Evolving Etiology and Management of Infections in the Hematologic Malignancy Patient

Lindsey R. Baden, MD Dana-Farber/Brigham and Women’s 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®.

Mycobacteria. Pseudomonas – Community • Respiratory viruses. . Coccidioides. No part of this publication may be reproduced or transmitted in any other form or by any means. Strongyloides – Geographic • Histoplasma. Listeria. C difficile. VRE. National Comprehensive Cancer Network®. All rights reserved. electronic or mechanical.Critical Factors in Assessing the Risk for Infection II • Epidemiologic exposures – Nosocomial • MRSA. without first obtaining written permission from NCCN®. Cryptococcus neoformans. Legionella. Legionella. Aspergillus. Blastomyces Copyright 2011©. Nocardia asteroides Pneumocystis asteroides. carinii. Salmonella. Aspergillus neoformans Aspergillus.

All rights reserved. increased immunosuppression. National Comprehensive Cancer Network®. . 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©. No part of this publication may be reproduced or transmitted in any other form or by any means. candida. electronic or mechanical. or mold • Sub-acutely post transplant (30-100 days) – ‘Classic’ immunocompromised infections: CMV. without first obtaining written permission from NCCN®. PCP • Remotely post transplant (>100 days) – Typically at risk for community acquired processes yp y y q p • N’er do well patient – GVHD.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.

National Comprehensive Cancer Network®. . No part of this publication may be reproduced or transmitted in any other form or by any means. All rights reserved. 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©. 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.

353:1052-1054 Copyright 2011©. drug-drug interactions. All rights reserved.. No part of this publication may be reproduced or transmitted in any other form or by any means.g. National Comprehensive Cancer Network®.Key Factors to Consider for Prophylaxis/Preemption • Pathogen – Pathogenesis • e. electronic or mechanical. without first obtaining written permission from NCCN®. Aspergillus (environmental) – Cause significant morbidity/mortality – How difficult is it to treat established disease • Therapy – Effective – Safe • adverse effects. Candida (GI/GU) vs. . 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.

PCP. All rights reserved. electronic or mechanical. without first obtaining written permission from NCCN®. No part of this publication may be reproduced or transmitted in any other form or by any means. Aspergillus. preemption)? Organisms of Interest for Prophylaxis. Preemption. CMV • Parasites – Strongyloides Copyright 2011©. .Which patient group(s). during what specific time frame have a high enough attach rate for the patient to benefit from prophylaxis (?vs. or Empiric Therapy • Bacteria – Gram-negative rods – MTb • Fungae – Candida. Cocci • Viruses – HSV. National Comprehensive Cancer Network®.

All rights reserved. electronic or mechanical.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/μL) Bodey et al. National Comprehensive Cancer Network®. Copyright 2011©. No part of this publication may be reproduced or transmitted in any other form or by any means. . (1966) Ann Intern Med 64:328-40. without first obtaining written permission from NCCN®.

No part of this publication may be reproduced or transmitted in any other form or by any means. All rights reserved. Piperacillin/gentamicin.Nature of the Host Defects • Neutropenia • Disruption of mucosal integrity • Devices compromising mechanical defenses (central lines.52(4):e56-93 Copyright 2011©. urinary catheters) Approach to Empiric Antibiotics When Fever Develops • Flora of concern – Predominantly: Enteric GNR and P aeurginosa • Established regimens – Ceftazidime. g g quinolone/gentamicin • Alter regimen if significant prior antimicrobial treatment or local antimicrobial resistance patterns of concern NCCN Guidelines at www. without first obtaining written permission from NCCN®.NCCN. Cefipime.org IDSA Guidelines CID 2011. electronic or mechanical. National Comprehensive Cancer Network®. Imipenem – Approx 65% patients will respond to Abx • B-lactam allergic patient – Aztreonam/gentamicin (no streptococcal coverage). .

52(4):e56-93 High vs. without first obtaining written permission from NCCN®. mucositis. NEJM 1999:341:312-8 and Freifeld et al.g. NEJM 1999.NCCN. No part of this publication may be reproduced or transmitted in any other form or by any means. concomitant factors (e.. therapy. electronic or mechanical. National Comprehensive Cancer Network®. .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.org IDSA Guidelines CID 2011. Low Risk Patients • Influenced by: – Underlying disease. 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. All rights reserved.341:305-11 Copyright 2011©. severity of neutropenia. If Abx stopped and patient remains neutropenia approximately 30% will become febrile again NCCN Guidelines at www.

