antifungal management in the haematology patient david w. denning university hospital of south...
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Antifungal management in the haematology patient
David W. DenningUniversity Hospital of South
ManchesterThe University of Manchester
Treatment
Invasive aspergillosis
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
Invasive aspergillosis
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
Why most and not all?
1. Amphotericin B is a broader spectrum agent
Arguments for not using voriconazole
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
Intrinsic and acquired resistance among the Aspergilli
A. nigerA. fumigatus
A. nidulans
Amphotericin B resistance
A. flavusA. terreus
Azole resistance
Species of Aspergillus causing IA
Species 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 8 4
Not speciated
167 16 18
Multiple 28
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
1. Amphotericin B is a broader spectrum agent – No
2. AmBisome is equivalent to voriconazole in IA
Arguments for not using voriconazole
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%
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
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)
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)
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%
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
Denning, CID 2007:45:1106
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
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
Viscoli et al, JAC 2009;64:1274
Survival by day 84 = 33/61 (54%)
33% response rate
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
Nivoix et al, Clin Infect Dis 2008;47:1176
Impact of voriconazole in real life
Voriconazole versus amphotericin B
[Spectrum/activity]
Favours Amp B
Mucorales possible
Azole resistant A. fumigatus
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
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
Arguments for not using voriconazole
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
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
Cerebral aspergillosis and voriconazole (n=81)
Schwartz et al, Blood 2005, Ruhnke personal comunication
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
Resistance in context of invasive aspergillosis
Verweij, NEJM 2007;356:1481
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%
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
Cytochrome P450 interactionsFluc Itra Posa Vori
Inhibitor
2C19 + +++ 2C9 ++ + ++ 3A4 ++ +++ +++ ++Substrate
2C19 +++ 2C9 + 3A4 +++ +
Dodds Ashley & Alexander. Drugs Today 2006;41:393.
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
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
Voriconazole levels in children
Pasqualotto et al, Arch Dis Child 2008;93:578
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
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
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
1
10
100
1000
10,000
100,000
0 70 140 210 280
days after first dose
Log 1
0 [
Conce
ntr
ati
on (
µg/L
)]
Data from Denning et al, Clin Infect Dis 2002;34:563
Possible toxicity
Very small children may metabolise voriconazole very fast and need dose escalation to ?7-
10mg/Kg BID or 200mg BID
Another challenge – immune reconstitution
Miceli, Cancer 2007;110:112; Caillot Eur J Radiol 2010;74:e172
Day 0
Day 7
Rapid neutrophil recovery & invasive aspergillosis
Todeschini et al, Eur J Clin Invest 1999;29:453
= bleeding from the lung and usually death
Immune reconstitution in invasive pulmonary aspergillosis, in AIDS
Patient HB Day +14, CD4 cells 84/uL
Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628
Patient HB Day +42, after AmB and ITZ
Immune reconstitution in invasive pulmonary aspergillosis, in AIDS
Patient HB Day +64, CD4 cells 340/uL, on
VRCSambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628
Patient HB Day +87, day of death
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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