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1 Optimal Prophylaxis: Case for Fluconazole/ Itraconazole Pranatharthi H. Chandrasekar, MD Wayne State University School of Medicine Karmanos Cancer Institute.

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Presentation on theme: "1 Optimal Prophylaxis: Case for Fluconazole/ Itraconazole Pranatharthi H. Chandrasekar, MD Wayne State University School of Medicine Karmanos Cancer Institute."— Presentation transcript:

1 1 Optimal Prophylaxis: Case for Fluconazole/ Itraconazole Pranatharthi H. Chandrasekar, MD Wayne State University School of Medicine Karmanos Cancer Institute

2 Outline 2 Fluconazole: Safety/Efficacy Itraconazole: Safety/Efficacy What has changed? -Treatment Practices -Epidemiology of Cand./Asp -Antifungal Resist.: Aspergillus Problems with newer azoles Summary :Fluconazole remains a useful drug for prophylaxis Cancer pts & stem cell recipients

3 3 Fungal 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

4 Fluconazole Prophylaxis in Hematopoietic Stem Cell Transplant Recipients *Statistical significance between fluconazole and placebo. Goodman JL, et al. N Engl J Med. 1992;326: Slavin MA, et al. J Infect Dis. 1995;171: 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 * * InfectionInfection- related mortality Overall mortality Patients (%) InfectionInfection- related mortality Overall mortality Patients (%)

5 Fluconazole Prophylaxis : Acute Leukemia 5 FluPlacebo Overall fungal fungal infection9%21%P=.02 Syst fungal infection4%8%P=NS Mortality Flu (400 mg/d)Placebo Def/Probable IFI932P=.0001 Deaths from IFI1/156/15P=.04 Benefit in: AML/induction therapy with cytarabine +anthracycline-based regimen Winston DJ et al, Ann Intern Med 1993;118:495 Rotstein C et al, Clin Infect Dis 1999; 28:331

6 Fluconazole : Survival 6 Independent predictor of overall survival/multivar analysis (matched, unrelated donor transplant) Meta analysis: IFI / fungus-related death (neutropenic patients : 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; 338:962 Kanda Y et al, Cancer 2000; 89:1611

7 7 ITRACONAZOLE : Prophylaxis in Hematopoietic Stem 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 SCTI (%)F (%)P Proven IFI Fungal-death Inv. Asperg MortNS GI Intolerance Winston DJ, Ann Intern Med 138: 705, Patients I : 7.5 mg/kg/d sol with condition regimen Inv. Fungal Inf Intent to Treat I F On TreatmentI < F(P.03) Inv. MoldI < F(P.03) Inv. CandI F Hepatotoxicity / GI Intolerance I : 36% ; F : 16% Marr KA, Blood 103: 1527, 2004.

8 Itraconazole 8 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; 38:127 Vardakas KZ et al, Br J Hematol 2005:131:22 Glassmacher A et al, J Clin Oncol 2003:21:4615

9 Itraconazole : Drawbacks 9 Suboptimal Bioavailability Inter patient variability Poor tolerability Capsule : Erratic bioavailability Drug interactions/CYP450 eg. Cyclophosphamide, Vincristine anthracyclines ? Greater toxicity Cardiotoxicity (negative inotropic effect) drug levels: clin failures/ fungal-free survival Marr K et al, Blood 2004;103:1527 Maertins J et al, J Antimicrob Chemother 2005;56:33 De Beule KL, Int J Antimicrob Agents Chemother 1996:6:175 Winston DJ et al, Ann Intern Med 2003;138:705

10 IDSA Guidelines: Prophylaxis Candidiasis 10 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 Flucon Pappas PG et al, Clin Inf Dis 2009;48:509

11 What is Changed/Known Now? 11 Treatment Practices Epidemiology of IFI/heme Ca, SCT Resistance in Aspergillus

12 Frequency of IFI : Influencing Factors 12 Cancer/Stem Cell Recipient Population Ac leukemia/status Salvage for relapse/refr Highest Risk Induction for newly diagnosedHigh Risk ConsolidationLow Risk Duration of Neutropenia Periph blood vs bone marrow Non-myeloablative vs myeloablative Mucositis – Non-myeloablative regimen GVHD & its therapy Antifungal Prophylaxis

13 Impact of Flucon Prophy : Stem Cell Population 13 Marr KA et al J Infect Dis 2000;181: vs (585 pts) Comm. Colonizer : C. alb. C. alb.: Flu Res. 5% Mort : 39% 20%

