ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENIC PATIENTS REVIEW OF TREATMENT CHOICES AND STRATEGIES

1. ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENIC PATIENTS REVIEW OF TREATMENT CHOICES AND STRATEGIES Jean KLASTERSKY, M.D., Ph. D. Institut Jules Bordet, Brussels, Belgium

2. G.S. MARTIN et al., NEJM 2003

3. Mc Neil M, CID 2001;13:;641-647

4. Frequency of non-Aspergillus mould infections at Fred-Hutchinson Cancer Research Center (Seattle). The number of patients who developed proven or probable infection with Fusarium species, Zygomycetes and Scedosporium species from 1985 through 1999 are shown

5. Pathogenic Candida species in BMT recipients : Candida species that caused candidemia are compared over 2 decades at the Fred Hutchinson Cancer Research Center. The incidence of candidemia decreased from 11.4 % in 1980-1986 (72) compared to 4.6 % after adoption of fluconazole for prophylaxis (1984-1997). Marr K & Bowden R, Transplant Infectious Diseases 1999;1:237-246.

6. Antifungal prophylaxis in leukemia patients : ECIL recommendations

7. Comparative trials of antifungal agents in candidemia and invasive candidasis

8. Why does the frequency of fungal infection increase ? • I.V. devices • Immunosuppression • Neutropenia • Broad spectrum antibiotics • Diabetes

9. Rational for Empirical Antifungal Therapy in Neutropenic Patients with Persistent Fever Delayed treatment increases mortality Success of antibacterial empirical therapy Early diagnosis of many fungal infections is difficult

10. An Algorithm for Therapy of Febrile Neutropenia after Initial Empirical Therapy with Broad Spectrum Antibiotics Follow Daily And Reassess After 72 Hours Clinical response Yes No Continue for 7 days Pathogen isolated Yes No Adjust to sensitivity Look for localized infection Use G/GM-CSF? Repeat cultures and serology Perform chest CT and BAL Addamphotericin, and possibly metronidazole, antivirals and/or G/GM-CSF as indicated Look for non infectious causes of fever 10

11. L. COREY and M. BOECKH, NEJM 2002

14. Infectious Complications in Each of the Groups Following Randomization KGC : cephalotin (Keflin), gentamicin, carbenicillin P.A. PIZZO et al, Am J Med 1982 14

15. Clinical Response in Persistently (4 days) Febrile Neutropenic Patients EORTC-IATCG, Am J Med 1989

16. Causes of Death with or without Empirical Ampho B in Persistently (4 Days) Febrile Neutropenic Patients

17. Randomized Studies Comparing Empirical Treatment with Antifungal Agents for Persisting Fever during Neutropenia

18. Measures of the Success (%) of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole or Caspofungin Ampho B Liposomal Ampho B Voriconazole Caspofungin (Ampho B) (Vori) (Caspo) N° of patients 344 343 422 539 415 556 Overall success 49.4 50.1 30.6 33.7 26.0 33.9 Resolution of fever 58.1 58.0 36.5 41.4 32.5 41.2 No breakthrough fungal infection 89.2 90.1 95.0 95.5 98.1 94.8 Resolution of baseline infection 72.7 81.8 66.7 25.9 46.2 51.9 Survival for 7 day 89.5 92.7 94.1 89.2 92.0 92.6 No discontinuation for toxic effects81.4 85.7 93.4 85.5 90.1 89.7 or lack of efficacy J. KLASTERSKY, NEJM 2004

19. Comments on the Walsh’s studies • Large prospective controlled trials • Composite score : « common language » • BUT • Survival and fever can be influenced by many other factors than just the nature of the empirical regimen • What is the difference between « baseline » FI (<72h) and « breakthrough » FI (>72h) ? • Discontinuation for toxicity or lack of efficacy : « mixing apples and pears» ?

