Transcript ANTIFUNGAL DEVELOPMENT

Optimal Prophylaxis: Case
for Fluconazole/
Itraconazole
Pranatharthi H. Chandrasekar, MD
Wayne State University School of Medicine
Karmanos Cancer Institute
1
Outline
• Fluconazole
• Itraconazole
: Safety/Efficacy
: Safety/Efficacy
Cancer pts & stem
cell recipients
•What has changed?
-Treatment Practices
-Epidemiology of Cand./Asp
-Antifungal Resist.: Aspergillus
• Problems with ‘newer’ azoles
• Summary :
Fluconazole remains a useful drug for
prophylaxis
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Fungal Infection Prevention — Practices

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
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
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
40
Patients (%)
Patients (%)
40
30
20
10
*
0
Infection
30
*
20
10
*
*
*
Infectionrelated
mortality
Overall
mortality
*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.
0
Infection
Infectionrelated
mortality
Overall
mortality
Fluconazole Prophylaxis : Acute Leukemia
Flu
Placebo
Overall fungal fungal infection 9%
21%
P=.02
Syst fungal infection
4%
8%
P=NS
Flu (400 mg/d)
Placebo
Def/Probable IFI
9
32
P=.0001
Deaths from IFI
1/15
6/15
P=.04
Mortality ≡
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
5
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
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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
304 Patients
I : 7.5 mg/kg/d sol with
condition regimen
180d Post SCT
I (%)
F (%)
P
Proven IFI
9
25
.01
Intent to Treat
I≡F
Fungal-death
9
18
.13
On Treatment
I<F
(P .03)
Inv. Asperg.
4
12
.12
Inv. Mold
I<F
(P .03)
NS
Inv. Cand
I≡F
Mort
GI
Intolerance
24
9
Winston DJ, Ann Intern Med 138: 705, 2003.
.02
Inv. Fungal Inf
Hepatotoxicity / GI Intolerance
I : 36% ; F : 16%
Marr KA, Blood 103: 1527, 2004.
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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
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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
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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
Flucon
Pappas PG et al, Clin Inf Dis 2009;48:509
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What is Changed/Known Now?
• Treatment Practices
• Epidemiology of IFI/heme Ca, SCT
• Resistance in Aspergillus
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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
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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%
□ 1980-1986
■ 1994-1997
Marr KA et al J Infect Dis 2000;181:309.
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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)
with C. krusei
35%
53%
Risks for C.krusei : Prior Af use; Heme Ca/SCT; Steroids; Neutropenia
Horn et al, Clin Infect Dis 2009; 48:1695
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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
Non alb Cand
C. glab
9
9
5
C. parap
3
C. trop
C. krusei
1
1
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Invasive Fungal Infections/Stem Cell Recipients: 2004-2007
PATH Registry (16 N Am Centers)
234 Adult SCT / 250 IFI
Inv Asp
Inv Can
Mortality (6 wk), IA
59%
25%
22%
Survival with IA > Survival with Cand/other
*Candida remains a significant pathogen
Neofytos D et al, Clin Infect Dis 2009; 48:265
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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
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Azole Resistance : Aspergillus fumigatus
1992 – 2008 (611 isol.)
Azole R
‘92-’97
Regional Mycology Lab, Manchester, UK
(519 isol, 1992 – 2007)
Resist to
Itra
34 (5%)
Cross Resist to
Vori
65%
Posa
74%
5% (20/400)
’08
11% (5/63)
Patient Data (14)
Mechanisms of Resistance
Multiple
•Prior Azole
• Aspergilloma + CCPA
• ABPA/bronchitis
• Acute Invasive Dis
• Cerebr Asperg
13
9
3
1
1
Novel Mutations in CYP51A target enzyme
Harrison E et al. ICAAC 2009, (#M-1720)
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
Interactions
Drug
Drug
Mechanism
Flu
Itr
Pos
Vor
Inhibitor
2C19
+
+++
2C9
++
+
3A4
++
+++
++
+++
++
Substrate
2C19
+++
2C9
+
3A4
+++
Dodds Ashley ES, Clin Infect Dis 2006;43 (Suppl 1):43
+
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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)
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Posaconazole Prophylaxis
(vs Flucon/Itra)
Acute Leuk/MDS (602 Pts)
Stem Cell Transplt/GVHD (600 Pts)
P (%)
F/I (%)
Prov/Prob IFI
(During Rx)
2
8
IA
1
7
All IFI (100 d)
5
11
Time to death
(within 100 d)
P=.035
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
P (%)
F (%)
Prov/Prob IFI
(During Rx)
2
8
IA
3
17
All IFI (16 wks)
5
9
Death 2° IFI
1
4
Overall mortality ≡
Therapeutic Drug Monitoring : Posaconazole
Interpatient Variability
• Stem Cell recip/GVHD
IFI (n=5)
No IFI (n=241)
Cmax (ng/mL)
Cavg (ng/mL)
635
1360
611
922
Krishna G et al Pharmacotherapy 2007; 27:1627
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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%);
Flu
: Baseline GM (+) :
30 (10%);
? Pre emptive rather than prophylactic trial
Overall Mortality not reduced
IFI 2 (10%)
IFI 7 (23%)
Cornely OA, New Engl J Med 356: 348, 2007.
Ullmann AJ, New Engl J Med 356: 335, 2007.
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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
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Fluconazole Prophylaxis: ? Pre Emptive Approach
Heme Ca/Neutropenia/Monitor with Serum Asp. GM Thrice wkly
• Routine Fluconazole Prophylaxis
Neutropenic Fever Episodes
Antifungal use if
(117)
• 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
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
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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.
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