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Discussion and analysis of the major
trials in invasive aspergillosis
David W. Denning
Director, National Aspergillosis Centre
University Hospital of South Manchester
[Wythenshawe Hospital]
The University of Manchester
Myconostica Ltd
Disclosures
Shareholder
F2G
Myconostica
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
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
1.
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
Antifungal susceptibility of
Aspergillus nidulans
Amphotericin B
micafungin
itraconazole
voriconazole
posaconazole
MIC90
4
0.062
2
2
1
ranges (μg/mL)
1–8 (52.3% ≥4)
0.062- 0.125
0.25–4
0.062–2
0.25–1
Peláez et al, ECCMID 2009; P1297
Filamentous fungi and antifungal drug activity
Highly active
Very active
Active
Inactive
Amphotericin B
Caspofungin
Voriconazole
% frequency
Posaconazole
75
5
5 2
1
10
1
1
Arguments for not using voriconazole
1. Amphotericin B is a broader spectrum agent – No
2. 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
} 21%
24
10
42
} 13%
Herbrecht, Denning et al, NEJM 2002;347:408
Survival after primary Rx with Amphotericin B or
Voriconazole
Survival (percent)
100
80
60
40
Voriconazole
Amphotericin B
20
0
0
2
4
6
8
Number of patients at risk
144 131 125 117
111
133 117
99
87
84
Overall logrank test p=0.015
10
12
Weeks
107
80
102 Voriconazole
77 Amphotericin B
Herbrecht, Denning et al, NEJM 2002;347:408
Impact of second line treatment after
voriconazole versus amphotericin B
Initial randomised Rx only
Success (CR+PR)/Total (%)
Voriconazole Ampho B
51/99 (51)
1/26 (4)
Patients who switched Rx
Lipid Ampho B
Itraconazole
Combination
25/52 (48)
5/14 (36)
11/17 (65)
0/1
Reason for switch
Intolerance
8/16 (50)
Insufficient clinical response 5/19 (26)
Chronic suppression
11/14 (79)
Overall success
76/144 (53)
41/107 (38)
14/47 (38)
18/38 (50)
0/9
27/72 (38)
4/21 (19)
6/10 (60)
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
Amphocil
AmB
Success (%) Tox (%)
13
83
15
83
Renal tox (%) Died (due to IA)(%)
23
59 (22)
41
67 (20)
Bowden et al Clin Infect Dis 2002;35:359
Response rates to 2 Ambisome doses in
invasive aspergillosis in neutropenia
100
90
80
Response 70
60
Rate %
Clinical
Radiological
50
Radiological
Clinical
40
30
20
10
0
1mg/kg
4mg/kg
Ellis et al, Clin Infect Dis 1998;27:1046
High-dose liposomal amphotericin B
Maximally tolerated dose study, 7.5 - 15mg/kg daily
44 patients, 21 proven / probable mould infection
MTD >15mg/kg
Responses in MITT, >7d Rx
Response rates (CR/PR)
Failure
7.5
5/7
2/7
10
3/7
1/7
12.5
4/5
1/5
15 mg/kg All (%)
4/12
16/29 (55)
5/12
13/29 (45)
Walsh et al, AAC 2001;45:3487
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
L-AmB 3
CR + PR
50%
Stop Rx
20%
Renal tox
14%
Died
28%
L-AmB 10
46%
32%
31%
41%
Cornely et al, Clin Infect Dis 2007;44:1289
AmBiload trial results
Response
LAmB 3 mg/kg (n = 107)
LAmB 10 mg/kg (n = 94)
Survival
L-AmB 3 mg/kg
L-AmB 10 mg/kg
Overall Response
P = NS
50
40
30
50 %
20
46%
p = 0.089
10
0
End of Treatment
Weeks
Cornely et al, Clin Infect Dis 2007;44:1289
Denning, CID 2007:45:1106
Denning, CID 2007:45:1106
Herbrecht et al, NEJM 2002:347:408
Arguments for not using voriconazole
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
1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA – No
3. 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
1.
2.
3.
4.
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
1.
2.
3.
4.
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)
5. 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
70
Multi-azole resistant
11%
5%
Itraconazole & posaconazole resistant
60
Itraconazole resistant
Fully susceptible
s
Number of patient cases
17%
50
7%
5%
40
3%
0%
30
0%
5%
20
7%
0%
10
0%
0
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
Year
Howard et al, Emerg Infect Dis 2009;15:1068
Manchester azole MIC distributions
250
50
200
200
40
150
100
Number of isolates
250
Number of isolates
Number of isolates
Posaconazole
Voriconazole
Itraconazole
150
100
30
20
50
50
10
0
0
0
?0.015 0.03
0.06 0.125 0.25
0.5
1
2
4
MIC mg/L
Itraconazole
MIC
(mg/L)
8
>8
?0.015 0.03
0.06 0.125 0.25
0.5
1
2
4
8
MIC mg/L
Voriconazole
MIC
(mg/L)
>8
?0.015 0.03 0.06 0.125 0.25
0.5
1
2
4
8
>8
MIC mg/L
Posaconazole
MIC
(mg/L)
modified EUCAST method - 0.5 x 105 not 1-2.5 x 105 cfu/mL
Howard unpublished
Arguments for not using voriconazole
1.
2.
3.
4.
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)
5. The patient might have azole resistant Aspergillus – maybe
6. Major drug interactions
Cytochrome P450 interactions
Fluc
Itra
Posa
Vori
+++
+++
++
++
Inhibitor
2C19
2C9
3A4
+
++
++
+
+++
Substrate
2C19
2C9
3A4
+++
+++
+
+
Dodds Ashley & Alexander. Drugs Today 2006;41:393.
Arguments for not using voriconazole
1.
2.
3.
4.
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)
5. The patient might have azole resistant Aspergillus – maybe
6. Major drug interactions – yes sometimes
7. Renal failure
Arguments for not using voriconazole
1.
2.
3.
4.
5.
6.
7.
8.
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
1.
2.
3.
4.
5.
6.
7.
8.
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)
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
Rapid neutrophil recovery & invasive aspergillosis
Todeschini et al, Eur J Clin Invest 1999;29:453
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
Invasive aspergillosis refractory to
voriconazole
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)
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327