Antifungal management in the haematology patient David W. Denning University Hospital of South Manchester The University of Manchester

Treatment

Invasive aspergillosis IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

Invasive aspergillosis Why most and not all? IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent

Frequency of mucormycosis in leukaemia 391 pts with leukaemia (225 with AML) and a filamentous fungal infection 80% neutropenia for >14 days, and 71% neutropenic at time of diagnosis 85% pulmonary infection Antemortem diagnosis in 79% Aspergillus 296 (76%) Mucorales 45 (11.5%) Fusarium 6 Other 4 Unidentified in 40 Overall mortality in 3 months 74%, 51% attributable Pagano et al, Hemtaologia 2001;86:862

Intrinsic and acquired resistance among the Aspergilli Amphotericin B resistance A. terreus A. nidulans A. flavus Azole resistance A. fumigatus A. niger

Species of Aspergillus causing IA Voriconazole RCT (MITT) TransNet (surveillance) MSG multicentre study A. fumigatus 85 (77%) 136 (74%) 171 (67%) A. flavus 7 16 41 A. niger 9 13 14 A. terreus 6 10 8 Other 3 4 Not speciated 167 18 Multiple 28 8

Filamentous fungi and antifungal drug activity Highly active Very active Scedosporium apiospermum Scedosporium prolificans Paeciilomyces varioti Paeciilomyces lilanicus Active A. fumigatus Fusarium spp A. flavus A. terreus A. nidulans Mucorales Inactive A. niger Amphotericin B Caspofungin Voriconazole 75 5 5 2 1 10 1 1 % frequency Posaconazole

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA

Randomised study of invasive aspergillosis with voriconazole versus amphotericin B 391 pts received either 1) Voriconazole 4 mg/d BID (after loading) for 12wks (or OLAT) or 2) AmB 1.0 mg/kg/d for 12wks (or OLAT) mITT analysis Success (%) Severe AEs (%) Renal tox (%) Died (all) (%) Vori 53 13 1 29 AmB 32 24 10 42 } 21% 13% Herbrecht, Denning et al, NEJM 2002;347:408

Survival after primary Rx with amphotericin B or voriconazole 2 4 6 8 10 12 20 40 60 80 100 Weeks Number of patients at risk 144 131 125 117 111 107 102 Voriconazole 133 117 99 87 84 80 77 Amphotericin B Overall logrank test p = 0.015 Voriconazole Amphotericin B Survival (percent) This is a graph of the survival of pts up to 12 weeks after enrollment. The dotted line of amphotericin shows a poorer survival rate from 3rd week of therapy Herbrecht, Denning et al, NEJM 2002;347:408

Impact of second line treatment after voriconazole versus amphotericin B Success (CR+PR)/Total (%) Voriconazole Ampho B Initial randomised Rx only 51/99 (51) 1/26 (4) Patients who switched Rx 25/52 (48) 41/107 (38) Lipid Ampho B 5/14 (36) 14/47 (38) Itraconazole 11/17 (65) 18/38 (50) Combination 0/1 0/9 Reason for switch Intolerance 8/16 (50) 27/72 (38) Insufficient clinical response 5/19 (26) 4/21 (19) Chronic suppression 11/14 (79) 6/10 (60) Overall success 76/144 (53) 42/133 (32) Patterson et al, Clin Infect Dis 2005;41:1448

Randomised study of invasive aspergillosis with Amphocil versus amphotericin B 174 pts received either 1) Amphocil 6 mg/d for >2wks after symptoms gone or 2) AmB 1.0 – 1.5 mg/kg/d >2wks after symptoms gone 70/174 (40%) in high risk (HSCT, liver Tx, AIDS, brain) ITT analysis Success (%) Tox (%) Renal tox (%) Died (due to IA)(%) Amphocil 13 83 23 59 (22) AmB 15 83 41 67 (20) Bowden et al Clin Infect Dis 2002;35:359

Randomised study of invasive aspergillosis with 2 doses of AmBisome 339 pts randomised to receive either 1) L-AmB 3 mg/d for 2+wks (169 randomised; 107 in MITT) or 2) L-AmB 10 mg/d for 2+wks (162 randomised; 94 in MITT) 44/201 (22%) high risk (HSCT, AIDS) MITT analysis CR + PR Stop Rx Renal tox Died L-AmB 3 50% 20% 14% 28% L-AmB 10 46% 32% 31% 41% Cornely et al, Clin Infect Dis 2007;44:1289

AmBiload trial results Response Weeks L-AmB 3 mg/kg L-AmB 10 mg/kg p = 0.089 Survival LAmB 3 mg/kg (n = 107) LAmB 10 mg/kg (n = 94) P = NS 50 Overall Response 40 30 50 % 46% 20 10 End of Treatment Cornely et al, Clin Infect Dis 2007;44:1289

Denning, CID 2007:45:1106

AmbiLoad study favours Ambisome compared to voriconazole because of better responding patient population, earlier diagnosis and possibly softer response criteria Denning, CID 2007:45:1106

Herbrecht et al, NEJM 2002:347:408

Open study of invasive aspergillosis with caspofungin as primary therapy 61 pts with chemotherapy or auto HSCT received Caspofungin 70 then 50mg IV daily  33% response rate Survival by day 84 = 33/61 (54%) Viscoli et al, JAC 2009;64:1274

