Treatment of Aspergillosis

John R. Perfect

Duke University Medical Center

Practice Guidelines for Aspergillosis*

Therapy

Invasive Aspergillosis• Amphotericin B deoxycholate (1-1.5 mg/kg/d) BIII• Lipid formulations of amphotericin B AII• Itraconazole BII

Aspergilloma• Surgery CIII

Allergic Bronchopulmonary Aspergillosis• Steroids BIII• Itraconazole BIt

* Clin. Infect. Dis. 30:696-709, 2000t N. Engl. J. Med. 342:756-762, 2000

Aspergillosis Outcome

Heme-Onc Ptsa All patientsb

1998 1995

3 month survival 44/130 (36%) 56/148 (38%)*

___________ ____________

*Death Rate of 62% in 3 months

Death due to Aspergillosis 40%

Death due to underlying disease 10%

Other causes/unknown 8%

a Denning, et al, J. Infect. 37:173-180, 1998b MSG Retrospective Study, 1995

Strategies To Overcome Drug Resistance

(1) Accurate and rapid diagnosis

(2) Immune modulation

(3) Drug prescription

(4) Prophylaxis/Empiric strategies

(5) Surgery

(6) Drug combination

(7) New drugs

Accurate and Rapid Diagnosis

Aspergillosisgalactomannan; glucan

Candidiasis arabinitol, mannan, enolase, glucan

PCR (Awaits its day)

Except for Cryptococcosis/Histoplasmosis

accurate and rapid diagnosis for invasive

mycoses not available.

Immunomodulation in Mycoses

• Cytokines well-studied at basic science

level

• Theoretically, important in this immunocompromised population

• Clinically, not optimized for treatment

(successes, failures, or no impact)

An EORTC Multicentre Prospective Survey of Invasive Aspergillosis in Hematological Patients:

Diagnosis and Therapeutic Outcome.*

130 cases 20 hospitals 8 countriesUse of growth factors did not appear to influenceoutcome

*Denning, et al, J. Infect. 37:173-180, 1998

Aspergillus Treatment (G-CSF)*During Neutropenia

0 4500 WBC Deaths

Rapid < 5 days 4/8 (50%)

Slow > 5 days 2/12 (17%)

*Todeschini, EMM Meetings, Barcelona, 2000

Dosing

• We still do not optimize triazole

pharmacokinetics

• What is optimal daily dose for lipid

products of amphotericin B

• What about administering drugs at specific

site? (i.e., aerosols)

AmbisomeAspergillosis %

(No.) CR/PR

1 mg/kg 41 64 t

4 mg/kg 46 48

5 mg/kg 17 77 5 mg/kg 52 52 vs 29 (AmB) �_______________________________________________________ t Ellis et al. Clin. Infect. Dis. 27:1406-1412, 1998

Chopra et al. Brit. J. Haem. 86:754-760, 1994

� Leenders et al. Brit. J. Haem. 103:205-212, 1998

Aerosolized ABLC for Fungal Prophylaxis in Lung Transplants*

• Safe (> 100 pts) < 3% toxicity

• No pulmonary infections; occ. fungemia

• 50 mg (Respigard II) 100 mg (for vent)

• Randomized study ABLC vs AmB

Palmer et al

*Transplantation, 2000

Prophylaxis

• Primary focus for success

• 10% rule

• Aspergillus ?

Empirical Antifungal Therapy in Neutropenia (AmB vs Ambisome)*

Breakthrough Fungal InfectionsAmbisome

Aspergillosis 5

Candidiasis 3

Other 2

10

Ambisome < AmB

Ambisome < Amb

Walsh et al, NEJM, 1999

AmB

11

12

3

26 P >0.01

(Infusion-related Rxn)

(Nephrotoxicity)

Empirical Antifungal Therapy in Neutropenia (Vori vs Ambisome)Breakthrough Fungal Infections

VorI

Aspergillosis 4

Candidiasis 2

Dimorphic Moulds 0

Zygomytcosis 2

8(1%)

Vori < Ambisome

Vori < Ambisome* Walsh et al - ICAAC, 2000

Ambisome

13

6

2

0

21 (9%) P = 0.03

(Infusion-related Rxn)

(Nephrotoxicity)

Surgery

• Debulking may be helpful (Aspergillus/Zygomycetes)

• Must be individualized and many times not clinically possible

Drug CombinationsAspergillosis

. AmB + 5FC

. AmB + Rifampin

Polyenes + Azoles (Antagonism vs Additive)

. AmB + ITZ (Sequential)

AmB vs AmB/ITZ

Death Rate 36.6% 8.3%

. New drugs + old drugs (improve fungicidal activity)

More data urgently needed!

