Optimal Prophylaxis: Case for Fluconazole/ Itraconazole

1. Optimal Prophylaxis: Case for Fluconazole/ Itraconazole Pranatharthi H. Chandrasekar, MDWayne State University School of MedicineKarmanos Cancer Institute

2. Outline • 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. 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. Placebo Infection Infection-relatedmortality Overallmortality Fluconazole Prophylaxis in Hematopoietic Stem Cell Transplant Recipients Fluconazole 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 * Patients (%) Patients (%) * * * * Infection Infection-relatedmortality Overallmortality *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.

5. Fluconazole Prophylaxis : Acute Leukemia Winston DJ et al, Ann Intern Med 1993;118:495 Rotstein C et al, Clin Infect Dis1999; 28:331

6. Fluconazole : Survival • 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. ITRACONAZOLE : Prophylaxis in Hematopoietic Stem Cell Transplant Recipients

8. Itraconazole • 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 Hematol2005:131:22 Glassmacher A et al, J ClinOncol2003:21:4615

9. Itraconazole : Drawbacks • 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 AntimicrobChemother2005;56:33 De Beule KL, Int J Antimicrob Agents Chemother1996:6:175 Winston DJ et al, Ann Intern Med 2003;138:705

10. IDSA Guidelines: Prophylaxis Candidiasis Pappas PG et al, ClinInfDis2009;48:509

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

12. Frequency of IFI : Influencing Factors • Cancer/Stem Cell Recipient Population • Ac leukemia/status • Salvage for relapse/refr Highest Risk • Induction for newly diagnosed High Risk • Consolidation Low 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 FluconProphy : Stem Cell Population • ‘80-’86 vs. ‘94-’97 (585 pts) • Comm. Colonizer : C. alb. • C. alb.: Flu Res. 5% • Mort : 39% → 20% • □ 1980-1986 • ■ 1994-1997 Marr KA et al J Infect Dis 2000;181:309.

14. Candidemia : 2004 – 2008 (N. America) Horn et al, Clin Infect Dis2009; 48:1695

15. Candidemia : Karmanos Cancer Institute6/05 → 6/09

16. Invasive Fungal Infections/Stem Cell Recipients: 2004-2007PATH Registry (16 N Am Centers) Neofytos D et al, Clin Infect Dis2009; 48:265

17. Aspergillus : Azole Resistance Pfaller MA et al, J ClinMicrobiol2008, 46:2568

18. Azole Resistance : Aspergillus fumigatus

20. Problems with ‘Newer’ Azoles

21. Azole-Mediated Cytochrome P450 Drug-Drug Interactions Dodds Ashley ES, ClinInfect Dis 2006;43 (Suppl 1):43

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(vsFlucon/Itra)

24. Therapeutic Drug Monitoring : Posaconazole Krishna G et al Pharmacotherapy 2007; 27:1627

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

26. IDSA Guidelines: Prophylaxis Aspergillosis Walsh TJ et al Clin Infect Dis2008;46:327

27. Fluconazole Prophylaxis: ? Pre Emptive Approach Maertens J et al, Clin Infect Dis2005;41:1242

28. Summary

29. Summary