Evolving Etiology and Management of Infections in the Hematologic Malignancy Patient

Lindsey R. Baden, MD Dana-Farber/Brigham and Womens Cancer Center

Educational Objectives
Summarize the most common pathogens (including antibiotic-resistant pathogens) currently affecting patients with hematologic malignancies Select appropriate antimicrobial regimens for the treatment of patients with hematologic malignancies that minimize the contribution to the rise of drug-resistant pathogens

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Fundamental Principles
Infection is a function of
Pathogen exposure
Reservoir, vector, mode of transmission
Candida: person to person with acquisition likely via ingestion (GI tract reservoir) or via catheters Aspergillus: air, ?water with acquisition via the respiratory tract

Host susceptibility
Net state of immunosuppression

Critical Factors in Assessing the Risk for Infection I

Net State of Immunosuppression
D Dose, d ti sequence of immunosuppressive duration, fi i medications (e.g., pulse steroids, OKT3) Rejection Leukopenia Breakdown of barriers, devitalized tissue ( , ) Metabolic factors (malnutrition, uremia) Infection w/ immunomodulating viruses (CMV, HIV)

Consequence of invasive procedures

Supportive (lines, Foley, ET tube) Technical aspect of the surgery

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Critical Factors in Assessing the Risk for Infection II

Epidemiologic exposures
Nosocomial
MRSA, VRE, C difficile, Aspergillus, Legionella, Pseudomonas

Community
Respiratory viruses, Legionella, Mycobacteria, Cryptococcus neoformans, Aspergillus neoformans Aspergillus, Nocardia asteroides Pneumocystis asteroides, carinii, Listeria, Salmonella, Strongyloides

Geographic
Histoplasma, Coccidioides, Blastomyces

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Transplant ID Principles
Immediate transplant period (<1m)
95% of infections are related to mucositis and f i f ti l t dt iti d neutropenia: bacterial, candida, or mold

Sub-acutely post transplant (30-100 days)

Classic immunocompromised infections: CMV, PCP

Remotely post transplant (>100 days)

Typically at risk for community acquired processes yp y y q p

Ner do well patient

GVHD, increased immunosuppression, protein-calorie malnutrition At risk for all of the above

normal host Intensity of I i f signs and symptoms

compromised host h t

Time

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Microbial Mi bi l burden

compromised host

normal host Time

Antibiotic Strategies
Therapeutic
Treat established clinical infection Diagnostic dilemma vs. therapeutic emergency

Prophylactic
Given to all members of a population to prevent the occurrence of clinical infection

Preemptive
Given to the individuals at the highest risk for clinical infection based on a laboratory or epidemiologic marker

Empiric
Given to individuals with signs of a possible infection

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Key Factors to Consider for Prophylaxis/Preemption

Pathogen
Pathogenesis
e.g., Candida (GI/GU) vs. Aspergillus (environmental)

Cause significant morbidity/mortality How difficult is it to treat established disease

Therapy
Effective Safe
adverse effects, drug-drug interactions, evolutionary stress

Dose Affordable

Kinetics
What is the risk period (beginning and end)

Effect of Antimicrobial Prophylaxis on the Rate of and Time to Infection

Baden L. N Engl J Med 2005;353:1052-1054

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Which patient group(s), during what specific time frame have a high enough attach rate for the patient to benefit from prophylaxis (?vs. preemption)?

Organisms of Interest for Prophylaxis, Preemption, or Empiric Therapy

Bacteria
Gram-negative rods MTb

Fungae
Candida, Aspergillus, PCP, Cocci

Viruses
HSV, CMV

Parasites
Strongyloides

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Neutropenia as a Risk Factor for Infection

50 45

In nfections per 1000 Days

40 35 30 25 20 15 10 5 0 < 100 100-500 500-1000 1000-1500 > 1500

Neutrophil Count (cells/L)

Bodey et al. (1966) Ann Intern Med 64:328-40.

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Nature of the Host Defects

Neutropenia Disruption of mucosal integrity Devices compromising mechanical defenses (central lines, urinary catheters)

Approach to Empiric Antibiotics When Fever Develops

Flora of concern
Predominantly: Enteric GNR and P aeurginosa

Established regimens
Ceftazidime, Piperacillin/gentamicin, Cefipime, Imipenem Approx 65% patients will respond to Abx

B-lactam allergic patient

Aztreonam/gentamicin (no streptococcal coverage), g g quinolone/gentamicin

Alter regimen if significant prior antimicrobial treatment or local antimicrobial resistance patterns of concern
NCCN Guidelines at www.NCCN.org IDSA Guidelines CID 2011;52(4):e56-93

