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
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
Species of Aspergillus causing IA
Species
A. fumigatus
Voriconazole
RCT (MITT)
TransNet
(surveillance)
MSG
multicentre
study
85 (77%)
136 (74%)
171 (67%)
A. flavus
7
16
41
A. niger
9
13
14
A. terreus
6
10
8
Other
3
8
4
167
16
18
Not
speciated
Multiple
28
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
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
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
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
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)
Random voriconazole concentrations in
adults receiving 3mg/Kg BID
Log 10 [Concentration (µg/L)]
100,000
Possible toxicity
10,000
1000
100
Very small children may metabolise
voriconazole very fast and need dose
escalation to ?7-10mg/Kg BID or
200mg BID
10
1
0
70
140
210
280
days after first dose
Data from Denning et al, Clin Infect Dis 2002;34:563
Another challenge – immune
reconstitution
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
13 years and counting
Over 2M pages read monthly in >125 countries
Supported by the Fungal Research Trust – 20 year anniversary in 2011