole • Aspergilloma + CCPA • ABPA/bronchitis • Acute Invasive Dis• Cerebr Asperg

139311

Novel Mutations in CYP51A target enzyme

Howard SJ et al, Emerg Infect Dis 2009;15:1068

Thus

Since

• Risk for Cand/Asp infections in Ac Leukemia/Stem Cell Recipients is widely varied

• Candida remains a significant pathogen

• Mortality from non-albicans (‘Flu- resistant’) candida infections remains low

• Frequency of azole-resistance in Aspergillus is low

Fluconazole (?itraconazole) remain as useful prophylactic drugs in the majority of patients

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Problems with

‘Newer’ Azoles

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Azole-Mediated Cytochrome P450 Drug-Drug Azole-Mediated Cytochrome P450 Drug-Drug InteractionsInteractions

Dodds Ashley ES, Clin Infect Dis 2006;43 (Suppl 1):43

Drug

Drug

Mechanism Flu Itr Pos Vor

Inhibitor

2C19 + +++

2C9 ++ + ++

3A4 ++ +++ +++ ++

Substrate

2C19 +++

2C9 +

3A4 +++ +

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Voriconazole Prophylaxis : Allogeneic SCT (’03-’06)Voriconazole Prophylaxis : Allogeneic SCT (’03-’06)

Prospective, Randomized, Double Blind Trial (600 pts) [Vori vs Flu]

Duration d 0 d + 100/+180

Serum GM twice wkly x 60d, 1-2 wkly until d +100

IFI :

Proven/Prob/Presumptive IFI : Similar in 2 arms

Fungal Free Survival (6 mos) : Similar

Event free / Overall Survival : Similar

Concl : Efficacies of V and F are similar with close monitoring and early therapy

Wingard JR, Am Soc Hem 2007 (#163)

Posaconazole ProphylaxisPosaconazole Prophylaxis(vs Flucon/Itra)(vs Flucon/Itra)

Acute Leuk/MDS (602 Pts)

P (%) F/I (%)

Prov/Prob IFI(During Rx)

2 8

IA 1 7

All IFI (100 d) 5 11

Time to death P=.035 (within 100 d)

Overall mortality ↓ with Posa

Ullman AJ et al, N Engl J Med 2007;356:335Cornely OA et al, N Engl J Med 2007;356:348

Stem Cell Transplt/GVHD (600 Pts)

P (%) F (%)

Prov/Prob IFI (During Rx)

2 8

I A 3 17

All IFI (16 wks) 5 9

Death 2° IFI 1 4

Overall mortality ≡

Therapeutic Drug Monitoring : PosaconazoleTherapeutic Drug Monitoring : Posaconazole

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Interpatient Variability

• Stem Cell recip/GVHD Cmax (ng/mL) Cavg (ng/mL)

IFI (n=5) 635 611

No IFI (n=241) 1360 922

Krishna G et al Pharmacotherapy 2007; 27:1627

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Posaconazole Prophylaxis : LimitationsPosaconazole Prophylaxis : Limitations Oral Bioavailability –

Ability eat fatty meal

Ac leukemia trialMost ‘probable’ cases : Dx by Asp. Galactomannan only; if removed, Ø advant. with Posa.

GVHD TrialPosa : Baseline GM (+) : 21 (7%); IFI 2 (10%)Flu : Baseline GM (+) : 30 (10%); IFI 7 (23%)? Pre emptive rather than prophylactic trialOverall Mortality not reduced

Cornely OA, New Engl J Med 356: 348, 2007.

Ullmann AJ, New Engl J Med 356: 335, 2007.

IDSA Guidelines: Prophylaxis IDSA Guidelines: Prophylaxis AspergillosisAspergillosis

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Walsh TJ et al Clin Infect Dis 2008;46:327

• Stem Cell Transpl/with Graft Versus Host Disease (GVHD)

• Acute myelogenous Leukemia/myelodysplastic syndrome

Posaconazole A-I

Itraconazole B-II

* “Because of the heterogeneity of risk for IA (in the above 2 populations), further study needed to identify which patients may benefit the most….”

Fluconazole Prophylaxis: ? Pre Emptive ApproachFluconazole Prophylaxis: ? Pre Emptive Approach

Heme Ca/Neutropenia/Monitor with Serum Asp. GM Thrice wkly

• Routine Fluconazole Prophylaxis

Neutropenic Fever Episodes (117)

Antifungal use if • Asp GM x consecutive 2 positive

• CT abnorm & BAL (+) Aspergillus

Compared to emp. Approach, antifungal use reduced by 78%

Survival with IFI, 64%

Maertens J et al, Clin Infect Dis 2005;41:1242

SummarySummary

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• Fluconazole : Markedly diminished frequency of candidiasis in stem cell recipients and pts with acute myelogenous leukemia

• Itraconazole : Effective, usefulness mainly limited by drug intolerance

• Non-albicans candida have emerged as pathogens; mortality rate remains stable

• Frequency of aspergillosis: Wide variability in stem cell and leukemia populations; zygomycosis and others: Low frequency

• Better delineation of hi-risk subgroups for IFI needed

SummarySummary

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• Long-term use of Voricon/Posacon: Drug interaction/toxicities/resistance/cost

• Polyenes/Echinocandins : parenteral drugs, not suited for prophylaxis

• Thus, Fluconazole is a useful drug; with surveillance tools (fungal antigens, pcr, CT), the drug remains useful despite the emergence of molds.