14 Candidemia : 2004 – 2008 (N. America) 14 Prospective Antifungal Therapy (PATH) Alliance (Registry) Non albicans cand54% C. albicans 46% Distribution of NAC: C. glab.* > C. parap. > C. trop. > C. krusei* (*Prior Flucon use.) Overall mort (12-wk)35% with C. krusei53% Risks for C.krusei : Prior Af use; Heme Ca/SCT; Steroids; Neutropenia Horn et al, Clin Infect Dis 2009; 48:1695

15 Candidemia : Karmanos Cancer Institute Candidemia : Karmanos Cancer Institute 6/05 6/09 15 Prior to Flucon Prophylaxis~ 15/year Fluconazole Prophy. Since 1994 Ac myelog leukemia (Neutropenia) Stem Cell recip (Pre-engraftment) # Pts with Candidemia19 C. albicans9 Non albCand9 C. glab5 C. parap3 C. trop1 C. krusei1

16 Invasive Fungal Infections/Stem Cell Recipients: PATH Registry (16 N Am Centers) Adult SCT / 250 IFI Inv Asp59% Inv Can 25% Mortality (6 wk), IA22% Survival with IA > Survival with Cand/other *Candida remains a significant pathogen Neofytos D et al, Clin Infect Dis 2009; 48:265

17 Aspergillus : Azole Resistance 17 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

18 Azole Resistance : Aspergillus fumigatus 1992 – 2008 (611 isol.) Azole R92-975% (20/400) 0811% (5/63) Mechanisms of Resistance Multiple Harrison E et al. ICAAC 2009, (#M-1720) Regional Mycology Lab, Manchester, UK (519 isol, 1992 – 2007) Resist toItra34 (5%) Cross Resist toVori65% Posa74% Patient Data (14) Prior Azole Aspergilloma + CCPA ABPA/bronchitis Acute Invasive Dis Cerebr Asperg Novel Mutations in CYP51A target enzyme Howard SJ et al, Emerg Infect Dis 2009;15:1068

19 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 19

20 Problems with Newer Azoles 20

21 21 Azole-Mediated Cytochrome P450 Drug-Drug Interactions Dodds Ashley ES, Clin Infect Dis 2006;43 (Suppl 1):43 Drug MechanismFluItrPosVor Inhibitor 2C C9+++ 3A Substrate 2C C9+ 3A4++++

22 22 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)

23 Posaconazole Prophylaxis (vs Flucon/Itra) Acute Leuk/MDS (602 Pts) P (%)F/I (%) Prov/Prob IFI (During Rx) 28 IA17 All IFI (100 d)511 Time to death P=.035 (within 100 d) Overall mortality with Posa Ullman AJ et al, N Engl J Med 2007;356:335 Cornely OA et al, N Engl J Med 2007;356:348 Stem Cell Transplt/GVHD (600 Pts) P (%)F (%) Prov/Prob IFI (During Rx) 28 I A317 All IFI (16 wks)59 Death 2° IFI14 Overall mortality

24 Therapeutic Drug Monitoring : Posaconazole 24 Interpatient Variability Stem Cell recip/GVHD Cmax (ng/mL)Cavg (ng/mL) IFI (n=5) No IFI (n=241) Krishna G et al Pharmacotherapy 2007; 27:1627

25 25 Posaconazole Prophylaxis : Limitations Oral Bioavailability – Ability eat fatty meal Ac leukemia trial Most probable cases : Dx by Asp. Galactomannan only; if removed, Ø advant. with Posa. GVHD Trial Posa: Baseline GM (+) :21 (7%);IFI 2 (10%) Flu: Baseline GM (+) :30 (10%);IFI 7 (23%) ? Pre emptive rather than prophylactic trial Overall Mortality not reduced Cornely OA, New Engl J Med 356: 348, Ullmann AJ, New Engl J Med 356: 335, 2007.

26 IDSA Guidelines: Prophylaxis Aspergillosis 26 Walsh TJ et al Clin Infect Dis 2008;46:327 Stem Cell Transpl/with Graft Versus Host Disease (GVHD) Acute myelogenous Leukemia/myelodysplastic syndrome PosaconazoleA-I ItraconazoleB-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….

27 Fluconazole 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

28 Summary 28 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

29 Summary 29 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.


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