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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 EnormousConsiderations in Clinical Trials of Combination Antifungal Therapy:

John H. Powers CID 39: S228: 2004

Surrogate Endpoints Rare/non-existent

Multiple Companies Needed for Studies

Historical Trials Problematic

Relatively Few Agency Approved Drugs

Standard of Care May Be Combinations

Unique Aspects of Combination Treatment for Fungal Infections

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:AspergillosisMucormycosisFusarium, Scedoporium, and other mouldsCoccidiomycosis

ProbableCryptococcosisCandidiasis: 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

WarfarinCyclosporinTacrolimusSulfonureasStatinsBenzodiazepines

Vinca AlkaloidsSirolimusRifabutinRifampicinTerfenadine

Relevance of Combination Antifungal Therapy: Some Key Questions

Are the doses of the investigational drugs appropriate?

Synergism vs Cryptococcal MeningitisN Engl J Med: 301:126, 1979

0

20

40

60

80

100

Combo Amb

Su

ccess %Combo

5-FC: 150mg/kg/d + Amb: 0.3 mg/kg/d

AMB: 0.4 mg/kg/d

67%

41%

51 Courses, 10wks AMB Alone vs. 6 Weeks of Combo

Relevance of Combination Antifungal Therapy: Some Key Questions

Is the endpoint of the study meaningful?

Underlying Condition of Patient

All Cause Mortality

Fungal Related Mortality

Break Through Fungal Infection

Composite Endpoint

Microbiologic Cure

Clinical Cure

Time of the End Point Analysis

Surrogate Marker End Point

Cost of Care

Use of Alternative Strategies

Toxicity

Retrospective Subgroup Analysis

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 StudySingh et al. Transplantation 81:320, 2006

P

Combination

Lipid Ampho Group

Days Post Diagnosis

Pro

babili

ty o

f Surv

ival

Vori + Caspo

N=40

N=47

P=0.1Vori + Caspo MortalityDue to IA: 26%

LAMB Grp MortalityDue to IA: 43%

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=31

n=16

P=.048

Survival After Combination Therapy for Aspergillosis: Marr et al. Clin Inf Dis

40:1074, 2005

0102030405060708090

100

0 60 120 180 240 300 360Vori

Vori + Caspo

Voriconazole

Pro

bab

ilit

y o

f S

urv

ival

%

Days After Diagnosis

P=0.26

The benefit of the combination treatment seen at 90 dayswas not present when the survival at a year was analyzed.

One year data related to causes of

death

Marr in Response to Cesaro and Visintin: CID

40:1075, 2005

Pro

babili

ty o

f S

urv

ival

Death

Du

e T

o IA

Death

Fro

m O

ther

Vori

Combo

Combo

Combo

Pro

babili

ty o

f S

urv

ival

Death

Du

e T

o IA

Death

Fro

m O

ther

Vori

Combo

Combo

Combo

Vori

Vori

Vori + Caspo

*

*

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)

All Cause Mortality

Caspo + OLAT

N=31P=0.1

N=63

*More immunostim

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 Attributable Death in Patients Receiving and not Receiving Voriconazole

Other

Voriconaozle

Pro

babili

ty o

f D

eath

Due t

o IA

No. of Days After IA Diagnosis

P=.03N=54

N=176

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

Non-myeloablative Suppression

Stem Cell Transplantation

Improved Diagnosis of Aspergillosis

Use of Voriconazole

Interpreting Historical Controls May Be Highly Complex

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 StudyResponse=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)

0

10

20

30

40

50

60

70

80

Resp

onse

Perc

ent

Day 14 EOT Week 12

Combo

AMB

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

Survival at Week 12: High Dose Ambisome 80% Combo 100%

Combination Salvage Therapy of Invasive Aspergillosis in Patients with Hematologic Malignancy: Which

Caspofungin-Containing Regimen?Raad et al. 47th ICAAC Abstract M-624, 2007

(Retrospective, Salvage Study)

0102030405060708090

100

Res AM IAM RT

LPAMB

Vor + CaVori + Caspo

ResResponse

RateAll CauseMortality

IA MortalityRenal

Toxicity

Perc

en

t

*

*: Sig

*LP-AMB +

Caspo

59

33

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)

59 52 48% 85%

33 58 12% 64%

Number of Patients

Patientage

Acute Leukemia

GCSFOr

Other

Caspo +LPAMB

Caspo + Vor

All Statistically Significant

Single Agent or Combination to Treat Invasive Aspergillosis?

