Infections in Cancer Patients Antifungal Drugs

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Infections in Cancer Patients-Antifungal Drugs

• Johan Maertens
• Dept of Hematology
• Acute leukemia and stem cell transplantation unit
• University Hospital Gasthuisberg
• Leuven, Belgium

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Drugs and Availability
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Antifungal AgentsThe Last 50 Years
of drugs
L-AmB ABCD ABLC
Terbinafine
Amphotericin B (1958)
Itraconazole
Griseofulvin
Fluconazole
Ketoconazole
Miconazole
Nystatin
5-FC
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Different mechanism of action
Candins
Azoles and Polyenes
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Properties of the available antifungal agents
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Posaconazole vs. voriconazole characteristics
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Key epidemiological data
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Incidence of fungal infections in patients with
hematological malignancies receiving azole
prophylaxis Italian data
Aspergillus 90 Zygomycetes 4 Fusarium
4 Others 2
Candida 91 Esp. Non-albicans! Cryptococc
us 4 Trichosporon 4 Others
2
Pagano L et al. Haematologica 2006 91 1068-1075
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Antifungal prophylaxis worksagainst yeasts
Mahfouz T Anaissie E. Curr Opinion Invest Drugs
2003 4 974
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Candidemia in cancer patientshematological
malignancy vs. solid tumor
Hanna H et al. ICAAC 2005 abstract M-989
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Treatment options
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The continuum of invasive fungal infection From
colonization to disease
Pre-emptive Therapy
Colonization
Full-blown disease
Signs symptoms
No disease
Sequelae
Targeted prophylaxis
Prophylaxis In high-risk patient
Therapy
Empirical High-risk patient on antibiotics with
fever
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A theoretical approach
Martino R et al. Br J Haematol 2005, 132 138
(modified) Maertens J et al. Curr Opinion Infect
Dis 2006
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Dealing with MouldsAspergillus and other
filamentous fungiTreatment Options in Documented
Disease
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Evolution of elements determining success or
failure
success
antifungal
condition
host defense
Thanks to Prof Ben de Pauw
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Published Randomized Comparative
TrialsFirst-line Invasive Aspergillus Infections
Salvage 40
50
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Voriconazole the agent of choice

• Improved outcome compared to previous algorithm
• - Vori 32 vs. cAmB 13 in HSCT
• CNS aspergillosis
• - Historical success lt 10 response
• - 81 patients (32 HSCT)
• Overall 35 favorable response 22 survival in
  HSCT
• Bone aspergillosis
• - 20 cases 55 favorable response
• Activity against other mould infections
• - Fusarium spp., Scedosporium spp.

Herbrecht et al, NEJM 2002 347 408 - Schwartz
et al, Blood 2005 106 2641 Mouras et al, CID
2005 40 1141 - Donnelly de Pauw, Clin
Microbiol Infect 2004 10107
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but

• Watch for drug interactions
• - cyclosporin A, tacrolimus, sirolimus
• Significant adverse events
• - hepatic, visual, rash
• Non-linear pharmacokinetics
• - saturation of metabolism
• Genetic polymorphism of CYP2C19
• IV formulation accumulation of cyclodextrin in
• renal insufficiency
• No activity versus Zygomycetes
• - vori prophylaxis ? increased incidence of
  Zygomycetes

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Why do patients with IA fail antifungal therapy?

• Voriconazole therapeutic drug monitoring
• Retrospective study of 28 patients
• Drug monitoring because of progression (17) or
  toxicity (11)
• 15 of 17 with progression has a transplant and IA

Plt0.025
Smith et al. Antimicrob Agents Chemother 2006
50 1570-72
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Proven or probable IA Voriconazole
Prior azole therapy Voriconazole
contraindicated Potential for serious drug
interactions Hepatic impairment Moderate to
severe renal impairment and IV administration Unid
entified non-Aspergillus mould possible Children
lt 2 years of age Cardiac risk factors
VORICONAZOLE
ALTERNATIVE
NO
YES
Persistent/breakthrough infection Hepatic
impairment development Treatment intolerance
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Echinocandins First-Line Therapy?

