Transcript Relevance of Combination Antifungal Therapy: Some Key

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Relevance of Combination
Antifungal Therapy: Some Key
Questions
Is there a need for combination therapy in the first
place?
Does the toxicity risk merit the use in attaining a
“possible” mortality reduction?”
Are the doses of the investigational drugs
appropriate?
Is the endpoint of the study meaningful?
Practical Advantages of Antifungal
Combination Therapy
From Kontoyiannis and Lewis
Synergy
Broader Spectrum
Decreased Resistance
Pharmacokinetic Enhancement
Better Tolerance with Lower Doses
Combination Strategies Unique to
Fungal Infections
Overall Mortality Rates Very High
Toxicity of Antifungals is Significant
Fungal Diseases Relatively Rare
Drug Costs High
Superiority Trials for Efficacy Preferred
Costs of Studies Enormous
Considerations in Clinical Trials of
Combination Antifungal Therapy: John
H. Powers CID 39: S228: 2004
Unique Aspects of Combination
Treatment for Fungal Infections
Surrogate Endpoints Rare/non-existent
Multiple Companies Needed for Studies
Historical Trials Problematic
Relatively Few Agency Approved Drugs
Standard of Care May Be Combinations
Considerations in Clinical Trials of
Combination Antifungal Therapy: John
H. Powers CID 39: S228: 2004
Relevance of Combination Antifungal
Therapy: Some Key Questions
Is there a need for combination therapy in the first
place?
Definite:
Aspergillosis
Mucormycosis
Fusarium, Scedoporium, and other moulds
Coccidiomycosis
Probable
Cryptococcosis
Candidiasis: Especially specific forms such
as endocarditis, osteomyelitis, and endophthalmitis
Successfully Treated Candida krusei Infection of
the Lumbar Spine with Combined
Caspofungin/posaconazole Therapy: Schilling
et al. Medical Mycology Jan 2007
Relevance of Combination Antifungal
Therapy: Some Key Questions
Does the toxicity risk merit the use in
attaining a “possible” mortality
reduction?”
Voriconazole Interactions
Warfarin
Cyclosporin
Tacrolimus
Sulfonureas
Statins
Benzodiazepines
Vinca Alkaloids
Sirolimus
Rifabutin
Rifampicin
Terfenadine
Relevance of Combination Antifungal
Therapy: Some Key Questions
Are the doses of the investigational
drugs appropriate?
Synergism vs Cryptococcal Meningitis
N Engl J Med: 301:126, 1979
51 Courses, 10wks AMB Alone vs. 6 Weeks of Combo
100
AMB: 0.4 mg/kg/d
80
Success %
Combo
5-FC: 150mg/kg/d +
Amb: 0.3 mg/kg/d
67%
41%
60
40
20
0
Combo
Amb
Relevance of Combination Antifungal
Therapy: Some Key Questions
Is the endpoint of the study meaningful?
Underlying Condition of Patient
Time of the End Point Analysis
All Cause Mortality
Surrogate Marker End Point
Fungal Related Mortality
Cost of Care
Break Through Fungal Infection
Use of Alternative Strategies
Composite Endpoint
Toxicity
Microbiologic Cure
Retrospective Subgroup Analysis
Clinical Cure
Relationship Between Severity of Disease at
Baseline, As Measured by APACHE II, and Clinical
Outcomes: From Rex et al. Clin Inf Dis: 36:1221,
2003
Combination of Voriconazole and Caspofungin as Primary Therapy for Invasive
Aspergillosis in Solid Organ Transplant Recipients: A Prospective, Multicenter,
Observational Study
Singh et al. Transplantation 81:320, 2006
Vori + Caspo
Vori + Caspo Mortality
Due to IA: 26%
LAMB Grp Mortality
Due to IA: 43%
Probability of Survival
Combination
N=40
P=0.1
P
Lipid Ampho Group
Days Post Diagnosis
N=47
Singh et al. to Bal Regarding Mortality
Stratified by Disease
Transplantation, Letter p291, 2006
Conclusion:
Condition of the Patients
did not Influence Outcome
Combination Therapy for Invasive Aspergillosis:
Marr et al. : CID 39:737, 2004 (Retrospective,
Salvage)
Vori + Caspo
n=16
P=.048
n=31
Survival After Combination Therapy for
Aspergillosis: Marr et al. Clin Inf Dis 40:1074,
2005
Probability of Survival %
Days After Diagnosis
100
90
80
70
60
50
40
30
20
10
0
Vori + Caspo
P=0.26
Voriconazole
Vori
0
60
120
180
240
300
360
The benefit of the combination treatment seen at 90 days
was not present when the survival at a year was analyzed.