20. Toxicity of Empirical Antifungal Therapy % * Creatinine increase 2 x base line ** Visual hallucinations more frequent with voriconazole (4.3 % vs 0.5 %)

21. Measures of the Success (%) of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole or Caspofungin Ampho B Liposomal Ampho B Voriconazole Caspofungin (Ampho B) (Vorico) (Caspo) N° of patients 344 343 422 539 415 556 Overall success 49.4 50.1 30.6 33.7 26.0 33.9 Resolution of fever 58.1 58.0 36.5 41.4 32.5 41.2 No breakthrough fungal infection 89.2 90.1 95.0 95.5 98.1 94.8 Resolution of baseline infection 72.7 81.8 66.7 25.9 46.2 51.9 Survival for 7 day 89.5 92.7 94.1 89.2 92.0 92.6 No discontinuation for toxic effects81.4 85.7 93.4 85.5 90.1 89.7 or lack of efficacy J. KLASTERSKY, NEJM 2004

22. Cure of Base Line Fungal Infection * 2 studies **Outcome in the study comparing conventional ampho B to liposomal ampho B was 9/11 (81.8)

23. Choice of a suitable denominator for the evaluation of empirical therapy based on microbiological results

24. Outcome of Empirical Antifungal Therapy in Microbiologically Demonstrated Fungal Infections (FI) *p = 0.03

25. Summary of trials of empirical antifungal therapy that evaluated alternatives to amphotericin B J.R. Wingard, CID, 2004 * p< 0.5

26. 26

27. Aspergillus fumigatus

29. Galatomannan detection for the diagnosis of invasive aspergillosis • Approved by FDA; standard : optical density index > 0.5 in 2 consecutive samples ? • Positivity can preceed radiological findings • In probable or proven cases levels are often higher and increase within days • 81 % sensitivity; 89 % specificity; NPV:98 %; PPV:7-94 % • False negatives : prophylactic use of mold-active azoles, early antifungal therapy and others ? False positives : use of piperacillin-tazobactam and others ?

30. Aspergillus Infections (AI) in Empirical Therapy ° Assuming that 1/2 infections in the liposomal ampho B arm (*) and 4/7 infections in the voriconazole arm (**) were caused by Aspergillus

31. R. Herbrecht et al, N Engl J Med, 2002

32. 1.9 % 4.9 % (p = 0.02) T.J. Walsh et al, N Engl J Med 2002

33. T.J. Walsh et al, N Engl J Med 2004

34. T.J.Walsh et al, N Engl J Med 2004

35. 12 CR 6 PR voriconazole 2 SD rescue 12 No response (7 died < IFI) 8/12 : CR

36. K.A. MARR et al, CID 2004

37. N. Singh, Transplantation, 2006

38. The prevalence of fungal infections in patients receiving empirical therapy is 4-8 %

39. Prevalence of fungal infections in persistently neutropenic patients not receiving empirical therapy * Autopsy-based data

41. CID, 2005

42. The preemptive approach(adapted from Maertens et al.)« Possible IFI » Diagnostic evaluation for IFI

43. The preemptive approach(adapted from Maertens et al.)« Possible IFI » • Liposomal amphotericin B (5 mg/kg) IF • > 2 consecutives EIA for galactomannan assays > 0.5) OR • CT suggestive of IFI supported by microbiology

44. The preemptive approach of persistent febrile neutropenia in 88 patients(adapted from Maertens et al.) • Persistent fever 35/117 (29 %) episodes • Prevalence of IFI : 22 % (mortality 36 %) • No aspergillar infection was missed • Early therapy could be initiated in clinically not suspected cases • Significant (78 %) reduction in use of antifungals

45. CID, 2005

46. Empirical versus preemptive therapy (liposomal amphotericin B) in patients with persisting fever and neutropenia • Adapted from Maertens’ study • 35 patients with persistent fever need of a controlled study * Estimation from J. Klastersky, NEJM 2004

47. Blood, 2006

48. Empirical (E ) vs pre-emptive approach (PE) Design 293 patients c hematological malignancies R Antifungal therapy E PE . Persistent or recurrent fever . Persistent or recurrent fever + . pneumonia . mucositis . septic shock . sinusitis . skin lesions . aspergillus colonisation . + gamacto-mannan

49. Empirical (E ) vs pre-emptive approach (PE)

50. Estimated prevalence of invasive fungal infection (IFI) in neutropenic patients according to the management strategy in exemplative studies 1 Guiot, CID, 1994 2 Ullmann, NEJM, 2007 3 Walsh, NEJM, 2002 4 Cordonnier, Blood, 2006