_______________________________________________________* Mycoses Study Group, 1995

Aspergillosis*% Response Rates (CR/PR)

AmB (187) ITZ (58) AmB/ITZ (93)

Severe immunosuppression 24 40 41

Less immunosuppression 51 61 66

* Patterson et al. Medicine 79:250-260, 2000

New Antifungal Agents

• How can they help? (Better antifungal

spectrum; reduced toxicity, less drug

interactions; fungicidal activity; use in combination)

• Will they help? Yes (Here is why)

Almost New Antifungal Agents

- Lipid products of Amphotericin B (ABLC, Ambisome)• Effective in refractory cases of aspergillosis 40-45% cases

• Safety: nephrotoxicity matters (Wingard CID 29:1402-1407, 1999)

• Empirical use effective

• Cost

• Comparison of products (ABLC vs Ambisome) (Wingard, Clin. Infect. Dis. 31:1155-1163, 2000)

- Intravenous Itraconazole• Efficacy data

• Use during reduce renal function

Amphotericin B Lipid Complex*

Aspergillosis %

No. (Pts) CR/PR CR PR S F

ALL 170 42 17 25 13 45

Pulmonary 74 38 9 28 16 46Disseminated 27 30 15 15 11 59Sinus 14 64 36 29 7 29Single organ 15 67 40 27 0 33 extrapulmonary

* Walsh et al. Clin. Infect. Dis. 26:1383-1396, 1998

New AgentsTriazolesPosaconazole

Ravuconazole

Voriconazole

OthersR 120758, R 102557

KP 103, TAK 456, T 8581,

UR 9825

CandinsCapsofungin

FK 463

V- Echinocandin

(LY 303366)

PolyeneLiposomal Nystatin

OthersNikkomycin Z

Azasordarins

Pradimicins

Peptides

NYOTRAN(Liposomal Nystatin)

IA Refractory or Intolerant to Polyenes

• 4 mg/kg/d is well tolerated in treatment of

IA (27 days)

• 2/25 (8%) IRR; 3/25 (12%) nephrotoxicity

• Response (CR/PR) 6/19 (32%)

• 30 day survival (refractory pts) 7/16 (44%)Offner, et al, Abstr. 1102, 40th ICAAC, 2000

CASPOFUNGIN*IA Refractory or Intolerant to Polyenes

• 70 mg/50 mg/d is well tolerated in Rx of IA

• 3/54 (5.5% ) AE

Pulmonary (40) Disseminated (10) Single Organ (4)

CR/PR 18 (45%) 2 (20%) 2 (50%)

Stable/

Failure 22 (55%) 8 (80%) 2 (50%)

• Salvage therapy, favorable response 41%

*Maertens, et al, Abstr. 1103, 40th ICAAC, 2000

POSACONAZOLE (SCH456592)*• Oral preparation

• Oropharyngeal candidiasis (CR/PR >80%)

• Effective in coccidioidomycosis

• Open, non-comparative trial (800 mg/d)

(Invasive fungal infections refractory to standard Rx)

1 Month (% CR/PR)

Candidiasis (10) 80%

Aspergillus (22) 50%

Fusarium ( 5) 80%

Cryptococcus (12) 58%

Other (19) 74%

• AEs 6-12%

*Hachem RY, et al, Abstr. 1109, 40th ICAAC, 2000

Voriconazole Response Rates (CR/PR) inRefractory Aspergillosis

35

40

45

50

55

60

65

70

% C

R/P

R

All (n=51) Hematologic(n=38)

Non-hematologic(n=13)

Summary

• In the next 5 years the single biggest

advance for antifungal drug resistance will

be new drugs.

• They will not cure every infection or

prevent every infection as our immunocompromised population increases.

• But they will make a positive clinical

impact if properly studied!!!