One year data
related to causes of
death
Survival
Probability
ProbabilityofofSurvival
IA
ToIA
DueTo
Death
DeathDue
Other
FromOther
Death
DeathFrom
Marr in Response
to Cesaro and
Visintin: CID
40:1075, 2005
Vori + Caspo
Combo
Combo
Vori
Vori
Vori
Combo *
Combo
Combo
Combo
*
Vori
High-dose Caspofungin (100mg/d) Combination Antifungal
Therapy in Patients with Hematologic Malignancies and
Hematopoietic Stem Cell Transplantation: Safdar et al. Bone
Marrow Trans: 39:157:2007 (Retrospective)
Caspo + OLAT
*More immunostim
P=0.1
N=31
N=63
All Cause Mortality
Invasive Aspergillosis Following Hematopoietic
Cell Transplantation: Outcomes and Prognostic
Factors Associated with Mortality: Upton et al.
CID 44:531: 2007 (Retrospective, 405 Patients)
Probability of Attributable Death in Patients With IA according to Years
Year of Diagnosis
Invasive Aspergillosis Following Hematopoietic Cell
Transplantation: Outcomes and Prognostic Factors Associated
with Mortality: Upton et al. CID 44:531: 2007 (Retrospecive
Analysis of 405 Patients)
Probability of Death Due to IA
Probability of Attributable Death in Patients Receiving and not Receiving Voriconazole
Other
Voriconaozle
N=176
N=54
No. of Days After IA Diagnosis
P=.03
Invasive Aspergillosis Following Hematopoietic Cell
Transplantation: Outcomes and Prognostic Factors Associated
with Mortality: Upton et al. CID 44:531: 2007 (Retrospective
Analysis of 405 Patients)
Reasons for Improved Survival Over Time:
Change in Transplant Practices
Interpreting
Historical Controls
May Be Highly Complex
Non-myeloablative
Suppression
Stem Cell Transplantation
Improved Diagnosis of Aspergillosis
Use of Voriconazole
Selected Combination Studies
for Aspergillosis
Refractory Fungal Pneumonia in Patients with Acute
Leukemia: Successful Treatment with Combination
Caspofungin and Amphotericin B: Aliff et al. Cancer
97:1025, 2003 (Retrospective, Salvage Study)
Proven, Probable, and Possible (Most Possible)
30 Patients Total: Retrospective Study
Response=Improvement
All Patients n=30
60% Response
Chemotherapy for
Acute Leukemia
n=20
75% Response
Survival at Discharge Higher with Patients Having
a Favorable Response
Multicenter, Noncomparative Study of Caspofungin in
Combination With Other Antifungals as Salvage Therapy in Adults
With Invasive Aspergillosis. Maertens et al. Cancer 107:2888,
2006 (Open Label, Non-Comparative, Refractory or Intolerant)
High Dose Ambisome vs. Ambisome + Caspo
For Aspergillosis: Caillot et al. Cancer, Oct. 16,
2007
15 Patients Each Arm: High Dose AMB 10mg/kg, Standard 3mg/kg
Response Percent
80
70
60
50
Combo
AMB
40
30
20
10
0
Day 14
Survival at Week 12:
EOT
Week 12
High Dose Ambisome 80%
Combo 100%
Combination Salvage Therapy of Invasive Aspergillosis in
Patients with Hematologic Malignancy: Which CaspofunginContaining Regimen?
Raad et al. 47th ICAAC Abstract M-624, 2007 (Retrospective,
Salvage Study)
59
*
Percent
100
90
80
70
60
50
40
30
20
10
0
33
*
LP-AMB +
Caspo
LPAMB
Vori +
Vor
+ Ca
Caspo
*: Sig
Res
Response
Res
Rate
All Cause
IA Mortality
Mortality
AM
IAM
Renal
Toxicity
RT
Combination Salvage Therapy of Invasive
Aspergillosis in Patients with Hematologic Malignancy:
Which Caspofungin-Containing Regimen?
Raad et al. 47th ICAAC Abstract M-624, 2007
(Salvage Study)
Number of
Patients
Patient
age
Acute
Leukemia
GCSF
Or
Other
Caspo +LPAMB
59
52
48%
85%
Caspo + Vor
33
58
12%
64%
All Statistically Significant
Single Agent or Combination to Treat Invasive
Aspergillosis?
