Selection of an optimal Selection of an optimal antifungal for treatment of antifungal for treatment of tif tif l f l f t t t t t t f f invasive aspergillosis: invasive aspergillosis: invasive aspergillosis invasive aspergillosis : susceptibility/resistance, adverse reactions, susceptibility/resistance, adverse reactions, drug interactions drug interactions drug interactions drug interactions John Bennett M D John Bennett M D John Bennett, M.D. John Bennett, M.D.
Disclosures Disclosures � No disclosures to report � No disclosures to report
Choices for aspergillosis Choices for aspergillosis Choices for aspergillosis Choices for aspergillosis Polyene Polyene: liposomal ( Polyene Polyene: liposomal ( : liposomal (AmBisome : liposomal (AmBisome AmBisome), lipid AmBisome) lipid ), lipid ) lipid complex (ABLC) complex (ABLC) Intravenous or oral Intravenous or oral azole Intravenous or oral Intravenous or oral azole azole: Voriconazole azole: : Voriconazole Voriconazole Voriconazole, , Isavuconazole Isavuconazole Intravenous I t I t Intravenous echinocandin echinocandin: hi hi di di : caspofungin caspofungin, f f i i , micafungin micafungin? ? Oral only Oral only azole azole: : posaconazole posaconazole, , itraconazole itraconazole
Issues in drug choice Issues in drug choice Issues in drug choice Issues in drug choice � Can the patient take oral alimentation? � Can the patient take oral alimentation? Can the patient take oral alimentation? Can the patient take oral alimentation? � How urgent is the need for Rx? How urgent is the need for Rx? � Is the Aspergillus species known? I th I th Is the Aspergillus species known? A A ill ill i i k k ? ? � Are drug interactions manageable? Are drug interactions manageable? � How tenuous is the patient’s renal How tenuous is the patient’s renal function? function? � How certain do we need to be that the How certain do we need to be that the drug is effective? drug is effective? drug is effective? drug is effective?
Oral alimentation Oral alimentation Oral alimentation Oral alimentation � Posaconazole levels up 2.6 fold with nonfat Posaconazole levels up 2.6 fold with nonfat p food; 4 fold up with fatty meal food; 4 fold up with fatty meal � Response improved with higher level Response improved with higher level � Quartile � Quartile Quartile Quartile C av Improved with posa C av Improved with posa C av C av Improved with posa Improved with posa of blood level (ng/ml) of blood level (ng/ml) 1 1 124 124 124 124 24% (4/17) 24% (4/17) 24% (4/17) 24% (4/17) 2 411 411 53% (9/17) 53% (9/17) 3 719 719 53% (9/17) 53% (9/17) 4 1250 1250 75% (12/16) 75% (12/16) � Walsh, CID 2007:44:2 Walsh, CID 2007:44:2- -12 12
Urgency: time to steady state Urgency: time to steady state Urgency: time to steady state Urgency: time to steady state � Posaconazole: 5 � Posaconazole: 5 Posaconazole: 5-7 days to steady state Posaconazole: 5 7 days to steady state. 7 days to steady state 7 days to steady state. Loading not possible. Loading not possible. � Itraconazole: IV no longer available Oral � Itraconazole: IV no longer available. Oral Itraconazole: IV no longer available Oral Itraconazole: IV no longer available. Oral loading over 3 days. loading over 3 days. � Voriconazole, echinocandins, ampho B: V Voriconazole, echinocandins, ampho B: V i i l l hi hi di di h h B B loading in 24 hrs or less loading in 24 hrs or less
Ampho B resistance in Ampho B resistance in A A Aspergillus terreus Aspergillus terreus ill ill � 3- -5% isolates are 5% isolates are A. terreus % A. terreus � Walsh JID 2003: Exp infection response to Walsh JID 2003: Exp infection response to ampho poor ampho poor � Steinbach, AAC 2004: Am B MIC 4X higher Steinbach, AAC 2004: Am B MIC 4X higher � Hachem, Cancer 2004: 28% response to ampho Hachem, Cancer 2004: 28% response to ampho with A. terreus with ith ith A t A t A. terreus , 39% with , 39% with A. fumigatus 39% 39% ith ith A f A. fumigatus A f i i t t � Lass Lass- -Fl Flö örl, Brit J Hem 2005: compared 32 pts rl, Brit J Hem 2005: compared 32 pts with with A. terreus with A terreus with A terreus vs 35 with other Asp species: A. terreus vs 35 with other Asp species: vs 35 with other Asp species: vs 35 with other Asp species: Infection more often disseminated (63% vs 32%) Infection more often disseminated (63% vs 32%) and poorer response to ampho 21% vs 46% and poorer response to ampho 21% vs 46%
