Discussion and analysis of the major trials in invasive aspergillosis David W. Denning Director, National Aspergillosis Centre University Hospital of South

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

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

Invasive aspergillosis

IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

Invasive aspergillosis


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

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

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


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

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

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

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

Herbrecht et al, NEJM 2002:347:408


2. AmBisome is equivalent to voriconazole in IA – No

3. Patient was on itraconazole prophylaxis




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



3. Patient was on itraconazole prophylaxis – No

4. The patient has cerebral aspergillosis


Cerebral aspergillosis and voriconazole (n=81)

Schwartz et al, Blood 2005, Ruhnke personal comunication




4. 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

Howard et al, Emerg Infect Dis 2009;15:1068

11%

17%

7%

5%

5%

0%

0%

5%

3%

7%

0%0%

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





5. The patient might have azole resistant Aspergillus – maybe

6. Major drug interactions


Cytochrome P450 interactionsFluc Itra Posa Vori

Inhibitor

2C19 + +++ 2C9 ++ + ++ 3A4 ++ +++ +++ ++Substrate

2C19 +++ 2C9 + 3A4 +++ +

Dodds Ashley & Alexander. Drugs Today 2006;41:393.






6. Major drug interactions – yes sometimes

7. Renal failure








7. Renal failure – only IV therapy needed for any duration

8. 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

Marr et al, Clin Infect Dis 2004:39:797

RetrospectiveAmB failuresMost HSCT30/47 proven IA

Multivariate analysisP=0.008 for combination and survival







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


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)

Documents

Discussion and analysis of the major trials in invasive aspergillosis David W. Denning Director, National Aspergillosis Centre University Hospital of South