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Directed therapy for fungal infections - latest advances

Directed therapy for fungal infections - latest advances. Rosemary Barnes Focus on aspergillosis. Total UK antifungal expenditure c £112 million Rising by 9% pa. Problem. Antifungal expenditure is completely out of proportion with the scale of the problem

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Directed therapy for fungal infections - latest advances

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  1. Directed therapy for fungal infections - latest advances Rosemary Barnes Focus on aspergillosis

  2. Total UK antifungal expenditure c £112 million Rising by 9% pa Problem • Antifungal expenditure is completely out of proportion with the scale of the problem • Incidence of IFD in ICU (candida) <0.6% • Aspergillus infection in haematological malignancy (0.5-12%) • Aspergillus in SOT <5% • Harrison D et al Fungal Infection Risk Evaluation (FIRE) Study. Health Technol Assess 2013;17(3). • Pagano L et al. Haematologica 2006; 91: 1068-1075 • Pagano L et al. Clin Infect Dis 2007; 45: 1161-1170

  3. Reasons • Infection associated with significant morbidity and mortality • Signs and symptoms of systemic infection are nonspecific • Conventional diagnostic techniques are suboptimal • Delays in treatment associated with poorer outcome

  4. Choices choices choices Febrile despite antibiotics Empirical therapy Diagnosis Change antibiotics

  5. Decision tree yes Fever no

  6. Decision tree yes no yes No diagnosis Fever no yes no

  7. Decision tree yes no yes yes no yes no No diagnosis Anxiety Fever no yes yes no no yes no

  8. Decision tree yes no yes yes no no yes yes no yes yes no yes no no No diagnosis Anxiety Out of hours Fever no yes yes yes no no yes no no yes yes no no yes no

  9. Decision tree yes no yes yes no no yes yes no yes yes no yes no no Empirical therapy No diagnosis Anxiety Out of hours Fever no yes yes yes no no yes no no yes yes no no yes no No therapy

  10. Aim of a directed strategy include all patients likely to have invasive fungal infection and treat them with the safest and most effective drug exclude all patients unlikely to have invasive fungal disease and adopt a WAIT-and-SEE policy

  11. Maertens et al. (2012) Haematologica 97(3): 325-327.

  12. Consensus criteria • Aimed to provide definitions for proven, probable and possible fungal infection that could facilitate clinical research • Designed for use in clinical trials • Highly selective population • Not representative of real life clinical practice • Focus on specific radiological signs • Focus on defining DISEASE • needs to shift towards INFECTION • Needs a diagnostic approach • biomarkers De Pauw et al CID 2008, 46

  13. The biomarkers • Antigen tests • Galactomannan (aspergillus) • Beta D glucan (pan-fungal-ish) • Lateral flow device • Molecular • Aspergillus specific • Panfungal • Commercial (…….)

  14. Galactomannan - in serum • useful test in surveillance: high NPV • Performance in • haematological malignancy better than in SOT • neutropenic > corticosteroid treated group • Adults >children • Influenced by pre-test probability (ie sensitivity increases with prevalence) • EORTC/MSG criteria heavily dependent on test being performed • Recommended by ECIL

  15. Galactomannan – meta-analyses 30 studies > 7000 patients • Prevalence 7.7% • sensitivity78% (61% to 89%) • specificity 81% (72% to 88%). • cut-off 0.5: 100 patients: • 2 patients with IA, will be missed, • 17 patients will be treated unnecessarily • cut-off 1.5 OD: • 3 IA patients will be missed • 5 patients will be treated unnecessarily • results were very heterogeneous. • Insufficient data to look at clinical utility http://www.thecochranelibrary.com

  16. BAL • 0.5 approved by FDA • On the basis of clinical validity • PPV of GM BAL is 100% at an OD index cutoff of ≥3 • only 76% at ≥ 0.5 (but NPV is high) Pre test probability PUO GM pos CT BAL Maertens et al CID 2009

  17. Beta D Glucan • 4different commercial tests • Heterogenous data : retrospective vs. prospective; • Different cut offs • “panfungal” – except cryptococcus and mucoracous moulds • Sensitivity, specificity variable but NPV high • High false-positives: up to 30% - bacteraemia, antibiotics, pre-/analytical contaminations • complex analytical procedures • Analytical validity established • Utility data limited • Included in EORTC/MSG criteria

