discussion and analysis of the major trials in invasive aspergillosis david w. denning director,...
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![Page 1: Discussion and analysis of the major trials in invasive aspergillosis David W. Denning Director, National Aspergillosis Centre University Hospital of South](https://reader035.vdocument.in/reader035/viewer/2022070305/5513e46655034674748b55e1/html5/thumbnails/1.jpg)
Discussion and analysis of the major trials in invasive
aspergillosis
David W. DenningDirector, National Aspergillosis Centre
University Hospital of South Manchester [Wythenshawe Hospital]
The University of ManchesterMyconostica Ltd
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Disclosures
Shareholder F2GMyconostica
Consultant (last 5 years)
Basilea, Vicuron (now Pfizer), Pfizer, Schering Plough, Indevus, F2G, Nektar, Daiichi, Sigma Tau, Astellas, Gilead and York Pharma
Research grant (last 5 years)
Astellas, Merck, Pfizer, F2G, OrthoBiotech, Indevus, Basilea, AstraZeneca, the Fungal Research Trust, the Wellcome Trust, the Moulton Trust, the Medical Research Council, the Chronic Granulomatous Disease Research Trust, the National Institute of Allergy and Infectious Diseases, NIHR, and the European Union
Speaker’s bureau
Schering Plough, Astellas, Merck, GSK, Myconostica Dianippon and Pfizer
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Invasive aspergillosis
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
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Invasive aspergillosis
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
Why most and not all?
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1. Amphotericin B is a broader spectrum agent
Arguments for not using voriconazole
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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 infectionAntemortem diagnosis in 79%
Aspergillus 296 (76%)Mucorales 45 (11.5%)Fusarium 6Other 4Unidentified in 40
Overall mortality in 3 months 74%, 51% attributable
Pagano et al, Hemtaologia 2001;86:862
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Intrinsic and acquired resistance among the Aspergilli
A. nigerA. fumigatus
A. nidulans
Amphotericin B resistance
A. flavusA. terreus
Azole resistance
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Antifungal susceptibility of Aspergillus nidulans
MIC90 ranges (μg/mL)Amphotericin B 4 1–8 (52.3% ≥4)micafungin 0.062 0.062- 0.125itraconazole 2 0.25–4 voriconazole 2 0.062–2 posaconazole 1 0.25–1
Peláez et al, ECCMID 2009; P1297
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Amphotericin B
Filamentous fungi and antifungal drug activity
Active
Very activeHighly active
InactiveA. f
umig
atus
A. flav
us
A. nig
er
Muc
oral
es
Sced
ospo
rium
api
ospe
rmum
A. ter
reus
A. nid
ulan
s
Sced
ospo
rium
pro
lifica
ns
Fusa
rium
spp
Paec
iilom
yces
var
ioti
Paec
iilom
yces
lilani
cus
Voriconazole
Posaconazole
Caspofungin
75 5 5 2 1 10 1 1% frequency
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA
Arguments for not using voriconazole
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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)
Herbrecht, Denning et al, NEJM 2002;347:408
mITT analysis Success (%) Severe AEs (%) Renal tox (%) Died (all) (%)
Vori 53 13 1 29
AmB 32 24 10 42 }21% }13%
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Survival after primary Rx with Amphotericin B or Voriconazole
0 2 4 6 8 10 120
20
40
60
80
100
WeeksNumber of patients at risk144 131 125 117 111 107 102 Voriconazole133 117 99 87 84 80 77 Amphotericin BOverall logrank test p = 0.015
Voriconazole Amphotericin BS
urvi
val (
perc
ent)
Herbrecht, Denning et al, NEJM 2002;347:408
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Impact of second line treatment after voriconazole versus amphotericin B
Patterson et al, Clin Infect Dis 2005;41:1448
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 switchIntolerance 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)
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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
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Response rates to 2 Ambisome doses in invasive aspergillosis in neutropenia
ClinicalRadiological
ClinicalRadiological
Response
Rate %
1mg/kg 4mg/kg
60
50
80
10
70
20
40
30
0
100
90
Ellis et al, Clin Infect Dis 1998;27:1046
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Maximally tolerated dose study, 7.5 - 15mg/kg daily44 patients, 21 proven / probable mould infection
MTD >15mg/kg
Responses in MITT, >7d Rx 7.5 10 12.5 15 mg/kg All
(%)Response rates (CR/PR) 5/7 3/7 4/5 4/12 16/29
(55)Failure 2/7 1/7 1/5 5/12 13/29
(45)
High-dose liposomal amphotericin B
Walsh et al, AAC 2001;45:3487
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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)
Cornely et al, Clin Infect Dis 2007;44:1289
MITT analysis CR + PR Stop Rx Renal tox Died
L-AmB 3 50% 20% 14% 28%
L-AmB 10 46% 32% 31% 41%
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AmBiload trial results
Cornely et al, Clin Infect Dis 2007;44:1289
LAmB 10 mg/kg (n = 94)
LAmB 3 mg/kg (n = 107)
P = NS
0
10
20
30
40
50
Ov
era
ll R
esp
on
se
50 % 46%
End of Treatment
Response
Weeks
L-AmB 3 mg/kg
L-AmB 10 mg/kg
p = 0.089
Survival
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Denning, CID 2007:45:1106
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Denning, CID 2007:45:1106
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Herbrecht et al, NEJM 2002:347:408
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. Patient was on itraconazole prophylaxis
Arguments for not using voriconazole
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. Patient was on itraconazole prophylaxis
Arguments for not using voriconazole
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Prophylactic Itraconazole
Glasmacher & Prentice J Antimicrob Chemother 2005; 56 (Suppl 1): i23.