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Approach to Empiric Antibiotics When Fever Develops

Role for specific Gram-positive coverage Gram positive
Only when a likely Gram-positive source is identified such as an infected catheter

Role for anaerobic coverage

When evidence for oral, abdominal or perianal infection

Duration of empiric antibiotics

Until ANC > 500 If BM failure then re-assess goals of antibiotics after 14 days of afebrility. If Abx stopped and patient remains neutropenia approximately 30% will become febrile again
NCCN Guidelines at www.NCCN.org IDSA Guidelines CID 2011;52(4):e56-93

High vs. Low Risk Patients

Influenced by:
Underlying disease, therapy, severity of neutropenia, concomitant factors (e.g., mucositis, catheters)

Typically low risk patients with <10 days neutropenia and no other complicating condition
Consider oral antibiotics
ciprofloxacin /amoxicillin/clavulanate potassium vs ceftazidime (71% vs 67% effective) ciprofloxacin /amoxicillin/clavulanate potassium vs ceftriaxone/amikacin (86% vs 84% effective)
Kern et al. NEJM 1999:341:312-8 and Freifeld et al. NEJM 1999;341:305-11

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Kaplan-Meier Estimates of Survival Free from Fever among All Patients (Panel A), Patients with Acute Leukemia (Panel B), and Patients with Solid Tumors or Lymphoma (Panel C)

Bucaneve G et al. N Engl J Med 2005;353:977-987

Characteristics of Bacterial Isolates and Number with Resistance to Levofloxacin

Bucaneve G et al. N Engl J Med 2005;353:977-987

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Mortality Rates in the Treated Population

Bucaneve G et al. N Engl J Med 2005;353:977-987

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Case 3
63 yo F undergoing induction chemotherapy for AML. 4weeks into therapy develops fevers and elevated AlkPhos. Abd CT demonstrates multiple abscesses in the liver and spleen. Biopsy demonstrate C albicans.

General Risk Factors for IFI

Immunosuppression
Prolonged neutropenia, allograft issues, rejection

Host
Renal failure, DM, malnutrition

Large inoculum
Environmental exposure (even remote), colonization w/ pathogen, pathogen broad spectrum antimicrobial use

Permissive co-infections
CMV, ?HHV-6

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Prevention Strategies for IFI: Key Concepts Prophylaxis

Fluconazole diminishes invasive Candida infections
Unclear role for: amphotericin B (varying doses IV/Inh) itraconazole doses, IV/Inh),

Empiric
F+N for > 96h of appropriate antimicrobials for GNRs ?Dose: 0.3, 0.5, 0.7, 1.0 mg/kg ampho all used by different major centers. ? Role for lipid formulations Itraconazole (IV), caspofungin, ?voriconazole

P Preemption ti
Colonized with a pathogenic species (Aspergillus) Radiologic or molecular evidence of infection Molecular markers
Caillot J Clin Onc 1997;15:139 Boogaerts Ann Intern Med 2001;135:412 Caillot CID 2001;33 Maertens ICAAC 2000;40:371 abstr 1103

IFI Prophylaxis: Oncology - BMT

When is the risk period?
Neutropenia, GVHD (acute/chronic)

Who is at highest risk?

Allogeneic BMT, likely relapsed leukemia Limited benefit for Auto-BMT, induction chemo

Evolving risk factors

Novel chemo (targeted therapies), mini-allos I Immune-modulators (G-CSF) d l (G CSF)

Pathogens of greatest interest

Candida, Aspergillus

Drugs studied
Fluc, Itra, Ampho (Inh, PO, IV), NYS, Vori, Micafungin

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Prevention of IFI in Allo-BMT

Fluconazole use decreases invasive yeast infections during transplant period
Dose 400mg qd Day 0 until engraftment/d75

Associated with the emergence of resistant yeast species (C krusei and glabrata)
7 fold increase risk for C krusei infection but less C albicans and tropicalis 40% vs 17% rate of colonization with C krusei

One study w/ increased mold infections associated w/Flu prophylaxis

18 vs 29% of autopsied patients (RR 0.4, p=.009)
Slavin JID 1995:171;1545, Marr Blood 2000:96;2055 and van Burik Medicine 1998;77:246-54 Goodman NEJM 1992:326;845 and Wingard NEJM 1991;325:1274

Candida Species Before and After Fluconazole Prophylaxis

585 patients undergoing 70 BMT, 1994-97. 60 Fluc 400 mg for 75 days. 50 Colonization during azole prophylaxis: 44% overall, No. patients 40 30 38.4% C. krusei, 37% C. g glabrata. 20 10 34 episodes of Candidemia: C. glabrata (47%), C. 0 parapsilosis (23%), C. krusei (20%)
Marr et.al. JID 181:309-16, 2000
1980-86 1994-97