Kubin et al. 46th ICAAC, Abstract M-899, 2006
Retrospective 146 proven/probable primary cases
Mono
Caspo + Vori
N=124
N=22
47 AMB: 33 Vori
Response
24%
21%
12 Week
Mortality
55%
46%
Caspofungin Plus Posaconazole vs. Liposomal
Amphotericin B for Aspergillosis: Raad et al. 45th ICAAC,
Abstract M-1035, 2004
Retrospective, 238 Proven/Probable Cases with
Hematological Malignancy
1999-2003
LAMB + Caspo
N=48
Posa + Caspo
N=43
Response
14%
29%
Excluding ICU
24%
32%
Survival at Discharge Higher with Posa Combination Therapy
Micafungin, Alone or in Combination with Other Systemic
Antifungal Agents, for the Treatment of Acute Invasive
Aspergillosis: Denning et al. J of Infect, 53:337, 2006 (Open
Label, Non-Comparative, Prospective)
225 Patients
48 GVHD
83/225 Received Chemo
For Malignancy
100
90
80
70
60
50
40
30
20
10
0
Percent Survival
98/225 HSCT: 88/98 /allo
Primary
6/12
Salvage
9/22
5/17
Mica
Combo
Mica
60/174
Combo
Micafungin, Alone or in Combination Against
Aspergillus
Kontoyiannis et al. 46th ICAAC, Abstract M-878, 2006
Refractory in
Bone Marrow
Transplant
Patients
Response %
100
80
60
N=8
N=90
40
20
38%
24 %
0
Mica
Mica + Olat
Combination Strategies for
Non-Aspergillus Fungi
Fluconazole Plus Amphotericin B vs AMB Alone for Primary
Treatment of AIDS-Associated Cryptococcal Meningitis; Results of
a Phase II Trial
Pappas et al. 47th ICAAC Abstract M-626, 2007
Standard Therapy: 0.7 mg/kg AMB for 14 days then 8 weks of 400 mg Flu
Low Dose: AMB plus 400mg of Flu for 14 days then 400 mg Flu for 8weeks
High Dose: AMB plus 800mg of Flu for 14 days ten 800 mg Flu for 8 weeks
Success for End Point: CSF Cultures neg, neurological stability,
and survival at day 14
Fluconazole Plus Amphotericin B vs AMB Alone for Primary
Treatment of AIDS-Associated Cryptococcal Meningitis; Results of
a Phase II Trial
Pappas et al. 47th ICAAC Abstract M-626, 2007
Standard Rx
Low Dose
High Dose
Day 14
N=46
% Success: 41
N=42
% Success: 31
N=42
% Success: 55
Day 42
N=37
% Success: 76
N=35
% Success: 80
N=33
% Success: 85
N=38
% Success:76
N=32
% Success:88
N=28
% Success:93
Day 70
Activity of Caspofungin Alone and in Combination with
Amphotericin B Lipid Complex in a Murine Model of Fusariosis:
Ostrosky-Zeichner et al. 47th ICAAC Abstract M-1841, 2007
Percent Survival
25 Mice Per Group
100
90
80
70
60
50
40
30
20
10
0
*
Placebo
Caspo
P
CFG ABLC
A C +Combo
A5
ABLC C +Combo
10mg/kg 10mg/kg1010mg 5mg
Synergism of L-AMB and Micafungin Combination in
Murine Mucormycosis: Spellberg et at. 46th ICAAC,
Abstract M-1744, 2006
Survival %
100
90
80
70
60
50
40
30
20
10
0
Combo
L-AMB
Mica
P
Combination Polyene-Echinocandin Therapy in the
Treatment of Mucormycosis
Reed et al. 45th IDSA, Abstract 659, 2007
10 Year Retrospective Review
Endpoint: Survival for 30 Days Following Discharge
10 Patients Found: All rhinocerebral (9/10) CNS Involvement
Combination echinocandin + Polyene: 3/3 survivors
Polyene alone:
1/7 Survivors
Conclusion:
Prospective Investigation of combination PolyeneEchinocandin Therapy for the Treatment of Mucormycosis
is Warranted
The Iron Chelator Deferasirox Protects Mice From
Mucormycosis Through Iron Starvation:
Ibrahim et al. JCI 117:2649: 2007
Deferasirox
Placebo
Desferoxamine
The Iron Chelator Deferasirox Protects Mice From
Mucormycosis Through Iron Starvation:
Ibrahim et al. JCI 117:2649: 2007
Deferasirox
Chelator Combined
with L-AMB
Placebo
Desferoxamine
Summary: Relevance of Combination
Therapy
Majority of existing studies are anecdotal, retrospective,
and or non-comparative
Prospective, double blind studies are exceedingly problematic
in design issues and feasibility
Prospective, double blind, trials will be forthcoming
but highly restricted in number
Weight of the evidence is in favor of combination therapy
in seriously ill patients with invasive fungal infections
Until studies are completed, use combination therapy in
serious cases
Tolerance of the patient for the combination needs to be
carefully monitored to justify the use.
Grazie!