Transcript Clinical failure and its management

Clinical failure and its management
David W. Denning
Director, National Aspergillosis Centre
University Hospital South Manchester
[Wythenshawe Hospital]
The University of Manchester
Problems with antifungal therapy
1. Drug toxicity
2. Drug interactions and low blood levels
Drug toxicities
Common reasons for stopping therapies
Itraconazole
Nausea
Ankle swelling
Peripheral neuropathy
Fatigue
Voriconazole
Feeling ill
Confusion/hallucinations/poor concentration
Photosensitivity
Itraconazole
concentrations
in phase 2
studies
Denning et al, Am J Med 1994;97:135
Itraconazole concentrations in relation
to timing of samples
Tucker et al, J Am Acad Dermatol 1990;23:593-601
Optimising itraconazole levels – aim
between 5 and 17 mg/L
Lestner et al, Clin Infect Dis 2009; 49:928
Itraconazole for ABPA in CF
Itraconazole often
poorly absorbed and
variable penetration
into CF sputum
Sermet-Gaudelus, Antimicrob Ag Chemother 2001;45:1937.
Generic itraconazole (Sandoz)
Pasqualotto, Int J Antimicrob Ag 2007; 30:93
Approval of itraconazole by the
FDA and Europe in 1991
Voriconazole - metabolism
98% metabolised by liver
Primarily metabolised by CYP2C19 and CYP3A4, less
by CYP2C9.
Cirrhosis / prior alcohol abuse and elderly likely
predictors of slow metabolisers. Also genetic
polymorphism of CYP2C19.
Low levels likely in children, oral therapy and
unpredictable.
Usual dosing 150 – 300mg twice daily
Voriconazole datasheet
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
Voriconazole levels in children
Pasqualotto et al, Arch Dis Child 2008;93:578
Cytochrome P450 interactions
Fluc
Itra
Posa
Vori
+++
+++
++
++
Inhibitor
2C19
2C9
3A4
+
++
++
+
+++
Substrate
2C19
2C9
3A4
+++
+++
+
+
Dodds Ashley & Alexander. Drugs Today 2006;41:393.
New section on drug interactions which you can search very quickly
Problems with antifungal therapy
1. Drug toxicity
2. Drug interactions and low blood levels
3. Azole resistance, intrinsic and acquired
Chronic cavitary pulmonary aspergillosis
(CCPA) in HIV February 2005
32 yr old from Malawi, on HAART Rx
- haemoptysis
- Aspergillus precipitin titre 1/16
CT scan shows 2 large cavities with aspergillomas,
with additional lesions (October 2005)
Surgical
removal would
require a
pneumonectomy
So treated with
itraconazole
CCPA in HIV
February 2007
On HAART Rx, with low viral load, CD4 count >200
- New haemoptysis
- Aspergillus precipitin titre 1/32
MICs A. fumigatus Feb 2007
CXR & CT scan showed expansion
of inferior
cavity
Itraconazole
= >8.0mg/mL
Voriconazole = 0.5 mg/mL
Posaconazole = 1.0 mg/mL
February 2007
April 2007
CCPA in HIV - low itraconazole concentrations
Itraconazole concentrations
Nov 05
2.5 mg/L
Dec 05
3.4 mg/L
March 06
4.5 mg/L
July 06
6.7 mg/L
Feb 07
8.4 mg/L
Do low concentrations of antifungal
predispose to the development of resistance?
AF72
AF91
Test
inoculum
2x106/mL
microtitre,
RPMI 2%
glucose
35°C
48 hrs
Denning et al, JAC 1997;40:401
confirmation in vivo
AmB 5mg/Kg
AmB 5mg/Kg
Itra 75mg/Kg
Itra 75mg/Kg
Itra 25mg/Kg
controls
Strain 5 (AF 72)
G54 CYP51A mutation
Strain 6 (AF 91)
M220 CYP51A mutation
Denning et al, JAC 1997;40:401
Development of international standards
for susceptibility testing and breakpoints
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
MIC mg/L
Posaconazole
MIC
(mg/L)
modified EUCAST method - 0.5 x 105 not 1-2.5 x 105 cfu/mL
>8
Azole resistance in A. fumigatus in
Manchester 1997-2009
100
Multi-azole resistant
20%
Itraconazole & posaconazole resistant
90
Voriconazole resistant
Itraconazole resistant
80
Number of patient cases
Fully susceptible
70
14%
5%
60
17%
50
7%
5%
3%
40
0%
30
0%
5%
7%
20
0%
0%
1997
1998
10
0
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
Year
Bueid, J Antimicrob Chemother 2010;65:2116. Howard et al, EID 2009; 15:1068
Clinical features of patients with
azole resistant A. fumigatus
17 patients, 15 from UK, different cities
9 had CCPA, all with aspergilloma
3 had sputum isolate, with no treatment data
2 had ABPA
2 had IA
1 had Aspergillus bronchitis
13 of 14 patients had prior azole exposure
8 failed therapy and 5 failed to improve
(12 itraconazole, 1 voriconazole)
Howard et al, EID 2009; 15:1068
http://www.hpa-standardmethods.org.uk/documents/bsop/pdf/bsop57.pdf
Molecular detection of Aspergillus spp.