  18. Beta D Glucan-meta-analysis • 16 studies in 2979 patients • Included case-controlled studies • Included critical care, HM and solid organ cancer patients • Cut off 10-1000 pg/ml • Sensitivity 76.8% (67.1%–84.3%) • specificity 85.3% (79.6%–89.7%) • “area under ROC curve 0.89” • “good diagnostic accuracy” Karageorgopoulos et al Clin Infect Dis 2011;52(6):750

  19. PCR • The UK Fungal PCR consensus group • 2004 technically validated candida PCR • Made recommendations for aspergillus PCR • 2006 European Aspergillus PCR Initiative set up • 86 participants in 69 centres in 24 countries • defined a standard for PCR for Aspergillus • Whole blood • Serum • plasma • optimal methodology to evaluate the performance and impact • QCMD available White et al J MolecDiagn 2006; 8: 376 White et al J Clin Micro 2010: 48 1231 www.eapcri.eu/

  20. PCR • Single negative PCR to exclude disease • 2 consecutive PCRs to diagnose IA • Sensitivity 88% • Specificity 75% • DOR22 Mengoli et al Lancet Infectious Diseases. 2009; 9: 89-96

  21. “Directed/pre-emptive” therapy

  22. Galactomannan EIA • Open study • 136 episodes of neutropenia • Patients receiving flucon prophylaxis • daily EIA GM + early CT scanning in neutropenic febrile episodes • Antifungal given if 2 consecutive EIA GM results +ve (index ≥ 0.5) • and confirmed by BAL or CT Maertens et al. Clin Infect Dis 2005; 41: 1242

  23. Maertens et al • 35% of episodes met criteria for empirical antifungal but only7.7% treated on basis of pre-emptive therapy • Duration of fever not affected • 22 cases of IFD only one missed • 3 breakthrough infections • 2 candidaemias • 1 mucorales • No excess mortality or fungal related death • No impact on overall antifungal usage despite deceased empirical use

  24. Cordonnieret al CID 2009 48:1043 • 293 patients randomised • empirical or pre-emptive therapy • empirical arm received antifungals if they had persistent/recurrent fever after 4 days • pre-emptive patients given antifungal only if they showed • clinical and radiological signs of pneumonia/sinusitis • positive GM index ≥ 1.5 • Aspergillus colonization • Septic shock • CNS signs/periorbital inflammation • Diarrhoea/mucositis ≥ grade 3 • fever > 14 days

  25. Cordonnieret al • Survival was not significantly • “Non inferiority” demonstrated • pre-emptive patients had more IFI • 9.1% vs 2.7% • pre-emptive patients received significantly less antifungals • no significant cost savings were achieved • Used ampho B deoxycholate first -line

  26. Empirical vs. pre-emptiveantifungaltherapy Empirical Pre-emptive IFI in Pre-emptive IFI in Empirical Cordonnier et al, Clin Infect Dis, 2009; 48: 1042-1051

  27. Pagano et al Haematologica 2011; 96:1363 • Observational: Empiric versus “pre-emptive” • Data collection 397 HM patients • 190 empiric ; 207”pre-emptive” • More IFD in pre-emptive arm • Increased mortality and antifungal use in “pre-emptive arm” • Fever driven, no screening, diagnostic work up not standardized • some GM usage, no PCR • Pre-emptive group largely diagnosed on basis of HRCT

  28. randomised study of a PCR directed versus an empirical antifungal more than 400 SCT patients Safe Improved survival at 30 days (not 100) No reduction in antifungal drug use. Nested PCR to guide antifungal therapy 42 patients with cancer, neutropenia AmB required in only 2 patients PCR Lin et al. Clin Infect Dis. 2001;33:1621-1627 Hebartet al. Blood 2004;104: 59A.

