# Presentation: 460648

## 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, 2000*
***t****  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, 1998*
- b *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

*Aspergillosis*	galactomannan; 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 countriesUse of growth factors did not appear to influenceoutcome

- **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)

## Ambisome

- Aspergillosis   %
- 				_(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 Infections

- _Ambisome_
-      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 Combinations

- Aspergillosis
- 		. 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         46
- Disseminated	  27		  30		15	   15	      11         59
- Sinus		  14		  64		36	   29	        7         29
- Single organ	  15		  67		40	   27	        0         33
-   extrapulmonary
**  Walsh et al.  Clin. Infect. Dis. 26:1383-1396, 1998*

##                New Agents

- _	__**Triazoles**_
- 	Posaconazole
- 	Ravuconazole
- 	Voriconazole
- _	__**Others**_
- 	R 120758, R 102557
- 	KP 103, TAK 456, T 8581,
- 	UR 9825
- _	_

- _	__	__**Candins**_
- 		Capsofungin
- 		FK 463
- 		V- Echinocandin
- 		(LY 303366)
- _	__	__**Polyene**_
- 		Liposomal Nystatin
- _	__	__**Others**_
- 		Nikkomycin 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) inRefractory Aspergillosis

## 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!!!