in sputum
Laboratory result
Culture positive for A. fumigatus
qPCR positive for Aspergillus spp
ABPA
CPA
Normals
0/19
7/42
(16.7%)
0/11
15/19
(78.9%)
30/42
(71.4%)
4/11
(36.4%)
Denning et al. Clin Infect Dis 2011;
CF and Aspergillus cultures
Pre-sonication
Post-sonication
Baxter, unpublished
Routine culture cfu versus qPCR for Aspergillus
Sputum and BAL
Sample
BL
AC
PC
VC
culture
qPCR
culture
qPCR
culture
qPCR
culture
qPCR
Sputum before
8
32.8
1
32.8
2
33.6
0
34.8
Ist trap
33
28.9
0
37.8
2
36.9
0
33.4
Ist wash (520mL)
0
38
0
30.3
0
33.5
2
33.5
BAL (10-70 mL)
0
37.2
0
32.8
0
33.1
12
34
LLL trap
1
32.7
RML BAL
0
neg
RUL BAL 10mL
0
33.4
RLL (120mL)
0
31.2
0
31.4
LLL BAL
Sputum after
3
32.2
0
29.6
0
34.9
culture
JO
1
qPCR
34.6
E. dermatiditis
Kirwan, AAA 2012 Abstract
Direct detection of resistance
mutations in clinical specimens, without
positive cultures
Laboratory result
ABPA
CPA
Normals
Culture positive for A. fumigatus
0/19
7/42 (16.7%)
0/11
15/19
(78.9%)
30/42
(71.4%)
4/11
(36.4%)
qPCR positive for Aspergillus spp
A. fumigatus CYP51A mutation
detected directly from qPCR
positive sample
6/8 (75%) 12/24 (50%)
NT
Denning, Clin Infect Dis 2011;52:1123
Problems with antifungal therapy
1. Drug toxicity
2. Drug interactions and low blood levels
3. Azole resistance, intrinsic and acquired
4. Antifungal failure (without resistance/low
azole blood levels etc)
5. Immune reconstitution or other ‘switching’ of
immune response
Aspergillomas in CF
Turcios – www.aspergillus.ac.uk
Felton, Clin Infect Dis 2010; 51:1383.
Second and third line antifungal
therapy for ABPA and/or asthma
• 26 patients, ABPA (n = 21) or SAFS (n = 5).
• All patients had failed itraconazole (n=14) or developed
adverse events (n=12)
Chishimba et al, J Asthma . In press
Second and third line antifungal
therapy for ABPA and/or asthma
• 26 patients, ABPA (n = 21) or SAFS (n = 5).
• All patients had failed itraconazole (n=14) or developed adverse events
(AEs) (n=12)
• 34 courses of therapy, 25 with voriconazole and 9 with posaconazole.
• Voriconazole responses: 17/25 (68%) at 3 months, 15/20 (75%) at 6
months and 12/16 (75%) at 12 months,
• Posaconazole responses: 7/9 (78%) at 3, 6 and 12 months for
posaconazole.
• 18/24 (75%) discontinued oral corticosteroids, 12 of them within 3 months
of starting antifungal therapy.
• 6/23 (26%) patients on voriconazole had AEs requiring discontinuation
before 6 months compared to none on posaconazole (p=0.15).
• 4 relapsed (57%), 1 at 3 months and 3 at 12 months after
discontinuation.
Chishimba et al, J Asthma . In press
Inhaled amphotericin B
Dose and reconstitution
• Dose can be increased in 5mg/1ml
stages up to 20mg/4mls twice a
day or a maximum daily treatment
dosage of 1mg/kg
• Reconstitution:
– 10ml water for injection added
to 50mg yellow powder (5mg per
ml)
– (2ml therefore yields 10mg
dose)
– Consider residual volume of
nebuliser!
Compressors
• Need servicing regularly!
• To drive most nebulisers an output of at
least 8 L/m is required
The Pari LC plus with exhaust filter
Features:
• Fill volume 2ml-8ml
• Delivers approx 65%
respirable dose
• Can go through the
dishwasher
• Can survive boiling in
water
Nebuliser
chamber
Comparison of Pari LC versus other nebulisers
Another challenge – immune
reconstitution
Day 0
Day 7
Miceli, Cancer 2007;110:112; Caillot Eur J Radiol 2010;74:e172
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
Several patients have increasing
breathlessness with antifungal therapy
Documented fall in DLCO in one patient
Deaths in others.
Mechanism unclear.
Likely benefit from steroids, needs
good antifungal cover.
Interferon gamma replacement
Both patients improved with γIFN
Kelleher, Eur Resp J 2006;27:1307
CPA treatment – IFN gamma?
Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80.
Management approach
1. Exclude low blood levels – be careful of large
dose increases with voriconazole
2. Fungal cultures – test for resistance
3. Exclude or treat bacterial co-infection
4. Use IV therapy if patient very ill
5. Consider surgical resection, gamma IFN,
inhaled AmB (if ABPA/SAFS),
6. Long term IV therapy for CPA feasible and
partially effective.