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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. Drug toxicity Drug interactions and low blood levels. Drug toxicities

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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


Clinical failure and its management

Problems with antifungal therapy

  • Drug toxicity

  • Drug interactions and low blood levels


Clinical failure and its management

Drug toxicities

Common reasons for stopping therapies

ItraconazoleNauseaAnkle swellingPeripheral neuropathyFatigueVoriconazoleFeeling illConfusion/hallucinations/poor concentrationPhotosensitivity


Itraconazole concentrations in phase 2 studies
Itraconazole concentrations in phase 2 studies

Denning et al, Am J Med 1994;97:135


Itraconazole concentrations in relation to timing of samples
Itraconazole concentrations in relation to timing of samples

Tucker et al, J Am Acad Dermatol 1990;23:593-601


Clinical failure and its management

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 for ABPA in CF

Itraconazole often poorly absorbed and variable penetration into CF sputum

Sermet-Gaudelus, Antimicrob Ag Chemother 2001;45:1937.


Clinical failure and its management

Generic itraconazole (Sandoz)

Pasqualotto, Int J Antimicrob Ag 2007; 30:93



Voriconazole metabolism
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


Clinical failure and its management

Possible toxicity

Very small children may metabolise voriconazole very fast and need dose escalation to ?7-10mg/Kg BID or 200mg BID

Random voriconazole concentrations in adults receiving 3mg/Kg BID

100,000

10,000

1000

Log 10 [Concentration (µg/L)]

100

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
Voriconazole levels in children

Pasqualotto et al, Arch Dis Child 2008;93:578


Cytochrome p450 interactions
Cytochrome P450 interactions

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



Clinical failure and its management

Problems with antifungal therapy quickly

  • Drug toxicity

  • Drug interactions and low blood levels

  • Azole resistance, intrinsic and acquired


Clinical failure and its management

32 yr old from Malawi, on HAART Rx quickly - haemoptysis- Aspergillus precipitin titre 1/16CT 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


Clinical failure and its management

On HAART Rx, with low viral load, CD4 count >200 quickly - New haemoptysis- Aspergillus precipitin titre 1/32CXR & CT scan showed expansion of inferior cavity

February 2007

April 2007

CCPA in HIV February 2007

MICs A. fumigatus Feb 2007Itraconazole = >8.0mg/mLVoriconazole = 0.5 mg/mLPosaconazole = 1.0 mg/mL


Clinical failure and its management

Itraconazole concentrations quickly Nov 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
microtitre, quickly RPMI 2% glucose 35°C 48 hrs

Test inoculum

AF72

AF91

2x106/mL

Denning et al, JAC 1997;40:401


Confirmation in vivo
confirmation in vivo quickly

AmB 5mg/Kg

AmB 5mg/Kg

Itra 75mg/Kg

Itra 75mg/Kg

Itra 25mg/Kg

controls

Strain 6 (AF 91)M220 CYP51A mutation

Strain 5 (AF 72)G54 CYP51A mutation

Denning et al, JAC 1997;40:401



Clinical failure and its management

Posaconazole MIC (mg/L) testing and breakpoints

Voriconazole MIC (mg/L)

Itraconazole MIC (mg/L)

Manchester azole MIC distributions

modified EUCAST method - 0.5 x 105 not 1-2.5 x 105 cfu/mL


Azole resistance in a fumigatus in manchester 1997 2009
Azole resistance in testing and breakpointsA. fumigatus in Manchester 1997-2009

20%

14%

5%

17%

7%

5%

3%

0%

0%

5%

7%

0%

0%

Bueid, J Antimicrob Chemother 2010;65:2116. Howard et al, EID 2009; 15:1068


Clinical features of patients with azole resistant a fumigatus
Clinical features of patients with azole resistant testing and breakpointsA. 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


Clinical failure and its management

http://www.hpa-standardmethods.org.uk/documents/bsop/pdf/bsop57.pdfhttp://www.hpa-standardmethods.org.uk/documents/bsop/pdf/bsop57.pdf


Molecular detection of aspergillus spp in sputum
Molecular detection of http://www.hpa-standardmethods.org.uk/documents/bsop/pdf/bsop57.pdfAspergillus spp.in sputum

Denning et al. Clin Infect Dis 2011;


Cf and aspergillus cultures
CF and Aspergillus cultureshttp://www.hpa-standardmethods.org.uk/documents/bsop/pdf/bsop57.pdf

Pre-sonication

Post-sonication

Baxter, unpublished


Routine culture cfu versus qpcr for aspergillus sputum and bal
Routine culture cfu versus qPCR for Aspergillushttp://www.hpa-standardmethods.org.uk/documents/bsop/pdf/bsop57.pdfSputum and BAL

Kirwan, AAA 2012 Abstract


Direct detection of resistance mutations in clinical specimens without positive cultures
Direct detection of resistance mutations in clinical specimens, without positive cultures

Denning, Clin Infect Dis 2011;52:1123


Clinical failure and its management

Problems with antifungal therapy specimens, without positive cultures

  • Drug toxicity

  • Drug interactions and low blood levels

  • Azole resistance, intrinsic and acquired

  • Antifungal failure (without resistance/low azole blood levels etc)

  • Immune reconstitution or other ‘switching’ of immune response


Aspergillomas in cf
Aspergillomas in CF specimens, without positive cultures

Turcios – www.aspergillus.ac.uk


Clinical failure and its management

Felton, Clin Infect Dis 2010; 51:1383. specimens, without positive cultures


Clinical failure and its management

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


Clinical failure and its management

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



Dose and reconstitution
Dose and reconstitution asthma

  • 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
Compressors asthma

Need servicing regularly!

To drive most nebulisers an output of at least 8 L/m is required


The pari lc plus with exhaust filter
The Pari LC plus with exhaust filter asthma

  • Features:

  • Fill volume 2ml-8ml

  • Delivers approx 65% respirable dose

  • Can go through the dishwasher

  • Can survive boiling in water

Nebuliser chamber




Clinical failure and its management

Day 0 asthma

Day 7

Miceli, Cancer 2007;110:112; Caillot Eur J Radiol 2010;74:e172


Clinical failure and its management

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


Clinical failure and its management

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


Clinical failure and its management

Several patients have increasing breathlessness with antifungal therapyDocumented fall in DLCO in one patientDeaths in others.Mechanism unclear.Likely benefit from steroids, needs good antifungal cover.


Interferon gamma replacement
Interferon gamma replacement antifungal therapy

Both patients improved with γIFN

Kelleher, Eur Resp J 2006;27:1307


Cpa treatment ifn gamma
CPA treatment antifungal therapy– IFN gamma?

Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80.


Clinical failure and its management

Management approach antifungal therapy

  • Exclude low blood levels – be careful of large dose increases with voriconazole

  • Fungal cultures – test for resistance

  • Exclude or treat bacterial co-infection

  • Use IV therapy if patient very ill

  • Consider surgical resection, gamma IFN, inhaled AmB (if ABPA/SAFS),

  • Long term IV therapy for CPA feasible and partially effective.