  29. In Cardiff • 549 high-risk haematology patients entering neutropenic pathway 2005-2010 • audited and followed up for a minumum of 12 months • Twice weekly antigen and PCR testing (or GvHD) • Itraconazole prophylaxis or AmBisome 7mg/kg/weekly • Empiric antifungals not used unless • Clinical/mycological evidence of disease • Itraconazole levels were subtherapeutic or unmeasured • First 125 patients analysed for safety and proof of concept • Data collected on compliance, incidence of IFD and efficacy of prophylaxis Barnes et al Journal of Clinical Pathology 2009

  30. Incidence of IFD (2005-2011) • Invasive aspergillosis 9.6% • 6 histologically proven (2 postmortem) • 4 pulmonary (2 with dissemination) • 2 invasive sinusitis • 47 probable • (23 possible IA) • Invasive Candidal infection 2% • 12 proven • 4 C. albicans, 3C. glabrata, 2C. tropicalis, 1C. parapsilosis, 1C. guilliermondii, 1 mixedC. albicans+ C. glabrata • 1 probable • 2 non-aspergillus moulds • 1 Mucoraceous mould, 1 Scedosporiumprolificans • Incidence of proven/probable IFD 12.3%

  31. IA disease status of subjects By EORTC/MSG diagnostic criteria • Proven – 6 • Probable – 47 • Possible – 23 • NEF – 473 • 248 of NEF showed some signs suggestive of IA • EIA positive n=36 • PCR positive n=136 • EIA and PCR positive n=75 • Aspergillus isolated n=5

  32. Diagnostic accuracy • Explore analytical validity. Clinical validity, clinical utility • Sensitivity specificity • PPV, NPV, LR, DORs • Use ROC analysis to explore different thresholds for defining “cases” • EORTC/MSG • EORTC – GM EIA • EORTC + PCR • Dual biomarker positivity • Multiple positives versus single

  33. Statistical parameters By EORTC/MSG criteria

  34. Proven/probable disease versus no IFDDiagnostic odds ratio Ascertainment bias

  35. Positive likelihood ratio 15.8 11.2 10.5

  36. Negative likelihood ratio 0.05 0.03

  37. ROC plot PCR + EIA Proven/prob/poss Proven/prob curve (AUC): 0.910 (95% CI: 0.872-0.948)

  38. Performance of PCR • Utility in proven/probable n=53 • First marker positive • PCR in 23 • EIA in 15 • PCR and EIA simultaneously positive in 7 • radiological features in 8 • In 85% biomarkers preceded specific radiological signs (range 1-118d)

  39. Diagnostic accuracy • Screening by PCR AND GM EIA can enable a diagnosis of IA to be excluded • Positive PCR +GM EIA or multiple positive PCRs or EIAs can be used to accurately diagnosis IA • specificity 84.4%; sensitivity >90% DOR>50 • Biomarkers are earliest markers in 85% of cases • Use antifungals more cost effectively

  40. Antifungal expenditure • Similar units typically spending £1-2 mill pa

  41. Use of biomarkers • Regular screening throughout period or risk • Screening during fever only • Diagnostic testing during refractory fever only • Confirmation when specific radiological signs are present • None - empiric therapy

  42. Strategy Used • Influenced by • Risk of IFD • Prevalence affects utility of diagnostic tests • ECIL recommend screening if IFD 5-10% • Prophylaxis used • Mould active reduces utility of diagnostic tests • Availability of • Diagnostic tests • Protective environments/HEPA filtered air

  43. Incidence of IFD after posaconazole therapy Pagano et al Haematological 2012; 97:963

  44. Effect of antifungal therapy McCulloch et al J Clin Path 2012; 65:83 Marr K A et al. Clin Infect Dis. 2005;40:1762-1769

  45. High risk patient Prevalence8- ≥10% *For example: PCR and GM, or Multiple GM No Mould active prophylaxis – Screening regime Mould active prophylaxis used – Diagnostic regime Twice weekly screening of blood samples: Galactomannan, And Aspergillus PCR HRCT and BAL when infection suspected Diagnostic testing during refractory fever with Beta D glucan (serum) and Aspergillus PCR (BAL and blood or serum), galactomannan (BAL and serum) Single Positive biomarker Continue screening process >1 biomarker positive* triggers diagnostic workup to include relevant radiology and BAL if indicated Targeted antifungal therapy for clinically diagnosed infection only with biomarker confirmation No consistent clinical signs or symptoms indicates need for possible pre-emptive therapy Any consistent clinical signs or symptoms indicates need for antifungal therapy Example

  46. exposure at risk infection disease Pre-emptive Prophylaxis Targetted

  47. Any Questions?

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