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

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Presentation on theme: "1 ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENIC PATIENTS REVIEW OF TREATMENT CHOICES AND STRATEGIES Jean KLASTERSKY, M.D., Ph. D. Institut Jules Bordet, Brussels,"— Presentation transcript:

1 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 2 G.S. MARTIN et al., NEJM 2003

3 3 Mc Neil M, CID 2001;13:;

4 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 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 (72) compared to 4.6 % after adoption of fluconazole for prophylaxis ( ). Marr K & Bowden R, Transplant Infectious Diseases 1999;1:

6 6 Antifungal prophylaxis in leukemia patients : ECIL recommendations

7 7 Comparative trials of antifungal agents in candidemia and invasive candidasis Response rateOverall mortality Fluconazole vs amphotericin B70 % vs 79 %33 % vs 40 % Itraconazole vs amphotericin B35 % vs 41 %40 % ABLC vs amphotericin B63 % vs 68 %41 % vs 39 % Caspofungin vs amphotericin B73 % vs 62 %30 % vs 34 % Voriconazole vs amphotericin B41 % vs 41 %36 % vs 42 % Micafungin vs Ambisome89 % vs 89 % Anidulafungin vs fluconazole75 % vs 60 %26 % vs 31 %

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

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

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 YesNo Pathogen isolated Adjust to sensitivity Look for localized infection Use G/GM-CSF? Continue for 7 days Repeat cultures and serology Perform chest CT and BAL Add amphotericin, and possibly metronidazole, antivirals and/or G/GM- CSF as indicated Look for non infectious causes of fever YesNo 10

11 11 Possible Causes of Persistent Fever Approximate frequency in high risk patients (%) Fungal infections susceptible to empirical therapy40 Fungal infections resistant to empirical antifungal therapy5 Bacterial infections (with cryptic foci and resistant organisms)10 Toxoplasma gondii, mycobacteria, or fastidious pathogens (legionella, mycoplasma, chlamydia, bartonella) 5 Viral infections (cytomegalovirus, Epstein-Barr virus, human herpes virus 6, varicella-zoster virus, herpes simplex virus) and respiratory pathogens such as parainfluenza virus, respiratory syncytial virus, influenza viruses 5 Graft-versus-host-disease after hematopoietic stem-cell transplantation10 Undefined (e.g. drug fever, toxic effects of chemotherapy, antitumor responses, undefined pathogens) 25 L. COREY and M. BOECKH, NEJM 2002

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14 14 Infectious Complications in Each of the Groups Following Randomization Randomization group N° Clinically documented BacterialFungal Viral Protozoal Shock Discontinue KGC Continue KGC alone KGC + Ampho B P.A. PIZZO et al, Am J Med 1982 KGC : cephalotin (Keflin), gentamicin, carbenicillin 14

15 15 Clinical Response in Persistently (4 days) Febrile Neutropenic Patients Ampho BNo Ampho Bp Value Overall All patients55/80 (68)39/77 (50)0.10 Prior antifungal prophylaxis No21/27 (78)9/20 (45)0.04 Yes19/31 (61)24/39 (61)NS Infection documentation Clinical22/29 (75)14/31 (41)0.03 Possible25/39 (64)20/33 (60)NS Granulocyte count at Day 4 < 100/µL31/45 (69)20/43 (46) /µL16/23 (70)14/21 (67)NS EORTC-IATCG, Am J Med 1989

16 16 Causes of Death with or without Empirical Ampho B in Persistently (4 Days) Febrile Neutropenic Patients Ampho BNo Ampho B Overall mortality (at day 30) *1114 Fungal infection**04 Bacterial infection12 Pulmonary infection (no bacterial or fungal pathogen identified at autopsy) 10 Other98 (*) p = NS between the two groups (**) p = 0.05 between the two groups EORTC-IATCG, Am J Med 1989