C albi

C trop

C glab

C krus

C para

Blood isolates

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Randomized Studies of Fluconazole Prophylaxis

Goodman FLU 400mg Placebo Slavin FLU 400mg Placebo Winston FLU 400mg Placebo Rotstein FLU 400mg Placebo Schaffner FLU 400mg Placebo Year 1992 N 179 177 1995 152 148 1993 123 132 1999 141 133 1995 75 76 AML/NHL 8 9 5 7 Leuk/Auto 3 17 11 11 Leukemia 4 8 1 3 BMT 7 18 28 55 Disease BMT Proven IFI (%) Mortality (%) 3 16 31 26

Cornely Blood 2003;101:3365-3372

Micafungin Prophylaxis in HSCT

Fluconazole (400) vs micafungin (50)
n= 882 PIII, randomized, double blind

Medication given during g g neutropenic period Success 73.5 vs 80%

van Burik CID 2004;39:1407

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Time to Proven or Probable Invasive Fungal Infection

Ullmann A et al. N Engl J Med 2007;356:335-347

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Proven or Probable Invasive Fungal Infection during the Treatment Phase

Cornely O et al. N Engl J Med 2007;356:348-359

Clinical Response and Reasons for Failure during the Treatment Phase

Cornely O et al. N Engl J Med 2007;356:348-359

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Case 5
63 year female develops facial y p pain and fever on d+10 of an allo-BMT for M2 AML. Her antimicrobial therapy included: ceftazidime and amphotericin B (0.5 mg/kg/day empirically begun 2 days earlier). An emergent head CT revealed the following: f ll i

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Bodey et al. (1966) Ann Intern Med 64:328-40.

1/20/07

1/26/07

2/05/07

2/23/07

4/04/07

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Empiric Anti-Fungal Therapy

CAB
Pizzo Am J of Med 1982;72:101-11 50 F+N pts

Amphotericin B
Walsh NEJM 1999;340:764-71 CAB vs AmB inc cr (34 vs 19%) 787 F+N pts 837 F+N pts.

Voriconazole
Walsh NEJM 2002;346:225-34

Itraconazole
Boogarts Ann Intern Med 2001;135:412-422 384 F+N pts.

Caspofungin
Walsh NEJM 2004;351:1391-1402 1000 F+N pts

Galactomannan
Prospective serial GM measurement in 362 consecutive high-risk treatment episodes in 191 patients (BMT and leukemic). Time period: 1/97-2/00. EORTC/MSG definitions of IFI with autopsy confirmation. Based on 2 or more positive GM samples.
Sensitivity Specificity Proven IA Probable IA Proven + probable IA Possible IFI 100 55.5 89.7 7.4 98.1 98.1 98.1 98.1 PPV 85.7 50 87.5 44.4 NPV 100 98.4 98.4 83.8

Maertens Blood 2001:97;1604

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Important Fungal Syndromes

Candidemia Hepatosplenic Candidiasis Invasive Pulmonary Aspergillosis Disseminated Aspergillosis

Issues to Consider with New Diagnostics for IFI

How many pathogenic species can be identified by a given diagnostic modality? Is Aspergillus detection enough? What is the gold standard for diagnosis? Diagnostic vs. therapeutic use? Does earlier diagnosis of an IFI matter? Is it the NPV or PPV that we are after? Are the performance characteristics equal across body sites of infection? Is the diagnostic technique exportable?

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

HSV
Approximately 80% of seropositive patients will reactivate HSV with neutropenia Typically oropharynx Acyclovir 400 mg po/iv bid is highly effective Emergence of resistance

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.

Typical Infectious Sources of Fever in the Setting of Neutropenia

Catheters Respiratory tract GI tract
Typhlitis, peri-rectal abscess, C diff

Routine evaluation
History, physical exam, CBC, SMA-7, LFTs, urine analysis, blood/sputum/urine cultures, CXR +/- CT Source identified in approximately 50% cases

Conclusion
Prophylaxis is a blunt hammer and should be supplanted by pre-emption Identification of high risk groups, during high risk periods is essential
Molecular markers hold great promise

Geographic and local organism burden are important Development of safe, effective, convenient antimicrobial agents will alter the equation Emergence of resistant organisms and medication g g toxicity remain significant concerns Novel therapies for the underlying condition leading to transplantation may shift the spectrum of the infectious complications - dynamic environment

Copyright 2011, National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from NCCN.