Herbrecht at al, New Engl J Med 2002:347:408-15

Open study of invasive aspergillosis with caspofungin as primary therapy 42 pts with allo HSCT , 24 eligible, Rx Caspofungin 70 then 50mg IV /d Unrelated donors in 16 patients; acute or chronic GVHD was present in 15, 12 patients were neutropenic (<500) at baseline, Median duration of caspofungin treatment was 24 days. At EOT, 10 (42%) had complete or partial response, 12 (50%) had progressing disease. At 12 wks, 8 patients (33%) had complete or partial response. Survival rates at week 6 and 12 were 79 and 50%, respectively. Herbrecht et al, BMT 2010; 45:1227

Herbrecht at al, New Engl J Med 2002:347:408-15

Impact of voriconazole in real life Nivoix et al, Clin Infect Dis 2008;47:1176

Voriconazole versus amphotericin B [Spectrum/activity] Favours voriconazole Much more active for IA (~20% better) Active against A. terreus Active against A. nidulans More active A. flavus Active against S. apiospermum Favours Amp B Mucorales possible Azole resistant A. fumigatus

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA – No Patient was on itraconazole prophylaxis

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA – No Patient was on itraconazole prophylaxis

Prophylactic Itraconazole Glasmacher & Prentice J Antimicrob Chemother 2005; 56 (Suppl 1): i23.

Increased AmB MICs after pre-exposure of A. fumigatus to itraconazole Kontoyiannis AAC 2000;44:2915

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA – No Patient was on itraconazole prophylaxis – No The patient has cerebral aspergillosis

Cerebral aspergillosis and voriconazole (n=81) Schwartz et al, Blood 2005, Ruhnke personal comunication

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA – No Patient was on itraconazole prophylaxis – No The patient has cerebral aspergillosis – No (beware interactions) The patient might have azole resistant Aspergillus

Resistance in context of invasive aspergillosis Verweij, NEJM 2007;356:1481

Azole resistance in Manchester in A. fumigatus 11% 17% 7% 5% 0% 3% Howard et al, Emerg Infect Dis 2009;15:1068

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA – No Patient was on itraconazole prophylaxis – No The patient has cerebral aspergillosis – No (beware interactions) The patient might have azole resistant Aspergillus – maybe Major drug interactions

Cytochrome P450 interactions Fluc Itra Posa Vori Inhibitor 2C19 + +++ 2C9 ++ 3A4 Substrate Dodds Ashley & Alexander. Drugs Today 2006;41:393.

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA – No Patient was on itraconazole prophylaxis – No The patient has cerebral aspergillosis – No (beware interactions) The patient might have azole resistant Aspergillus – maybe Major drug interactions – yes sometimes Renal failure

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA – No Patient was on itraconazole prophylaxis – No The patient has cerebral aspergillosis – No (beware interactions) The patient might have azole resistant Aspergillus – maybe Major drug interactions – yes sometimes Renal failure – only IV therapy needed for any duration My patient is a young child and I am worried about blood levels

Voriconazole levels in children Pasqualotto et al, Arch Dis Child 2008;93:578

Combination therapy – invasive aspergillosis Retrospective AmB failures Most HSCT 30/47 proven IA Multivariate analysis P=0.008 for combination and survival Marr et al, Clin Infect Dis 2004:39:797

Arguments for not using voriconazole Amphotericin B is a broader spectrum agent – No AmBisome is equivalent to voriconazole in IA – No Patient was on itraconazole prophylaxis – No The patient has cerebral aspergillosis – No (beware interactions) The patient might have azole resistant Aspergillus – maybe Major drug interactions – yes sometimes Renal failure – only IV therapy needed for any duration My patient is a young child and I am worried about blood levels – yes use 7mg/Kg BD (200mg BD orally) and consider combination therapy with an echinocandin and measure levels

Choice of antifungal for aspergillosis Priority sequence Voriconazole (unless drug interaction) AmBisome 3mg/Kg (if not ‘nephro-critical’) OR caspofungin/micafungin (if not neutropenic) 3. Posaconazole (oral only, if no drug interactions) 4. Itraconazole

When not to use voriconazole as primary therapy? Absolute contraindications Drug interactions (ie rifampicin, carbamazepine, phenytoin etc) Voriconazole used as prophylaxis (but not itraconazole or posaconazole) Resistance to voriconazole (esp zygomycosis, A. lentulus or azole resistance) Relative contraindications Renal failure (IV only) Young children (need higher dose ?+ other agent) Severe hepatic dysfunction Interacting drugs (ie sirolimus)

Random voriconazole concentrations in adults receiving 3mg/Kg BID 100,000 Possible toxicity 10,000 1000 Log 10 [Concentration (µg/L)] Very small children may metabolise voriconazole very fast and need dose escalation to ?7-10mg/Kg BID or 200mg BID 100 10 1 70 140 210 280 days after first dose Data from Denning et al, Clin Infect Dis 2002;34:563

Another challenge – immune reconstitution 45

Day 0 Day 7 Miceli, Cancer 2007;110:112; Caillot Eur J Radiol 2010;74:e172

Rapid neutrophil recovery & invasive aspergillosis = bleeding from the lung and usually death Todeschini et al, Eur J Clin Invest 1999;29:453

Immune reconstitution in invasive pulmonary aspergillosis, in AIDS Patient HB Day +14, CD4 cells 84/uL Patient HB Day +42, after AmB and ITZ Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628

Immune reconstitution in invasive pulmonary aspergillosis, in AIDS Patient HB Day +64, CD4 cells 340/uL, on VRC Patient HB Day +87, day of death Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628

Conclusions Voriconazole is the treatment of choice for invasive aspergillosis For those with toxicity, significant drug interactions or azole resistance, an echinocandin or lipid AmB is appropriate Current treatments are partially successful but more oral therapies are needed Immune reconstitution poorly understood, but probably important Opportunities for immune therapies going forward

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