DRUG DRUG DRUG DRUG INTERACTIONS DRUG-DRUG INTERACTIONS DRUG INTERACTIONS DRUG INTERACTIONS � Voriconazole has many interactions, � Voriconazole has many interactions, Voriconazole has many interactions, Voriconazole has many interactions, posaconazole slightly less posaconazole slightly less � Blood levels of many drugs increased Blood levels of many drugs increased y y g g � Azole levels down with rifampin, rifabutin, Azole levels down with rifampin, rifabutin, efavirenz, Tegretol, phenytoin, other efavirenz, Tegretol, phenytoin, other � Echinocandin interactions with other drugs Echinocandin interactions with other drugs not significant though caspo levels down not significant though caspo levels down 30% with rifampin 30% with rifampin
Renal function and antifungals Renal function and antifungals Renal function and antifungals Renal function and antifungals � Liposomal ampho less nephrotoxic than � Liposomal ampho less nephrotoxic than Liposomal ampho less nephrotoxic than Liposomal ampho less nephrotoxic than ABLC; both less toxic than conv. Am B. ABLC; both less toxic than conv. Am B. Saline loading decreases nephrotoxicity Saline loading decreases nephrotoxicity Saline loading decreases nephrotoxicity Saline loading decreases nephrotoxicity � IV vori excipient (sulfobutyl cylodextrin) IV vori excipient (sulfobutyl cylodextrin) accumulates may not be toxic accumulates may not be toxic accumulates, may not be toxic. accumulates, may not be toxic. � No adjustment for oral vori, caspofungin, No adjustment for oral vori, caspofungin, micafungin micafungin i i f f i i
Effi Effi Efficacy in Rx of Efficacy in Rx of i i R R f f Aspergillosis Aspergillosis � Initial Rx: voriconazole, ampho Initial Rx: voriconazole, ampho p formulations approved formulations approved � Salvage Rx Salvage Rx � Caspofungin Caspofungin Caspofungin Caspofungin � Posaconazole (Europe) Posaconazole (Europe)
Micafungin or Caspofungin in Salvage Therapy of Invasive Aspergillosis Complete or Partial Complete or Partial Micafungin Micafungin Caspofungin Caspofungin Response to Response to > >1 dose 1 dose Primary Therapy Primary Therapy 6/12 (50%) 6/12 (50%) N/A N/A Salvage Therapy Salvage Therapy Intolerant Intolerant 3/4 (75%) 3/4 (75%) 9/12 (75%) 9/12 (75%) Failure Failure Failure Failure 6/18 (33%) 6/18 (33%) 6/18 (33%) 6/18 (33%) 28/59 (47%) 28/59 (47%) 28/59 (47%) 28/59 (47%) Issues: Micafungin dose 75-225 mg. What is intolerant? How long was the failing drug given? How long was the failing drug given? Denning et al. J Infect. 2006; Maertens et al. Denning et al. J Infect. 2006; Maertens et al. Clin Infect Dis Clin Infect Dis . 2004; 39: 1563 . 2004; 39: 1563- -71. 71.
What about combination therapy? What about combination therapy? What about combination therapy? What about combination therapy? � Synergy � Synergy Synergy in vitro Synergy in vitro in vitro unimpressive in vitro unimpressive unimpressive unimpressive � Experimental animal infections show slight E E Experimental animal infections show slight i i t l t l i i l i f l i f ti ti h h li ht li ht advantage with combination over advantage with combination over i di id i di id individual drugs if doses are low individual drugs if doses are low l d l d if d if d l l � Clinical data on combinations are not Clinical data on combinations are not convincing convincing
COMBINATION THERAPY COMBINATION THERAPY Ch Ch Chart reviews of voriconazole +caspofungin Chart reviews of voriconazole +caspofungin t t i i f f i i l l f f i i for invasive aspergillosis at the Fred for invasive aspergillosis at the Fred Hutchinson Cancer Research Center Hutchinson Cancer Research Center H t hi H t hi C C R R h C h C t t � Salvage Rx: V+C in 16 pts had better 3 mos Salvage Rx: V+C in 16 pts had better 3 mos survival than earlier (1997 survival than earlier (1997- -2001) group of 31 pts 2001) group of 31 pts with V alone. Marr CID 2004; 39:797 with V alone. Marr CID 2004; 39:797 � Initial Rx: 90 day survival in I.A. improved from Initial Rx: 90 day survival in I.A. improved from ca. 28% to ca 45% between 1996 ca. 28% to ca 45% between 1996-2004. No ca. 28% to ca 45% between 1996 ca. 28% to ca 45% between 1996 2004. No 2004. No 2004. No survival advantage for V+C as initial Rx. Upton survival advantage for V+C as initial Rx. Upton CID 2007;44:531 CID 2007;44:531
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