• Caspofungin
• 12 baseline Aspergillus infections in the caspo
  vs. L-amphoB empirical study RR 42
• 32 consecutive hematology patients with proven
  and probable IA RR 18/32 (56)
• Anidulafungin
• No data
• Micafungin
• 12 cases CR PR 50

Walsh et al., NEJM Denning D et al., J Infect
2006 , Candoni et al., Eur J Haematol 2005
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Revival of Amphotericin B AmBiload
Presented by Oliver Cornely at ASH 2005
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AmBiload Study Overall Response Safety
Presented by Oliver Cornely at ASH 2005
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Treatment of IA Conclusions

• Voriconazole drug of choice in first-line
  therapy
• AmBisome 3 mg/kg a good alternative
• Echinocandins data pending
• Abelcet
• promising activity in real life setting but no
  comparative trials
• Large database in pediatrics
• Salvage treatment rule of 40
• Combination (first line or salvage) insufficient
  data
• Adjunctive measures

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Dealing with YeastsCandida Treatment Options
in Documented Disease
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Why do patients with Candida infections fail
antifungal therapy?

• In vitro susceptibility and association with
  outcome of initial antifungal therapy in
  candidemia in cancer patients
• 144 candidemia cases MDACC (98-01)
• 30 albicans
• 24 glabrata
• 23 parapsilosis
• 12 krusei
• 9 tropicalis
• Independent factors for poor outcome presence of
  leukemia, allogeneic HSCT, ICU stay at onset
• Inappropriate antifungal therapy, defined by
  daily dose and in vitro susceptibility, was not
  shown consistently to be a significant factor

Antoniadou at al. Medicine 2003 82 309-21
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Relationship between hospital mortality and the
timing of antifungal treatment
Percent hospital mortality
Delays in start of antifungal treatment (hours)
Morrell et al. AAC 2005 49 3640-3645 See also
Garey et al. CID 2006 43 25-31
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Randomized Comparative Trials First-line
Invasive Candida Infections (non-neutropenic)
60-70
30-40
All non-inferiority studies
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In vitro susceptibilities of 46 fluconazole-R
isolates of C. glabrata
Pfaller et al. J Clin Microbiol 2004 3142
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Caspofungin vs. Amphotericin B for invasive
candidiasis
Successful outcome at End of IV Therapy
Caspofungin
100
Amphotericin B
90
81
73
80
71/88
62
65
80/109
70
63/97
60
71/115
50
Success ()
50
7/14
40
40
4/10
30
20
10
0
Baseline neutropenia (n24)
MITT (n224) (Primary Analysis)
EP (n185) (Secondary Analysis)
Mora-Duarte et al. NEJM 2002 347 2020
DiNubile et al. J Infect 2005 50 443
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Efficacy by Candida pathogen
Caspofungin n/m () 23/36 (64) 14/20
(70) 17/20 (85) 10/13 (77) 3/3
(100) 4/4 (100) 3/3 (100)
Amphotericin B n/m ()34/59
(58) 13/20 (66) 10/14 (71) 8/10
(80) 1/1 (100) 0/1 (0) 2/4 (50)
PathogenC. albicans C. parapsilosis C.
tropicalis C. glabrata C. guilliermondii C.
krusei Mixed infection
Mora-Duarte et al. NEJM 2002 347 2020
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Safety Results
80
75
Caspofungin
98/125
98/125
70
Amphotericin B
23
60
29/125
49
50
61/125
42
Proportion of Patients ()
40
48/114
25
26
30
20
26/105
33/125
20
23/114
11
8
10
3
13/114
8/95
3/114
0
Hypokalemia
Nephrotoxicity
Infusion- related events
Drug related AE
Drug related Discontinuation
Mora-Duarte et al. NEJM 2002 347 2020
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Recent data

• Micafungin 100 mg vs. Lip AmB 3 mg/kg (Ruhnke et
  al. ICAAC 2005)
• Non-inferior
• Anidulafungin 100 mg vs. fluconazole 400 mg
  (Reboli et al., ICAAC 2005)
• Anidulafungin superior
• Anidulafungin survival benefit, including C.
  albicans
• Micafungin 100 or 150 mg vs. caspofungin 70/50 mg
  (Betts et al., ICAAC 2006)
• No difference

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Conclusion