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Optimal Prophylaxis: Fluconazole vs Itraconazole in Cancer Patients

Explore the safety, efficacy, and changes in treatment practices of fluconazole and itraconazole for fungal infection prophylaxis in cancer patients, including the impact on mortality rates, infection risks, and optimal dosing. Discover the drawbacks and resistance issues with itraconazole, as well as the role of newer azoles like voriconazole and posaconazole. Stay informed on the latest guidelines and clinical trials regarding antifungal prophylaxis in hematopoietic stem cell recipients.

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Optimal Prophylaxis: Fluconazole vs Itraconazole in Cancer Patients

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  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

  19. Problems with ‘Newer’ Azoles

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

  21. 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)

  22. Posaconazole Prophylaxis(vsFlucon/Itra)

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

  24. 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.

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

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

  27. Summary

  28. Summary

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