17 17 Randomized Studies Comparing Empirical Treatment with Antifungal Agents for Persisting Fever during Neutropenia YEARSTUDYANTIFUNGAL AGENTS COMPARED Pizzo et al EORTC Viscoli et al. Malik et al. White et al.. Walsh et al. Winston et al. Wingard et al. Boogaerts et al. Walsh et al. Conventional ampho B vs no antifungal therapy Conventional ampho B vs fluconazole Conventional ampho B vs ampho B colloidal dispersion Conventional ampho B vs liposomal ampho B Conventional ampho B vs fluconazole Liposomal ampho B vs ampho B lipid complex Conventional ampho B vs itraconazole Liposomal ampho B vs voriconazole Liposomal ampho B vs caspofungin

18 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 Overall success Resolution of fever No breakthrough fungal infection Resolution of baseline infection Survival for 7 day No discontinuation for toxic effects or lack of efficacy J. KLASTERSKY, NEJM 2004

19 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) ? –Discontinuation for toxicity or lack of efficacy : « mixing apples and pears » ?

20 20 Toxicity of Empirical Antifungal Therapy % Conventional amphotericin Liposomal amphotericin VoriconazoleCaspofungin Total n° patients Chills Nephrotoxicity* Discontinuation for toxicity 1895**5 * Creatinine increase 2 x base line ** Visual hallucinations more frequent with voriconazole (4.3 % vs 0.5 %)

21 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 Overall success Resolution of fever No breakthrough fungal infection Resolution of baseline infection Survival for 7 day No discontinuation for toxic effects or lack of efficacy J. KLASTERSKY, NEJM 2004

22 22 Cure of Base Line Fungal Infection Conventional ampho B Liposomal ampho B VoriconazoleCaspofungin Total n° of patients * Response/n° (%) 8/11 (72.7) 20/44 (45.4)** 6/13 (46.2) 14/27 (51.9) * 2 studies **Outcome in the study comparing conventional ampho B to liposomal ampho B was 9/11 (81.8)

23 23 Choice of a suitable denominator for the evaluation of empirical therapy based on microbiological results (T. Walsh)(J. Klastersky) Success of therapyFailure of therapy No breakthrough FITotal n° patients- Cure of baseline FIN° of baseline FI- Breakthrough FI-Total of n° of patients No cure of baseline FI-Total of n° of patients

24 24 Outcome of Empirical Antifungal Therapy in Microbiologically Demonstrated Fungal Infections (FI) Ampho BLiposomal ampho B VoriconazoleCaspofungin (344)(961)(415)(556) Breakthrough FI37 (10.8)45 (4.6)8 (1.9)29 (5.2) No cure of base line FI3 (0.8)22 (2.2)7 (1.6)13 (2.3) Total failures*40 (11.6)67 (6.9 %)15 (3.6 %)42 (7.7 %) *p = 0.03

25 25 Summary of trials of empirical antifungal therapy that evaluated alternatives to amphotericin B Study drugs% of invasive fungal infections nArm 1Arm 2Arm 1Arm 2 687AmBL-Amb AmBItraconazole L-AmBVoriconazole5.01.9* 1095L-AmBCaspofungin * p< 0.5 J.R. Wingard, CID, 2004

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27 27 Aspergillus fumigatus

28 28

29 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 30 Aspergillus Infections (AI) in Empirical Therapy Liposomal ampho B VoriconazoleCaspofungin (961)(415)(556) Breakthrough AI21410 No cure of base line AI°13*4**7 Total failures24 (2.4 %)8 (1.9 %)17 (3.0 %) ° Assuming that 1/2 infections in the liposomal ampho B arm (*) and 4/7 infections in the voriconazole arm (**) were caused by Aspergillus

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

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

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

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

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

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

37 37N. Singh, Transplantation, 2006

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

39 39 Prevalence of fungal infections in persistently neutropenic patients not receiving empirical therapy Pizzo et al. (1982)18 EORTC (1989)28 * Guiot et al. (1993)26* Corey and Boeckh (2002)45 Maertens et al. (2005)21 * Autopsy-based data

