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Transcript of 1 Optimal Prophylaxis: Case for Fluconazole/ Itraconazole Pranatharthi H. Chandrasekar, MD Wayne...
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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.