Update on the Treatment of Invasive Fungal Infections for the Oncologist Coleman Rotstein MD University of Toronto University Health Network Toronto, Ontario

Epidemiology of Invasive Fungal Infections in Cancer Patients

Distribution of Nosocomial Pathogens in Cancer Patients 80

77 %

70 60 50 % Nosocomial 40 Infections 30 20

4%

2%

10 0 Bacterial

Fungal

Viral

Pathogen (Rotstein C et al. Infect Control Hosp Epidemiol 1988;9:13-19)

Epidemiology „

Invasive fungal infections cause considerable morbidity & mortality in cancer patients particularly those with neutropenia. (Schwartz et al. Cancer 1984;53:411-419) (Bodey et al. Eur J Clin Microbiol Infect Dis 1992;11:99-109) (Bow et al. Clin Infect Dis 1995;21:361-369)

Gradation of Risk of Invasive Fungal Infection In Cancer Patients Disease

Rates of Invasive Fungal Infection 1980s & 1990s 1960s & 1970s1

HSCT

20%-30%

21%-57%2,3

Acute Leukemia

20%-30%

19%-47%4

Lymphoma

10%-20%

NA

1%-5%

2%5

Solid Tumors

(1. Wingard JR, Leather HL. Oncology 2001;15:3512001;15:351-369. 2. De La Rosa GR, Champlin RE, Kontoiannis DP. Transpl Infect Dis 2002;4:32002;4:3-9. 3. Wakayam M, Shibuay K, Ando T et al. Mycoses 2002;45:1462002;45:146-151. 4. Bow E. Br J Haematol 1998;101(suppl1):11998;101(suppl1):1-4. 5. Montesinos J, Sola C, Maroto P et al. Eur J Clin Microbiol Infect Dis 2001;20:5692001;20:569-572.)

Clinical Characteristics of Patients with IFIs No. of Patients (%) Characteristic

1989-93

1994-98

1999-2003

Median Age (range)

44 (15-87)

49 (2-83)

53 (19-77)

AML

60/147 (41)

41/85 (48)

30/82 (37)

ALL

23/147 (16)

16/85 (19)

17/82 (21)

CML

25/147 (17)

5/85 (6)

5/82 (6)

NHL

15/147 (10)

9/85 (11)

9/82 (11)

CLL

8/147 (5)

3/85 (4)

9/82 (11)

Myelodysplastic Syndrome

8/147 (5)

5/85 (6)

6/82 (7)

Other

8/147 (5)

6/85 (7)

5/82 (6)

(Chamilos G et al. Haematologica 2006;91:986-989)

Epidemiology (cont’d) „

High mortality from IFIs: ‹ Mortality

rates due to fungal infections in pt. with malignancies range from 6% - 60% (EORTC. Am J Med 1989;86:668-672) (Guiot et al. Clin Infect Dis 1994;18:525-532)

Pathogenic Fungi

Etiology of Fungal Infection in Cancer Patients Candida spp (48%)

Other (21%)

Aspergillus spp (31%) (Data from Walsh et al. Rev Infect Dis. 1991;Bodey et al. Eur J Clin Microbiol Infect Dis. 1992; Vazquez et al. J Infect Dis. 1993; Pannuti et al. Cancer. 1992; Anaisse et al. Rev Infect Dis. 1989; Morrison et al. Am J Med. 1994)

Prevalence of IFIs in Hematological Malignancies: Autopsy Study 1989-93, 1994-98 & 1999-2003 - MD Anderson 35

Percent

30

Total IFI

25

15

Invasive Mold Infection Aspergillus

10

Candida

20

5 0 1989-93

1994-99

Time Period

1999-2003

(Chamilos G et al. Haematologica 2006;91:986-989)

Total Pathogens N=466

IFI’s in HSCTs 3.1 2.9

5.5 7.6 41.6 8.8

28.3

(Pappas PG. FOFI 2005)

Aspergillus Candida Other Moulds Unspecified Moulds Zygomycetes Fusarium PCP

Time to Onset of IFI for HSCTs 120 100 IA

# of IFI's

80

Candidiasis Fusarium

60

Other mould PCP

40

Unspec. mould Zygomycetes

20 0 Early Onset (0-30 days)

Intermediate Onset (30-60 days)

Late Onset (90+ days)

(PG Pappas: Transplant Associated Infection Surveillance Network) Network)

Origin of Pathogenic Fungi

Origin of Fungal Pathogens „

Candida spp. ¾

„

Endogenous organisms – normal commensals of skin, GI tract & GU tract

Aspergillus spp. ¾ ¾

Ubiquitous in environment Inhaled

Strategies for Treatment of Invasive Fungal Infections in Cancer Patients

(Marr K. Curr Treatment Options in Infect Diseases 2001)

Treatment for Candidemia/Invasive Candidiasis and Invasive Aspergillosis

Treatment of Candidemia/ Invasive Candidiasis

Two Key Principles of Treatment „

Hit Early

„

Hit Right

Mortality Rates with Delay in Therapy for Candidemia 41% ICU Patients 45

Test for trend p=.0009

37%

40

41%

Mortality Rate

35 30 25 20

24% 15%

15 10 5 0

Day 0

Day 1

Day 2

Day >= 3

Time to Initiation of Fluconazole for Candidemia (Garey KW et al. CID 2006;43:25-31)

Increased Hospital Mortality with Inadequate Antimicrobial Therapy for Candidemia „

„

Bloodstream infection-related mortality rate higher for patients receiving inadequate antimicrobial therapy 29.9% vs. 11.9% with adequate antimicrobial therapy (p