353:977-987 Characteristics of Bacterial Isolates and Number with Resistance to Levofloxacin Bucaneve G et al. electronic or mechanical. Patients with Acute Leukemia (Panel B).353:977-987 Copyright 2011©. N Engl J Med 2005. National Comprehensive Cancer Network®.Kaplan-Meier Estimates of Survival Free from Fever among All Patients (Panel A). without first obtaining written permission from NCCN®. No part of this publication may be reproduced or transmitted in any other form or by any means. All rights reserved. . and Patients with Solid Tumors or Lymphoma (Panel C) Bucaneve G et al. N Engl J Med 2005.

353:977-987 Copyright 2011©. without first obtaining written permission from NCCN®. National Comprehensive Cancer Network®. All rights reserved. electronic or mechanical. . N Engl J Med 2005.Mortality Rates in the Treated Population Bucaneve G et al. No part of this publication may be reproduced or transmitted in any other form or by any means.

DM. malnutrition • Large inoculum – Environmental exposure (even remote). 4weeks into therapy develops fevers and elevated AlkPhos. Biopsy demonstrate C albicans. without first obtaining written permission from NCCN®. No part of this publication may be reproduced or transmitted in any other form or by any means. colonization w/ pathogen. rejection • Host – Renal failure. electronic or mechanical. General Risk Factors for IFI • Immunosuppression – Prolonged neutropenia. allograft issues. pathogen broad spectrum antimicrobial use • Permissive co-infections – CMV. National Comprehensive Cancer Network®. .Case 3 63 yo F undergoing induction chemotherapy for AML. All rights reserved. ?HHV-6 Copyright 2011©. Abd CT demonstrates multiple abscesses in the liver and spleen.

Vori. IV/Inh).0 mg/kg ampho all used by different major centers. National Comprehensive Cancer Network®. All rights reserved. 1.BMT • When is the risk period? – Neutropenia. ? Role for lipid formulations – Itraconazole (IV). 0. • Empiric – F+N for > 96h of appropriate antimicrobials for GNRs – ?Dose: 0. IV). . No part of this publication may be reproduced or transmitted in any other form or by any means. likely relapsed leukemia – Limited benefit for Auto-BMT.7. Aspergillus • Drugs studied – Fluc. mini-allos – I Immune-modulators (G-CSF) d l (G CSF) • Pathogens of greatest interest – Candida.135:412 Caillot CID 2001. Itra. induction chemo • Evolving risk factors – Novel chemo (targeted therapies).15:139 Boogaerts Ann Intern Med 2001. Ampho (Inh.40:371 abstr 1103 IFI Prophylaxis: Oncology .33 Maertens ICAAC 2000. caspofungin. electronic or mechanical. 0. NYS.5. Micafungin Copyright 2011©. PO. GVHD (acute/chronic) • Who is at highest risk? – Allogeneic BMT.• Prevention Strategies for IFI: Key Concepts Prophylaxis – Fluconazole diminishes invasive Candida infections • Unclear role for: amphotericin B (varying doses IV/Inh) itraconazole doses. without first obtaining written permission from NCCN®.3. ?voriconazole • P Preemption ti – Colonized with a pathogenic species (Aspergillus) – Radiologic or molecular evidence of infection – Molecular markers Caillot J Clin Onc 1997.

009) Slavin JID 1995:171. No part of this publication may be reproduced or transmitted in any other form or by any means. 37% C.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 0.325:1274 Candida Species Before and After Fluconazole Prophylaxis •585 patients undergoing 70 BMT.77:246-54 Goodman NEJM 1992:326. 50 •Colonization during azole prophylaxis: 44% overall.4% C. without first obtaining written permission from NCCN®. C. 1994-97.845 and Wingard NEJM 1991. . No. 60 •Fluc 400 mg for 75 days. All rights reserved. electronic or mechanical. National Comprehensive Cancer Network®.2055 and van Burik Medicine 1998. glabrata (47%). g glabrata. 0 parapsilosis (23%). Marr Blood 2000:96. C. krusei.4. JID 181:309-16. 2000 1980-86 1994-97 C albi C trop C glab C krus C para Blood isolates Copyright 2011©.1545. p=. 20 10 •34 episodes of Candidemia: C. patients 40 30 38.al. krusei (20%) Marr et.

