clinical failure and its management david w. denning director, national aspergillosis centre...
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Clinical failure and its management
David W. DenningDirector, National Aspergillosis CentreUniversity Hospital South Manchester
[Wythenshawe Hospital]The University of Manchester
Problems with antifungal therapy
1. Drug toxicity
2. Drug interactions and low blood levels
ItraconazoleNauseaAnkle swellingPeripheral neuropathyFatigue
VoriconazoleFeeling illConfusion/hallucinations/poor concentrationPhotosensitivity
Drug toxicitiesCommon reasons for stopping therapies
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
Sermet-Gaudelus, Antimicrob Ag Chemother 2001;45:1937.
Itraconazole often poorly absorbed and variable penetration
into CF sputum
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 liverPrimarily 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
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
Voriconazole levels in children
Pasqualotto et al, Arch Dis Child 2008;93:578
Cytochrome P450 interactionsFluc 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
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)
Chronic cavitary pulmonary aspergillosis (CCPA) in HIV February 2005
Surgical removal would require a pneumonectomySo treated with itraconazole
On HAART Rx, with low viral load, CD4 count >200- New haemoptysis- Aspergillus precipitin titre 1/32
CXR & CT scan showed expansion of inferior cavity
CCPA in HIV February 2007
February 2007 April 2007
MICs A. fumigatus Feb 2007Itraconazole = >8.0mg/mLVoriconazole = 0.5 mg/mLPosaconazole = 1.0 mg/mL
Itraconazole concentrationsNov 05 2.5 mg/LDec 05 3.4 mg/LMarch 06 4.5 mg/LJuly 06 6.7 mg/LFeb 07 8.4 mg/L
CCPA in HIV - low itraconazole concentrations
Do low concentrations of antifungal predispose to the development of
resistance?
microtitre,
RPMI 2% glucose
35°C 48 hrs
2x106/mL
Test inoculum
AF72 AF91
Denning et al, JAC 1997;40:401
confirmation in vivo
Denning et al, JAC 1997;40:401
Strain 5 (AF 72)G54 CYP51A mutation
Strain 6 (AF 91)M220 CYP51A mutation
controls
Itra 25mg/Kg
Itra 75mg/Kg
AmB 5mg/Kg
Itra 75mg/Kg
AmB 5mg/Kg
Development of international standards for susceptibility testing and
breakpoints
Manchester azole MIC distributions
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
Azole resistance in A. fumigatus in Manchester 1997-2009
Bueid, J Antimicrob Chemother 2010;65:2116. Howard et al, EID 2009; 15:1068
0
10
20
30
40
50
60
70
80
90
100
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year
Num
ber
of
pat
ien
t ca
ses
Multi-azole resistant
Itraconazole & posaconazole resistant
Voriconazole resistant
Itraconazole resistant
Fully susceptible
0% 0%7%
3%
0%5%
5%
5%
7%
17%
0%
14%
20%
Clinical features of patients with azole resistant A. fumigatus
17 patients, 15 from UK, different cities
9 had CCPA, all with aspergilloma3 had sputum isolate, with no treatment data2 had ABPA2 had IA1 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
Denning et al. Clin Infect Dis 2011;
Laboratory result ABPA CPA Normals
Culture positive for A. fumigatus
0/197/42
(16.7%)0/11
qPCR positive for Aspergillus spp
15/19 (78.9%)
30/42 (71.4%)
4/11 (36.4%)
CF and Aspergillus cultures
Baxter, unpublished
Pre-sonication
Post-sonication
Routine culture cfu versus qPCR for AspergillusSputum and BAL
Kirwan, AAA 2012 Abstract
Sample BL AC PC VC JO
culture qPCR 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 (5-20mL) 0 38 0 30.3 0 33.5 2 33.5
BAL (10-70 mL) 0 37.2 0 32.8 0 33.1
LLL BAL 12 34
LLL trap 1 32.7
RML BAL 0 neg
RUL BAL 10mL 0 33.4
RLL (120mL) 0 31.2
Sputum after 3 32.2 0 29.6 0 34.9 1 34.6 0 31.4
E. dermatiditis
Direct detection of resistance mutations in clinical specimens,
without positive cultures
Laboratory result ABPA CPA Normals
Culture positive for A. fumigatus
0/197/42
(16.7%)0/11
qPCR positive for Aspergillus spp
15/19 (78.9%)
30/42 (71.4%)
4/11 (36.4%)
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.
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 (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.
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
Nebuliser chamber
Features:
• Fill volume 2ml-8ml• Delivers approx 65% respirable dose• Can go through the dishwasher• Can survive boiling in water
Comparison of Pari LC versus other nebulisers
Another challenge – immune reconstitution
Miceli, Cancer 2007;110:112; Caillot Eur J Radiol 2010;74:e172
Day 0
Day 7
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
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.