Prophylaxis, Empirical, Pre-emptive Therapy of Aspergillosis in Hematological Patients: Which Strategy?

Transcription

1 TIMM October 2009 Athens, Greece Prophylaxis, Empirical, Pre-emptive Therapy of Aspergillosis in Hematological Patients: Which Strategy? Georg Maschmeyer Dept. of Hematology, Oncology and Palliative Care Klinikum Ernst von Bergmann Potsdam, Germany

2 Mold and Yeast Infections in Patients with Hematological Malignancies: Trends All fungi Aspergillus spp Candida spp Other yeasts Other molds Year Pagano L et al (Italian Multicenter Study), Haematologica 2006;91:

3 Mold Infections in Patients with Hematological Malignancies: Prognosis 7.1% Pagano L et al (Italian Multicenter Study), Haematologica 2006;91:

4 Mold Infections in Patients Undergoing HSCT Italy, n = 3228 (1249 allogeneic, 1979 autologous) HSCT patients admitted to 11 Italian HSCT centers Incidence of proven/probable IA among allosct recipients: 8% Attributable mortality rate of IA in allosct recipients: 77% Pagano L et al (Italian Multicenter Study), Clin Infect Dis 2007;45:

5 Antifungal Management Strategies Highest-risk patient (eg, HSCT for Candida) No infection High-risk patient with persistent fever despite antibiotics Possible infection High index of suspicion (based on signs and symptoms) but without definitive diagnostic proof Probable infection Full-blown disease Proven infection Prophylaxis Empirical Therapy Pre-emptive Therapy Specific Treatment Increasing certainty of fungal infection

6 Rationale for Prophylaxis Outcome of IFI historically has been suboptimal and associated with high fatality rate Early diagnosis is difficult to make May become better with new diagnostics and worse with pre-emptive therapy Best available treatments => 52% CR/PR (IA), 65% (IC) Side effects Host defenses important for resolution of infection

7 Approaches to Antifungal Prophylaxis (AFP) Global: Administration of AFP to an entire population at risk Standardizes approach for all patients Potential excessive exposure to patients Targeted: Target those at highest risk Use a parameter of host susceptibility to determine the targeted group at risk e.g. mold-active AFP to patients with GvHD post allogeneic hematopoietic stem cell transplant e.g. mold-active AFP for pts with expected neutrophils <100 for >10 days (AML with aggressive ctx)

8 Primary Antifungal Prophylaxis in Hematologic Malignancies / HSCT Patients Incidence of IFI (%) FLU ITR MIC POS Placebo Goodman et al 1 * N=356 Slavin et al 2 * N=300 Marr et al 3 N=304 van Burik et al 4 N=882 Mattiuzzi et al 5 N=200 Cornely et al 6 N=602 Ullmann et al 7 N=600 1 Goodman JL et al, N Engl J Med 1992;326:845 2 Slavin MA et al, J Infect Dis 1995;171: Marr KA et al, Blood 2004;103: van Burik JA et al, Clin Infect Dis 2004;39: Mattiuzzi GN et al, Antimicrob Agents Chemother 2006;50:143 6 Cornely OA et al, New Engl J Med 2007;356:348 7 Ullmann AJ et al, New Engl J Med 2007;356:335 Incidence of IFI while on study treatment except where noted. * Proven Proven and probable Includes 4-week follow-up period

9 Updated Guidelines for Primary AF Prophylaxis Cornely OA et al (AGIHO), Haematologica 2009;94: Patient Population Conventional Chemotherapy Allogeneic Bone Marrow or Stem Cell Transplant Purpose Drug Dosage Reduction of Attributable Mortality Level of Evidence Fluconazole mg qd po C I Itraconazole oral solution mg/kg qd C I Itraconazole capsules Any dose C I Posaconazole 200 mg tid po A I Amphotericin B deoxycholate mg/kg q48h iv C II <0.5 mg/kg q48h iv C II 20 mg qd inhalation C I Liposomal amphotericin B 50 mg q48h B I Fluconazole 400 mg qd po A I Fluconazole mg qd po C I Itraconazole oral solution 400 mg qd C I Posaconazole 200 mg tid po A I Liposomal amphotericin B 1.0 mg/kg qd iv C I

10 Considerations for Systemic Antifungal Prophylaxis Risks: Emergence of multi-azole resistance? Effect on patterns of breakthrough infections Adverse events Potentially deleterious effects of drug interactionss

11 Antifungal Management Strategies Highest-risk patient (eg, HSCT for Candida) No infection High-risk patient with persistent fever despite antibiotics Possible infection High index of suspicion (based on signs and symptoms) but without definitive diagnostic proof Probable infection Full-blown disease Proven infection Prophylaxis Empirical Therapy Pre-emptive Therapy Specific Treatment Increasing certainty of fungal infection

12 Vancomycin in Neutropenic Pts with Fever Persisting after Piperacillin-Tazobactam Monotherapy (48-60 h) Randomized, double-blind, placebo-controlled study: P/T + vancomycin (n = 86) vs P/T + placebo (n = 79) Duration of neutropenia < 500 ANC/µl: 14 days P/T + V P/T + Plc Defervescence under therapy 45% 44% Median time to defervescence (days) 3.5 ± ± 0.8 Death from infection (day of death) 1 (14) 1 (35) Cometta A et al (EORTC-IATG), Clin Infect Dis 2003;37:382-9

