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

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Presentation on theme: "Clinical failure and its management David W. Denning Director, National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital]"— Presentation transcript:

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 1.Drug toxicity 2.Drug interactions and low blood levels

3 Itraconazole Nausea Ankle swelling Peripheral neuropathy Fatigue Voriconazole Feeling ill Confusion/hallucinations/poor concentration Photosensitivity Drug toxicities Common reasons for stopping therapies

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:

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

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 Random voriconazole concentrations in adults receiving 3mg/Kg BID , , days after first dose Log 10 [Concentration (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

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

13 Cytochrome P450 interactions FlucItraPosaVori Inhibitor 2C C A Substrate 2C C9 + 3A 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 1.Drug toxicity 2.Drug interactions and low blood levels 3.Azole resistance, intrinsic and acquired

16 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 pneumonectomy So treated with itraconazole

17 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 2007 Itraconazole = >8.0mg/mL Voriconazole = 0.5 mg/mL Posaconazole = 1.0 mg/mL

18 Itraconazole concentrations Nov mg/L Dec mg/L March mg/L July mg/L Feb 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 2x10 6 /mL Test inoculum AF72 AF91 Denning et al, JAC 1997;40:401

20 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

21 Development of international standards for susceptibility testing and breakpoints

22 Manchester azole MIC distributions Itraconazole MIC (mg/L) Voriconazole MIC (mg/L) Posaconazole MIC (mg/L) modified EUCAST method x 10 5 not x 10 5 cfu/mL

23 Azole resistance in A. fumigatus in Manchester Bueid, J Antimicrob Chemother 2010;65:2116. Howard et al, EID 2009; 15:1068 0% 7% 3% 0% 5% 7% 17% 0% 14% 20%

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

26 Molecular detection of Aspergillus spp. in sputum Denning et al. Clin Infect Dis 2011; Laboratory resultABPACPANormals Culture positive for A. fumigatus 0/19 7/42 (16.7%) 0/11 qPCR positive for Aspergillus spp 15/19 (78.9%) 30/42 (71.4%) 4/11 (36.4%)

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

28 Routine culture cfu versus qPCR for Aspergillus Sputum and BAL Kirwan, AAA 2012 Abstract SampleBLACPCVCJO cultureqPCRcultureqPCRcultureqPCRcultureqPCRcultureqPCR Sputum before Ist trap Ist wash (5- 20mL) BAL (10-70 mL) LLL BAL 1234 LLL trap RML BAL 0neg RUL BAL 10mL RLL (120mL) Sputum after E. dermatiditis

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

30 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

31 Aspergillomas in CF Turcios –

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

33 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)

34 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.

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 Nebuliser chamber Features: Fill volume 2ml-8ml Delivers approx 65% respirable dose Can go through the dishwasher Can survive boiling in water

39

40 Comparison of Pari LC versus other nebulisers

41 Another challenge – immune reconstitution

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

43 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

44 Immune reconstitution in invasive pulmonary aspergillosis, in AIDS Patient HB Day +64, CD4 cells 340/uL, on VRC Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628 Patient HB Day +87, day of death

45 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.

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):S

48 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.


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