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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