5 vs 80% van Burik CID 2004. electronic or mechanical. All rights reserved.101:3365-3372 Micafungin Prophylaxis in HSCT • Fluconazole (400) vs micafungin (50) – n= 882 – PIII. .39:1407 Copyright 2011©. randomized.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. double blind • Medication given during g g neutropenic period • Success 73. without first obtaining written permission from NCCN®. National Comprehensive Cancer Network®. No part of this publication may be reproduced or transmitted in any other form or by any means.

National Comprehensive Cancer Network®. N Engl J Med 2007. electronic or mechanical. .Time to Proven or Probable Invasive Fungal Infection Ullmann A et al. No part of this publication may be reproduced or transmitted in any other form or by any means. without first obtaining written permission from NCCN®.356:335-347 Copyright 2011©. All rights reserved.

without first obtaining written permission from NCCN®. N Engl J Med 2007. All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means. National Comprehensive Cancer Network®.356:348-359 Clinical Response and Reasons for Failure during the Treatment Phase Cornely O et al.356:348-359 Copyright 2011©. N Engl J Med 2007.Proven or Probable Invasive Fungal Infection during the Treatment Phase Cornely O et al. . electronic or mechanical.

Her antimicrobial therapy included: ceftazidime and amphotericin B (0.Case 5 63 year female develops facial y p pain and fever on d+10 of an allo-BMT for M2 AML. electronic or mechanical. An emergent head CT revealed the following: f ll i Copyright 2011©. . All rights reserved.5 mg/kg/day empirically begun 2 days earlier). National Comprehensive Cancer Network®. No part of this publication may be reproduced or transmitted in any other form or by any means. without first obtaining written permission from NCCN®.

1/20/07 1/26/07 2/05/07 2/23/07 4/04/07 Copyright 2011©. National Comprehensive Cancer Network®. (1966) Ann Intern Med 64:328-40. No part of this publication may be reproduced or transmitted in any other form or by any means. without first obtaining written permission from NCCN®. All rights reserved.Bodey et al. . electronic or mechanical.

• Voriconazole – Walsh NEJM 2002.351:1391-1402 1000 F+N pts Galactomannan Prospective serial GM measurement in 362 consecutive high-risk treatment episodes in 191 patients (BMT and leukemic). • Caspofungin – Walsh NEJM 2004.5 44.4 98. .1 98.346:225-34 • Itraconazole – Boogarts Ann Intern Med 2001.1604 Copyright 2011©.7 7.135:412-422 384 F+N pts.8 Maertens Blood 2001:97.4 83. electronic or mechanical.1 98. No part of this publication may be reproduced or transmitted in any other form or by any means.1 PPV 85. National Comprehensive Cancer Network®.7 50 87.72:101-11 50 F+N pts • Amphotericin B – Walsh NEJM 1999. 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.Empiric Anti-Fungal Therapy • CAB – Pizzo Am J of Med 1982.4 NPV 100 98. Time period: 1/97-2/00. All rights reserved.340:764-71 – CAB vs AmB inc cr (34 vs 19%) 787 F+N pts 837 F+N pts. without first obtaining written permission from NCCN®.4 98.5 89.1 98.

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

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. electronic or mechanical. . No part of this publication may be reproduced or transmitted in any other form or by any means. without first obtaining written permission from NCCN®.

. electronic or mechanical. CXR +/. 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 . C diff • Routine evaluation – History.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. peri-rectal abscess. National Comprehensive Cancer Network®. blood/sputum/urine cultures.Typical Infectious Sources of Fever in the Setting of Neutropenia • Catheters • Respiratory tract • GI tract – Typhlitis. CBC. without first obtaining written permission from NCCN®.dynamic environment Copyright 2011©. All rights reserved. effective. SMA-7. urine analysis. No part of this publication may be reproduced or transmitted in any other form or by any means. during high risk periods is essential – Molecular markers hold great promise • Geographic and local organism burden are important • Development of safe. physical exam. LFTs.