Two talks from the Mycology References Laboratory at the National Aspergillosis Centre, Nichola Duddy on "What happens to my sample?" and Caroline Moore on "Antifungal drugs - are you getting enough?"

1. Led by Graham Atherton Supported by Georgina Powell, Marie Kirwan & Debbie Kennedy NAC Centre Manager Chris Harris Talks given by Nicola Duddy and Caroline Moore Mycology Diagnostics Lab UHSM, Manchester National aspergillosis centre UHSM Manchester Support Meeting for Aspergillosis Patients Fungal Research Trust

2. Antifungal drugs – are you getting enough? Dr Caroline B. Moore Mycology Reference Centre University Hospital of South Manchester The University of Manchester

3. Are you getting enough? Or too much?

4. Checking antifungal drug levels……Therapeutic Drug Monitoring or TDM

5. When would we need TDM? Maximise effectiveness Minimise side-effects Our goal: Some drugs have a relationship between: - concentration (in blood) and improvement - concentration (in blood) and side-effects Hope WW et al. Curr Opin Infect Dis 2008; 21: 580

7. where we see variation within and between patientsHope WW et al. Curr Opin Infect Dis 2008; 21: 580

9. to check whether patient is taking the drug (compliance)

10. if we change the dose

11. if we think the drug isn’t workingHope WW et al. Curr Opin Infect Dis 2008; 21: 580

13. developing/worsening of side-effects

16. Post-dose: a set period of time after the drug has been taken, often 2 or 4 hours

18. Itraconazole

19. Itraconazole exhibits nonlinear kinetics Time to steady state ~14 days Itraconazole, ng/mL plasma Hours Barone JA et al. Antimicrob Agents Chemother 1993; 37: 778

20. Variation in itraconazole kinetics Less than 0.5mg/L Variation in post-dose concentrations Aspergillus in the lung ~17mg/L Post-dose itraconazole concentrations (mg/L) Berenguer J et al. Antimicrob Agents Chemother 1994; 38: 1303

21. Variation affects how well the drug works Lots of Aspergillus Relationship between drug level and amount of Aspergillus Aspergillus in the lung Less Aspergillus Post-dose itraconazole concentrations (mg/L) Berenguer J et al. Antimicrob Agents Chemother 1994; 38: 1303

22. Itraconazole: relationship between drug level and side-effects 17.1mg/L Probability of side-effects Probability of side-effects increase as drug level increases Pre-dose itraconazole concentrations (mg/L) Lestner JM et al. Clin Infect Dis 2009; 49: 928

23. Itraconazole audit ~20% too high ~40% too low Only ~ 40% of levels were satisfactory

24. Voriconazole

26. Disproportionate changes when dose altered

27. Time to steady state ~5 days Trifilio SM et al. Antimicrob Agents Chemother 2009; 53: 1793 Walsh TJ et al. Antimicrob Agents Chemother 2004; 48: 2166

29. critical illness

30. elderlyLog 10 [Concentration (µg/L)] 100 10 1 0 70 140 210 280 days after first dose Data from Denning DW et al. Clin Infect Dis 2002; 34: 563

31. Voriconazole: relationship between drug level and success SUCCESS 1 0.8 0.6 Probability Pre-dose level greater than 1.0mg/L was significantly better 0.4 0.2 LACK OF RESPONSE 0 0.125 0.25 0.5 1 2 4 8 16 Voriconazole pre-dose blood level, mg/L Pascual et al. Clin Infect Dis 2008; 46: 201

32. Voriconazole: relationship between drug level and neurological side-effects NEURO-LOGICAL TOXICITY 1 Pre-dose level greater than 5.5mg/L was significantly more toxic 90% probability at 8mg/L 0.8 0.6 Probability 0.4 0.2 15% probability at 5.5mg/L ABSENCE OF TOXICITY 0 0.125 0.25 0.5 1 2 4 8 16 Voriconazole pre-dose blood level, mg/L Pascual et al. Clin Infect Dis 2008; 46: 201

33. Posaconazole

35. Time to steady state ~7-10 days

36. Minimal differences between pre- and post-dose levelsCourtney R et al. Antimicrob Agents Chemother 2003; 47: 2788 Krishna G et al. Antimicrob Agents Chemother 2007; 51: 812

37. Posaconazole levels measured by a United States laboratory Range 0 - 6.57mg/L 16% had undetectable levels Posaconazole serum level (mg/L) Number of serum levels (n=202) Thompson et al. Antimicrob Agents Chemother 2009; 53: 2223

38. Posaconazole audit 34% of levels <1mg/L: too low 25% of levels >2mg/L ~40% of levels between 1 and 2mg/L

39. So keep taking your tablets!

40. Thank you to the Mycology team: Professor Malcolm RichardsonDr Caroline MooreNichola DuddyElaine TaylorPatrycja Kent Rebecca CollinsMartin McHughEmma DaviesMonika PergeJoanne Gill And to you! www.mycologymanchester.org