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

www.dgho-infektionen.de

TIMM-4 18 - 21 October 2009

Athens, Greece

www.ichs.org

Pagano L et al (Italian Multicenter Study), Haematologica 2006;91:1068-75

1999 2000 2001 2002 2003

6

5

4

3

2

1

0

All fungi Aspergillus spp Candida spp Other yeasts Other molds

Year

Mold and Yeast Infections in Patients with Hematological Malignancies: Trends 1999-2003

Pagano L et al (Italian Multicenter Study), Haematologica 2006;91:1068-75

7.1%

Mold Infections in Patients with Hematological Malignancies: Prognosis

Pagano L et al (Italian Multicenter Study), Clin Infect Dis 2007;45:1161-70

Mold Infections in Patients Undergoing HSCT Italy, 1999-2003

  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%

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

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

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)

1Goodman JL et al, N Engl J Med 1992;326:845 2Slavin MA et al, J Infect Dis 1995;171:1545 3Marr KA et al, Blood 2004;103:1527 4van Burik JA et al, Clin Infect Dis 2004;39:1407 5Mattiuzzi GN et al, Antimicrob Agents Chemother 2006;50:143 6Cornely OA et al, New Engl J Med 2007;356:348 7Ullmann AJ et al, New Engl J Med 2007;356:335

Goodman et al1*

N=356

Slavin et al2*

N=300

Marr et al3†

N=304

van Burik et al4†‡

N=882

Inci

denc

e of

IFI (

%)

0

5

10

15

20

25

30

2.8

15.8

7

18

7

15

1.6 2.4

Incidence of IFI while on study treatment except where noted.

* Proven † Proven and probable ‡ Includes 4-week follow-up period

6 6

Mattiuzzi et al5†

N=200

2

FLU

Placebo

MIC

POS

8 10

Cornely et al6†

N=602

ITR

Primary Antifungal Prophylaxis in Hematologic Malignancies / HSCT Patients

Ullmann et al7†

N=600

5

9

Updated Guidelines for Primary AF Prophylaxis Cornely OA et al (AGIHO), Haematologica 2009;94:113-22

Patient Population Purpose Drug Dosage Level of

Evidence

Conventional Chemotherapy

Reduction of

Attributable Mortality

Fluconazole 50-400 mg qd po C I Itraconazole oral solution 2.5-7.5 mg/kg qd C I

Itraconazole capsules Any dose C I

Posaconazole 200 mg tid po A I

Amphotericin B deoxycholate

0.5-1.0 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

Allogeneic Bone Marrow or Stem Cell Transplant

Fluconazole 400 mg qd po A I Fluconazole 50-200 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

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

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

Cometta A et al (EORTC-IATG), Clin Infect Dis 2003;37:382-9

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 4.3 ± 0.8

Death from infection (day of death) 1 (14) 1 (35)

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

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

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)

Comparison of „Walsh Studies“

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

Pre-emptive Therapy Definition and Rationale

 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

Treatment of a suspected or presumed fungal infection in advance of confirmation

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

Pre-emptive Treatment Based on Imaging Findings in Pulmonary Aspergillosis

Greene RE et al, Clin Infect Dis 2007;44:373-9

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 Eur J Cancer 2009;45:2462-72

Algorithm for the Clinical Management of Patients with Febrile Neutropenia

and Lung Infiltrates

Maschmeyer G et al (AGIHO), Eur J Cancer 2009;45:2462-72

Patients with Fever and Lung Infiltrates Benefit from First-Line Amphotericin B

Paul Ehrlich Society Study I vs II Schiel X et al (PEG Study II), Infection 2006;34:118-26

**) Exactly matching Caillot D et al, J Clin Oncol 1997;15:139-47

**

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

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;4:796-802

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

Clin Infect Dis 2006; 42:487–9

PCR: Not Ready for Primetime

Pre-emptive vs Empiric Treatment Studies

Study Comparison Number of subjects Conclusions

Cordonnier et al, 2006

Empiric vs pre-emptive in febrile neutropenic pts

Empiric: 150 Pre-emptive: 143

Less AF use with pre-emptive strategy; more IFI’s but no signif. increase in IFI-related mortality

Hebart et al, 2004

Empiric vs pre-emptive (PCR) in febrile allo HSCT pts

Empiric: 207 Pre-emptive: 196

More AF use with pre-emptive strategy; fewer IFI’s and reduction in mortality <28d

Maertens et al, 2005

Empiric vs pre-emptive (GM, CT) in febrile neutropenics

Total: 136 Less AF use with pre-emptive strategy with no missed cases of aspergillosis

Cordonnier C et al, Clin Infect Dis 2009;48:1042-51 Hebart H et al, ASH 2004, #192 Maertens J et al, Clin Infect Dis 2005;41:1242-50

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