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Increased AmB MICs after pre-exposure of A. fumigatus to itraconazole
Kontoyiannis AAC 2000;44:2915
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. Patient was on itraconazole prophylaxis – No
4. The patient has cerebral aspergillosis
Arguments for not using voriconazole
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Cerebral aspergillosis and voriconazole (n=81)
Schwartz et al, Blood 2005, Ruhnke personal comunication
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. Patient was on itraconazole prophylaxis – No
4. The patient has cerebral aspergillosis – No (beware interactions)
5. The patient might have azole resistant Aspergillus
Arguments for not using voriconazole
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Resistance in context of invasive aspergillosis
Verweij, NEJM 2007;356:1481
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Azole resistance in Manchester in A. fumigatus
Howard et al, Emerg Infect Dis 2009;15:1068
11%
17%
7%
5%
5%
0%
0%
5%
3%
7%
0%0%
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Manchester azole MIC distributions
Howard unpublished
0
50
100
150
200
250
?0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 8 >8
Numb
er of
isolat
es
Itraconazole MIC (mg/L)
0
50
100
150
200
250
?0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 8 >8
MIC mg/L
Numb
er of
isolat
es
Voriconazole MIC (mg/L)
0
10
20
30
40
50
?0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 8 >8
Numb
er of
isolat
es
Posaconazole MIC (mg/L)
modified EUCAST method - 0.5 x 105 not 1-2.5 x 105 cfu/mL
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. Patient was on itraconazole prophylaxis – No
4. The patient has cerebral aspergillosis – No (beware interactions)
5. The patient might have azole resistant Aspergillus – maybe
6. Major drug interactions
Arguments for not using voriconazole
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Cytochrome P450 interactionsFluc Itra Posa Vori
Inhibitor
2C19 + +++ 2C9 ++ + ++ 3A4 ++ +++ +++ ++Substrate
2C19 +++ 2C9 + 3A4 +++ +
Dodds Ashley & Alexander. Drugs Today 2006;41:393.
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. Patient was on itraconazole prophylaxis – No
4. The patient has cerebral aspergillosis – No (beware interactions)
5. The patient might have azole resistant Aspergillus – maybe
6. Major drug interactions – yes sometimes
7. Renal failure
Arguments for not using voriconazole
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. Patient was on itraconazole prophylaxis – No
4. The patient has cerebral aspergillosis – No (beware interactions)
5. The patient might have azole resistant Aspergillus – maybe
6. Major drug interactions – yes sometimes
7. Renal failure – only IV therapy needed for any duration
8. My patient is a young child and I am worried about blood levels
Arguments for not using voriconazole
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Voriconazole levels in children
Pasqualotto et al, Arch Dis Child 2008;93:578
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Combination therapy – invasive aspergillosis
Marr et al, Clin Infect Dis 2004:39:797
RetrospectiveAmB failuresMost HSCT30/47 proven IA
Multivariate analysisP=0.008 for combination and survival
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1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. Patient was on itraconazole prophylaxis – No
4. The patient has cerebral aspergillosis – No (beware interactions)
5. The patient might have azole resistant Aspergillus – maybe
6. Major drug interactions – yes sometimes
7. Renal failure – only IV therapy needed for any duration
8. 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
Arguments for not using voriconazole
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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
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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)
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Aspects of good care - aspergillosis
1. Start treatment as fast as possible, with voriconazole, if no contra-indications
2. If sinus, centrally located pulmonary, endocarditis, brain abscess or osteomyelitis, plan on surgery
3. Resolve neutropenia, if present, but don’t over correct
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Rapid neutrophil recovery & invasive aspergillosis
Todeschini et al, Eur J Clin Invest 1999;29:453
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Aspects of good care - aspergillosis
1. Start treatment as fast as possible, with voriconazole, if no contra-indications
2. If sinus, centrally located pulmonary, endocarditis, brain abscess or osteomyelitis, plan on surgery
3. Resolve neutropenia, if present, but don’t over correct
4. Reduce steroids and other immunosuppressants as much as possible
5. Check voriconazole levels
6. If culture positive, arrange species ID and MICs
7. Repeat CT scan (and GM) at ~2 weeks if rapidly progressive disease and at ~4 weeks of subacute disease
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Invasive aspergillosis refractory to voriconazole
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
Check plasma voriconazole levels and MICs
If neutropenic• Amphotericin B/AmBisome or posaconazole
preferred
If not neutropenic• Echinocandin or • Posaconazole or• AmBisome 3mg/Kg (3rd choice)
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