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

2. Outline Itraconazole : Safety/Efficacy What has changed?
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. Infection- related mortality
Fluconazole Prophylaxis in Hematopoietic Stem Cell Transplant Recipients
Fluconazole
Placebo
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
Slide 44
Goodman in 1992, and Slavin in 1995, conducted randomized, double-blind, placebo-controlled trials to evaluate fluconazole as antifungal prophylaxis for HSCT recipients.
Goodman and colleagues studied 356 autologous and allogeneic HSCT recipients from multiple centers, using large doses of fluconazole (400 mg/day) from the start of the conditioning period for a maximum of 10 weeks; 2.8% of fluconazole patients experienced systemic fungal infection versus 15.8% of placebo patients. Fewer infection-related deaths occurred in the fluconazole arm of the study. However, fluconazole did not significantly alter overall mortality.
In the second study, Slavin and co-workers sought to determine if a longer course of prophylaxis with fluconazole would improve survival or lower the incidence of infections. They administered fluconazole (400 mg/day for 75 days) to a primarily allograft-recipient population. The rate of infection in the fluconazole arm during prophylaxis was 10 of 152 patients (or 7%) versus 26 of 148 patients (or 18%) in the placebo arm (P=.004). The rate of fungal infection-related deaths by day 110 after transplant was 13% in the fluconazole arm and 21% in the placebo arm (P=.005). In contrast to the Goodman study, at day 110 the probability of overall survival was improved among fluconazole recipients (20% vs 35%, P=.004). *
Patients (%)
Patients (%) * * * *
Infection
Infection- related mortality
Overall mortality
Infection
Infection- related mortality
Overall mortality
*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 JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326:
Marr KA. Antifungal prophylaxis in hematopoietic stem cell transplant recipients. Curr Opin Infect Dis. 2001;14:
Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—a prospective, randomized, double-blind study. J Infect Dis. 1995;171:

5. Fluconazole Prophylaxis : Acute Leukemia
Placebo
Overall fungal fungal infection 9%
21%
P=.02
Syst fungal infection 4% 8%
P=NS
Mortality ≡
Flu (400 mg/d)
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;118:495
Rotstein C et al, Clin Infect Dis 1999; 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
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 18
.13
Inv. Asperg. 4 12
.12
Mort NS
GI Intolerance 24
.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
Inv. Cand
Hepatotoxicity / GI Intolerance
I : 36% ; F : 16%
Marr KA, Blood 103: 1527, 2004.

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 Hematol 2005:131:22
Glassmacher A et al, J Clin Oncol 2003:21:4615

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 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
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
Pappas PG et al, Clin Inf Dis 2009;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 Flucon Prophy : Stem Cell Population
‘80-’86 vs. ‘94-’97 (585 pts)
Comm. Colonizer : C. alb.
C. alb.: Flu Res. 5%
Mort : 39% → 20% □ ■
Marr KA et al J Infect Dis  2000;181:309.

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

15. Candidemia : Karmanos Cancer Institute 6/05 → 6/09
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
C. glab 5
C. parap 3
C. trop 1
C. krusei

16. Survival with IA > Survival with Cand/other
Invasive Fungal Infections/Stem Cell Recipients: PATH Registry (16 N Am Centers)
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 pathogen
Neofytos D et al, Clin Infect Dis 2009; 48:265

17. Aspergillus : Azole Resistance
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 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 13 9 3 1
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

20. Problems with ‘Newer’ Azoles

21. Azole-Mediated Cytochrome P450 Drug-Drug Interactions
Pharmacology_R1
3/25/2017 9:57 AM
Azole-Mediated Cytochrome P450 Drug-Drug Interactions
Drug
Mechanism
Flu
Itr
Pos
Vor
Inhibitor
2C19 +
+++
2C9 ++
3A4
Substrate
Dodds Ashley ES, Clin Infect 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 (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;356:335
Cornely OA et al, N Engl J Med 2007;356:348
Stem Cell Transplt/GVHD (600 Pts)
P (%)
F (%)
Prov/Prob IFI
(During Rx) 2 8
I A 3 17
All IFI (16 wks) 5 9
Death 2° IFI 1 4
Overall mortality ≡

24. Therapeutic Drug Monitoring : Posaconazole
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

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

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
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 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.