Clinical failure and its management

1. Clinical failure and its management David W. Denning Director, National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital] The University of Manchester

2. Problems with antifungal therapy • Drug toxicity • Drug interactions and low blood levels

3. Drug toxicities Common reasons for stopping therapies ItraconazoleNauseaAnkle swellingPeripheral neuropathyFatigueVoriconazoleFeeling illConfusion/hallucinations/poor concentrationPhotosensitivity

4. Itraconazole concentrations in phase 2 studies Denning et al, Am J Med 1994;97:135

5. Itraconazole concentrations in relation to timing of samples Tucker et al, J Am Acad Dermatol 1990;23:593-601

6. Optimising itraconazole levels – aim between 5 and 17 mg/L Lestner et al, Clin Infect Dis 2009; 49:928

7. Itraconazole for ABPA in CF Itraconazole often poorly absorbed and variable penetration into CF sputum Sermet-Gaudelus, Antimicrob Ag Chemother 2001;45:1937.

8. Generic itraconazole (Sandoz) Pasqualotto, Int J Antimicrob Ag 2007; 30:93

9. Approval of itraconazole by the FDA and Europe in 1991

10. 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

11. 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

12. Voriconazole levels in children Pasqualotto et al, Arch Dis Child 2008;93:578

13. Cytochrome P450 interactions Dodds Ashley & Alexander. Drugs Today 2006;41:393.

14. New section on drug interactions which you can search very quickly

15. Problems with antifungal therapy • Drug toxicity • Drug interactions and low blood levels • Azole resistance, intrinsic and acquired

16. 32 yr old from Malawi, on HAART Rx- 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

17. On HAART Rx, with low viral load, CD4 count >200- 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

18. 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?

19. microtitre, RPMI 2% glucose 35°C 48 hrs Test inoculum AF72 AF91 2x106/mL Denning et al, JAC 1997;40:401

20. confirmation in vivo 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

21. Development of international standards for susceptibility testing and breakpoints

22. Posaconazole MIC (mg/L) 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

23. Azole resistance in A. 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

24. 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

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

26. Molecular detection of Aspergillus spp.in sputum Denning et al. Clin Infect Dis 2011;

27. CF and Aspergillus cultures Pre-sonication Post-sonication Baxter, unpublished

28. Routine culture cfu versus qPCR for AspergillusSputum and BAL Kirwan, AAA 2012 Abstract

29. Direct detection of resistance mutations in clinical specimens, without positive cultures Denning, Clin Infect Dis 2011;52:1123

30. Problems with antifungal therapy • 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

31. Aspergillomas in CF Turcios – www.aspergillus.ac.uk

32. Felton, Clin Infect Dis 2010; 51:1383.

33. 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

34. 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

35. Inhaled amphotericin B

36. 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!

37. Compressors Need servicing regularly! To drive most nebulisers an output of at least 8 L/m is required

38. 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

40. Comparison of Pari LC versus other nebulisers

41. Another challenge – immune reconstitution

42. Day 0 Day 7 Miceli, Cancer 2007;110:112; Caillot Eur J Radiol 2010;74:e172

43. 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

44. 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

45. 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.

46. Interferon gamma replacement Both patients improved with γIFN Kelleher, Eur Resp J 2006;27:1307

47. CPA treatment – IFN gamma? Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80.

48. Management approach • 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.