40 40

41 41 CID, 2005

42 42 The preemptive approach (adapted from Maertens et al.) « Possible IFI » Diagnostic evaluation for IFI ReasonsProcedures. FN refractory for 5 days. FUO relapsing after 48 h with N. Signs or/and symptoms suggestive of IFI. Isolation of molds/hypae in URT. Galactomannan assays positive (> 0.5). HRCT of the chest (+ sinuses). Bronchoscopy +BAL - Smears + cultures for bacteria, fungi, mycobacteria, Legionella - PCR for CMV, HSV, VZV, Toxoplasma, Pneumocystis, Mycoplasma, Chlamydia

43 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 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 45 CID, 2005

46 46 Empirical versus preemptive therapy (liposomal amphotericin B) in patients with persisting fever and neutropenia Adapted from Maertens’ study 35 patients with persistent fever EMPIRICAL APPROACH *PREEMPTIVE APPROACH 1 episode of IA (2.4 %)10 episodes of IA (28 %) ? Death2 deaths (20 %) need of a controlled study * Estimation from J. Klastersky, NEJM 2004

47 47 Blood, 2006

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

49 49 Empirical (E ) vs pre-emptive approach (PE) Results E 150 patients PE 143 patients Diagnosed IFI4 (2.6 %)13 (9.0) p < 0.02 Overall survival147 (98 %)136 (95 %) NS IFI related mortality0 (0 %)3 (2.1 %) p = 0.12 Mean cost (euros) NS

50 50 Estimated prevalence of invasive fungal infection (IFI) in neutropenic patients according to the management strategy in exemplative studies N° patientsN° IFIPrevalence % Controls ¹ Prophylaxis ² (posaconazole) Empirical therapy ³ (voriconazole) Pre-emptive therapy (polyenes) Guiot, CID, Ullmann, NEJM, Walsh, NEJM, Cordonnier, Blood, 2006

51 51 Which Antifungal Drug is Best for the Empirical Treatment of Patients with Febrile Neutropenia? Few adverse effects (amphotericin B < lipid preparations < voriconazole = caspo) Superiority of action : –conventional amphotericin looks to be the least effective –voriconazole might be superior in reducing microbiologically proven failures –Cost Resistance

52 52 Average Daily Cost of Antifungal Therapy (Jules Bordet Bruxelles) DoseEuros Conventional Amphotericin B1 mg/kg8 Liposomal amphotericin B 3 mg/kg629 Voriconazole400 mg IV407 Voriconazole400 mg PO84 Caspofungin70 mg IV644

53 53 Sensitivity of common pathogenic fungi Amphotericin BVoriconazoleCaspofungin Candida sp.SSS C. lusitaniaeRSS C. kruseiSS**S C. glabrataSS**S Trichosporon sp.RSS Aspergillus sp.*SSS Fusarium sp.RSR MucoralesSRR C. neoformansSSR *Except terreus **MIC are higher than for C. albicans but still < 3 ng/ml

54 54 Antifungal therapy in persistently febrile neutropenic patients Voriconazole is presently the optimal choice for therapy and empirical therapy of suspected aspergillar infections Early therapy (empirical) is needed since mortality remains high (30-50 %) Empirical therapy reduces the incidence of IFI from + 25 % to %; the corresponding figures for liposomal ampho B and caspofungin being + 7 % Experience with the preemptive approach is still limited; it is demanding in terms of diagnostic procedures but it reduces the rate of overtreatment. There is evidence so far that pre-emptive therapy is inferior in efficacy and not more cost effective than the empirical approach Conclusions

55 55 Needs for Improvement of Neutropenic Febrile Patients with Persistent Fever to Avoid Overtreatment 1. Better diagnostic tools for EARLIER microbiological and clinical diagnosis : galactomannan, PCR, those caused by Aspergillus sp. 1. More accurate IDENTIFICATION OF PATIENTS at high risk of fungal infections (cf MASCC score)

56 56 Thank you for your kind attention and « Au revoir »


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