Kubin et al. 46th ICAAC, Abstract M-899, 2006

Response 24% 21%

12 Week Mortality

55% 46%

MonoN=124

47 AMB: 33 Vori

Caspo + VoriN=22

Retrospective 146 proven/probable primary cases

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

Survival at Discharge Higher with Posa Combination Therapy

LAMB + CaspoN=48

Posa + CaspoN=43

14% 29%

24% 32%

Response

Excluding ICU

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)

0102030405060708090

100

Mica Combo Mica Combo

Perc

en

t S

urv

ival

Primary Salvage

225 Patients

6/12

5/17

9/2260/174

98/225 HSCT: 88/98 /allo

48 GVHD

83/225 Received ChemoFor Malignancy

Micafungin, Alone or in Combination Against Aspergillus

Kontoyiannis et al. 46th ICAAC, Abstract M-878, 2006

0

20

40

60

80

100

Mica Mica + Olat

Resp

on

se %

38%24 %

N=8 N=90Refractory in Bone Marrow Transplant Patients

Combination Strategies forNon-Aspergillus Fungi

Fluconazole Plus Amphotericin B vs AMB Alone for Primary Treatment of AIDS-Associated Cryptococcal Meningitis;

Results of a Phase II TrialPappas 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 TrialPappas et al. 47th ICAAC Abstract M-626, 2007

N=46

% Success: 41

N=42

% Success: 31

N=42

% Success: 55

N=37

% Success: 76

N=35

% Success: 80

N=33

% Success: 85

N=38

% Success:76

N=32

% Success:88

N=28

% Success:93

Standard Rx Low Dose High Dose

Day 14

Day 42

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

0102030405060708090

100

P CFG ABLC C + A10

C + A 5Placebo Caspo10mg/kg

ABLC10mg/kg

Combo10mg

Combo5mg

Perc

en

t S

urv

ival

25 Mice Per Group

*

Synergism of L-AMB and Micafungin Combination in Murine Mucormycosis: Spellberg et at. 46th

ICAAC, Abstract M-1744, 2006

0102030405060708090

100

Combo L-AMB Mica P

Su

rviv

al %

Combination Polyene-Echinocandin Therapy in the Treatment of Mucormycosis

Reed et al. 45th IDSA, Abstract 659, 2007

10 Year Retrospective ReviewEndpoint: Survival for 30 Days Following Discharge10 Patients Found: All rhinocerebral (9/10) CNS Involvement

Combination echinocandin + Polyene: 3/3 survivorsPolyene alone: 1/7 Survivors

Conclusion:Prospective Investigation of combination Polyene-Echinocandin Therapy for the Treatment of Mucormycosis is Warranted

Desferoxamine

Placebo

Deferasirox

The Iron Chelator Deferasirox Protects Mice From Mucormycosis Through Iron

Starvation:Ibrahim et al. JCI 117:2649: 2007

Desferoxamine

Placebo

Deferasirox

The Iron Chelator Deferasirox Protects Mice From Mucormycosis Through Iron

Starvation:Ibrahim et al. JCI 117:2649: 2007

Chelator Combined with L-

AMB

Summary: Relevance of Combination Therapy

Majority of existing studies are anecdotal, retrospective,and or non-comparative

Prospective, double blind studies are exceedingly problematicin design issues and feasibility

Prospective, double blind, trials will be forthcomingbut highly restricted in number

Weight of the evidence is in favor of combination therapyin seriously ill patients with invasive fungal infections

Until studies are completed, use combination therapy inserious cases

Tolerance of the patient for the combination needs to be carefully monitored to justify the use.

Grazie!