13 Vancomycin in Neutropenic Pts with Fever Persisting after Piperacillin-Tazobactam Monotherapy (48-60 h) Cometta A et al (EORTC-IATG), Clin Infect Dis 2003;37:382-9

14 Empirical Antifungal vs No Antifungal Tx in High-Risk Neutropenic Patients with FUO persistent after 96 h Prospective, Randomized Study Fluconazole not significantly better than no antifungal Schiel X et al (PEG Study II), Infection 2006;34:118-26

15 Empiric Antifungal Treatment in High-Risk Patients with Persistent FUO Amphotericin B more effective than antibiotics (Pizzo 1982; EORTC 1989; PEG study-ii 1998) Fluconazole vs D-AmB: less toxic and equally effective (Viscoli 1996; Winston 2000); inferior (Schiel 2006) Itraconazole vs D-AmB: less toxic and equally effective (Boogaerts 2001) Liposomal vs D-AmB: less toxic and less breakthrough FI (Prentice 1997; Walsh 1989) Liposomal vs ABLC: less toxic (Wingard JA 2000) Voriconazole vs L-AmB: less toxic and less breakthrough FI (Walsh 2002) Caspofungin vs L-AmB: less toxic and at least as efficacious (Walsh 2004)

16 Comparison of Walsh Studies

17 Overview of Antifungal Management Strategies Highest-risk patient (eg, HSCT for Candida) No infection High-risk patient with persistent fever despite antibiotics Possible infection High index of suspicion (based on signs and symptoms) but without definitive diagnostic proof Probable infection Full-blown disease Proven infection Prophylaxis Empirical Therapy Pre-emptive Therapy Specific Treatment Increasing certainty of fungal infection

18 Pre-emptive Therapy Definition and Rationale Treatment of a suspected or presumed fungal infection in advance of confirmation High morbidity and mortality associated with established invasive fungal infection High costs associated with disseminated Candida infection and invasive aspergillosis Difficulty and uncertainty of diagnosis Rapid progression of disease Early treatment often associated with improved outcomes

19 Pre-emptive Antifungal Therapy: Approach Suspect of invasive fungal infection Obtain cultures, take biopsy whenever possible Initiate treatment, even before culture results are known Adjust antimicrobial therapy accordingly, once (if) results are available

20 Pre-emptive Treatment Based on Imaging Findings in Pulmonary Aspergillosis Greene RE et al, Clin Infect Dis 2007;44:373-9

21 Eur J Cancer 2009;45: Georg Maschmeyer, Potsdam Thomas Beinert, Wartenberg Dieter Buchheidt, Mannheim Oliver A. Cornely, Köln Hermann Einsele, Würzburg Werner Heinz, Würzburg Claus Peter Heussel, Heidelberg Christoph Kahl, Rostock Michael Kiehl, Frankfurt/Oder Joachim Lorenz, Lüdenscheid Herbert Hof, Mannheim Gloria Mattiuzzi, Houston, TX, USA

22 Algorithm for the Clinical Management of Patients with Febrile Neutropenia and Lung Infiltrates Maschmeyer G et al (AGIHO), Eur J Cancer 2009;45:

23 Patients with Fever and Lung Infiltrates Benefit from First-Line Amphotericin B ** **) Exactly matching Caillot D et al, J Clin Oncol 1997;15: Paul Ehrlich Society Study I vs II Schiel X et al (PEG Study II), Infection 2006;34:118-26

24 Proof of Pathogen: What We Need Well-defined technique Reliable Rapid Minimally invasive procedure Low volume sample Potential for serial monitoring Optimization of sensitivity and specificity Allows earlier diagnosis Measures response to therapy

25 Galactomannan as a Marker for Invasive Aspergillosis Approved for use in patients with cancer Serial monitoring in cancer patients increases sensitivity of assay Lower positive index cutoff (ie, 0.5 instead of 1.5) increases sensitivity in patients receiving systemic antifungal agents Rising index in consecutive samples increases specificity False positives - unresolved issue for pediatric and SOTxP recipients Utility for BAL and CSF under investigation Marr KA et al, J Infect Dis 2004;190:641-9 Kwak EJ et al, J Clin Microbiol 2004;42:435-8 Husain S et al, Am J Transplant 2004;4:

26 PCR: Not Ready for Primetime Clin Infect Dis 2006; 42:487 9

27 Pre-emptive vs Empiric Treatment Studies Study Comparison Number of subjects Conclusions Cordonnier et al, 2006 Hebart et al, 2004 Maertens et al, 2005 Empiric vs preemptive in febrile neutropenic pts Empiric vs preemptive (PCR) in febrile allo HSCT pts Empiric vs preemptive (GM, CT) in febrile neutropenics Empiric: 150 Pre-emptive: 143 Empiric: 207 Pre-emptive: 196 Total: 136 Less AF use with preemptive strategy; more IFI s but no signif. increase in IFI-related mortality More AF use with preemptive strategy; fewer IFI s and reduction in mortality <28d Less AF use with preemptive strategy with no missed cases of aspergillosis Cordonnier C et al, Clin Infect Dis 2009;48: Hebart H et al, ASH 2004, #192 Maertens J et al, Clin Infect Dis 2005;41:

28 Conclusions High-risk patients may benefit from systemic AF prophylaxis AlloHSCT Profound and prolonged neutropenia (AML and MDS with high local IA incidence rates) Trend to move away from empiric management of fever Newer diagnostics Facilitate the pre-emptive approach Substantial improvements in treatment