1. Infections in Patients With Cancer February 2015 Infections in Patients With Cancer1 A clinical review of risks to patients with immunocompromised systems Topics Discussed: Risk factors for infections in patients with cancer Microbial etiology of infection Antimicrobial resistance Impact of febrile neutropenia Risk factors for febrile neutropenia

2. Weaknesses in Host Defenses Can Markedly Increase the Risk of Infection in Patients With Cancer Factors that influence the risk of bacterial and fungal infection in patients with cancer: − Underlying disease − Immunosuppressive agents − Impaired bone marrow response, especially after multiple treatment regimens − Advanced age − Tissue damage February 2015 Infections in Patients With Cancer2

3. Facts About Infections and Cancer Opportunistic fungal infections are an important cause of infection and tend to occur later in the course of neutropenia than bacterial infections Common sites of infection in cancer patients with neutropenia include the gastrointestinal tract, skin, and lung Specific malignancies may be associated with immune dysfunctions that predisposes to infection with particular pathogens February 2015 Infections in Patients With Cancer3

4. Pathogens and Their Sites of Infection February 2015 Infections in Patients With Cancer4 Sites of Infection and Common Pathogens in Patients With Cancer L. Monocytogenes S. Aureus S. Pneumoniae S. Bovis Coagulase-negative Staphylococci Central Nervous System Coagulase-negative Staphylococci S. aureus Gram-negative bacilli C. albicans Bloodstream E. coli Proteus C. albicans Candida spp. Aspergillius spp. Urinary S. aureus S. pyogenes E. coli P. aeruginosa Klebsiella spp. Aspergillus spp. Skin/Soft Tissue Pseudomonas spp. E. coli Klebsiella spp. C. septicum C. difficile Candida spp. Gastrointestinal Streptococcus spp. Methicillin-resistant Staphylococci Pseudomonas A. veronii E. coli Respiratory

5. Infections and Cancer Infections Associated With Different Cancers DiseaseProminent DefectPredominant Infections Acute leukemiaNeutropenia, skin and mucosmembrane lesions Gram-positive cocci, gram-negative bacilli, Candida spp., Aspergillus spp., Fusarium spp., Trichosporon spp. Hairy cell leukemiaNeutropenia, impaired T-cell function Gram-negative bacilli, gram-positive cocci, mycobacteria Chronic lymphocytic leukemia, multiple myeloma HypogammaglobulinemiaEncapsulated organisms, S. pneumoniae, H. influenzae; N. meningitides Hodgkin’s diseaseImpaired T-cell functionPneumocystis spp., Cryptococcus spp., mycobacteria, Toxoplasma spp., Listeria spp., Cryptosporidium spp., Candida spp. Bone marrow transplant recipient Tissue necrosisGram-positive cocci, gram-negative bacilli, anaerobes Breast cancerLocal obstruction, tissue necrosis Gram-positive cocci, gram-negative bacilli, anaerobes Lung cancerLocal obstruction, tissue necrosis Mixed aerobic and anaerobic enteric flora Non-Hodgkin’s lymphomaT- and B-cell dysfunctionPneumocystis spp. Adapted from Kufe DW, et al. eds. Holland-Frei Cancer Medicine. 6th edition. Hamilton, ON: BC Decker, Inc; 2003. Adapted from Longo D, et al. Harrison’s Principles of Internal Medicine, 18th edition. United States: McGraw-Hill; 2011. February 2015 Infections in Patients With Cancer5

6. Microbial Etiology of Infection in Cancer Patients With Febrile Neutropenia Patients with chemotherapy-induced neutropenia frequently developed fever − 10%–50% of patients with solid tumors − >80% of patients with hematologic malignancies Changing paradigms in the microbiology of infections is causing increasing concern in cancer patients with febrile neutropenia (FN) Within the past 20 years the microbiology of infections has shifted with gram-positive organisms becoming increasingly common February 2015 Infections in Patients With Cancer6

7. Changes in Types of Infections Shift in microbes may be attributable to routine use of central venous catheters, use of quinolone prophylaxis, and increased use of proton pump inhibitors S S Single-Organism Bacteremias: EORTC-IATG Trials Data from the European Organization for Research and Treatment of Cancer-International Antimicrobial TherapyGroup (EORTC-IATG) and trials conducted from 1985 to 2000. Adapted from Viscoli C, et al. Clin Infect Dis. 2005;40(suppl 4):S240–S245. February 2015 Infections in Patients With Cancer7

8. Changes in Types of Infections Shift in microbes may be attributable to routine use of central venous catheters, use of quinolone prophylaxis, and increased use of proton pump inhibitors Data from the European Organization for Research and Treatment of Cancer-International Antimicrobial TherapyGroup (EORTC-IATG) and trials conducted from 1985 to 2000. Adapted from Viscoli C, et al. Clin Infect Dis. 2005;40(suppl 4):S240–S245. February 2015 Infections in Patients With Cancer8 Origins of Fever Patients With Neutropenia

9. Risk Assessment February 2015 Infections in Patients With Cancer9 Risk assessment for FN should consider the myelotoxicity of treatment regimen − Patients considered to be at high-risk when the treatment regimen has a >20% risk of FN Risk assessment for FN should also consider disease-, treatment-,and patient-specific risk factors − Risk for FN is dependent upon the underlying malignancy, type and intensity of chemotherapy regimen, need for concomitant radiation therapy, and degree of bone marrow involvement − Common patient-related risk factors for FN include advanced age, poor performance status, poor nutritional status, poor hepatic and/or renal function, pre-existing neutropenia/infection, and prior chemotherapy

10. Review of Risk Factors Risk factors for FN are listed below: Risk Factors for FN Adapted from NCCN Clinical Practice Guidelines in Oncology. V.1.2011. Adapted from Lyman GH. J Natl Compr Canc Netw. 2005;3:557–571. February 2015 Infections in Patients With Cancer10 Disease-Related Underlying malignancy Degree advanced age (≥65 years) Recent surgery Poor performance status Poor nutritional status Renal dysfunction Treatment-Related Previous history of severe neutropenia with similar chemotherapy Type of chemotherapy Planned relative dose intensity >80% Pre-existing neutropenia or lymphocytopenia Extensive prior chemotherapy Concurrent or prior radiation therapy to marrow-containing bone Patient-Specific Advanced age (≥65 years) Recent surgery Poor performance status Poor nutritional status Renal dysfunction Hepatic dysfunction/elevated bilirubin Pre-existing neutropenia Pre-existing infection/open wounds

11. Infections in Patients With Cancer Key Points Patients with cancer have increased susceptibility to bacterial and fungal infections Changing paradigms in microbiology of infections is causing increasing concern in cancer patients with FN Increase in drug-resistant pathogens poses additional challenges in cancer patients with FN FN remains a significant cause of morbidity, mortality and increased cost in patients with cancer receiving myleosuppressive chemotherapy Evaluation of risk factors for FN should be based on myelotoxicity of chemotherapy regimen and the assessment of specific disease-, individual patient-, and regimen-related risk factors February 2015 Infections in Patients With Cancer11