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Immunosuppression and Infections in patients with Neoplasia

Immunosuppression and Infections in patients with Neoplasia. Ioannis Chatzinikolaou MD, PhD Medical Oncologist Collaborating R esearch Fellow The University of Crete Heraklion, Greece. Infectious Complications in Patients with Neoplasia. Predisposing Factors

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Immunosuppression and Infections in patients with Neoplasia

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  1. Immunosuppression and Infections in patients with Neoplasia Ioannis Chatzinikolaou MD, PhD Medical Oncologist Collaborating Research Fellow The University of Crete Heraklion, Greece

  2. Infectious Complications in Patients with Neoplasia Predisposing Factors (due to disease or treatment) • Granulocytopenia • Cellular immune dysfunction • Humoral immune dysfunction • Iatrogenic procedures (indwelling catheters) • Obstructive phenomena • Central Nervous System dysfunction • Alterations in microbial flora

  3. Morbidity and Financial Burden of Infections in Patients with Neoplasia • Number of patients with cancer and infectious complications hospitalized (USA): 60,000 / year • Average cost of hospitalization: $13,372 • Morbidity due to infection: 10% • Solid tumors: 8% (lung: 13.4%, breast: 3.6%) • Leukemia: 14%, Lymphoma: 9% • Morbidity higher in confirmed infections: invasive aspergillosis (39%), candidiasis (37%), Gram (-)ve sepsis (34%), Gram (+)ve sepsis(21%) Cagiarro et al. Cancer 2005;103:1916 Kuderer et al. Cancer 2006;106:2258

  4. Febrile NeutropeniaGeneral PrinciplesDefinition • Neutrophils : <500 /mm3 or 1000 /mm3 with projection of reduction to <500 /mm3 within 24-48 hours • Temperature (mouth) • a wave >38.3 oC or • 38 oC lasting >1 hour and repeated within 12 hours Freifeld et al. Clin Infect Dis 2011;52:42-31

  5. Febrile Neutropenia General Principles • Appears in 10 % - 50 % of patients with solid tumors • Often characteristic signs and symptoms of infection are absent • 50% of febrile neutropenic patients have infection • 20% of febrile neutropenic patients + PMN <100 /mm3 have septicemia • Careful examination, including oral cavity, genitalia and anus may reveal the site of infection. • Frequent inability to identify the pathogen • Untreated infection rapidly disseminates and may be fatal. • Delays in administration of appropriate antibiotics result in suboptimal responses. Sepkowitz K.A. Clin Infect Dis 2005;40 Suppl 4:S253-6 Pizzo P.A. N Engl J Med 1993;328:1323

  6. Bacteremia in febrile neutropenic cancer patients • 2142 patients with febrile neutropenia from cancer chemotherapy • 499 (23%) patients with bacteremia • Gram-positive: 57% • Gram-negative: 34% • Polymicrobial bacteremias: 10% Klastersky et al. Int J Antimicrob Agents 2007; 30(Suppl 1): S51–9.

  7. Febrile NeutropeniaTreatment • Emergency situation • Treatment initiation within 2 hours • Morbidity >70% if delay of initiation of antimicrobial chemotherapy • A) Risk assessment • B) Antimicrobial coverage • Wide spectrum • Local microbial flora susceptibility pattern • Previous antimicrobial therapy Sepkowitz K.A. Clin Infect Dis 2005;40:S253 Schimpff SC et al. N Engl J Med 1971;284:1061

  8. Febrile NeutropeniaPatient Risk Assessment Low risk patients • Outpatient status at time of fever development • No acute comorbidity indicating hospitalization • ≤ 100 cells / mm 3for < 7 days • ECOG: 0-1 • No hepatic / renal insufficiency Or • MASCC Risk Index score ≥ 21 Freifeld et al. Clin Infect Dis 2011;52:427-31 National Comprehensive Cancer Network (NCCN) Guidelines, version 1.2013

  9. Febrile NeutropeniaPatient Risk Assessment High risk patients • Inpatient status at time of fever development • Significant medical comorbidity (ex. GI, CNS) / clinically unstable • ≤ 100 cells / mm 3 for > 7 days • Suspected / proven catheter - relater infection • Hepatic insufficiency (LFT ≥ 5 UNL) • Renal insufficiency (creatinine clearance <30 mL/min) • Uncontrolled / progressive cancer • Pneumonia or other complex infection at presentation • Alemtuzumab • Mucositis grade 3-4 Or • MASCC Risk Index score < 21 Freifeld et al. Clin Infect Dis 2011;52:427-31 National Comprehensive Cancer Network (NCCN) Guidelines, version 1.2013

  10. Multinational Association for Supportive Care in Cancer (MASCC) Risk Index • Max Scoring : 26 • Low risk patient score: ≥ 21 • PPV: 91% , Specificity: 68%, Sensitivity: 71% Klastersky et al J Clin Oncol 2000;18(16)3038-51

  11. Outpatient Therapy: Prerequisites • Stabilization of patient’s clinical status • Education of patient and family • Mental competence – manual dexterity • Distance – transportation – home conditions • 24 hour companion – telephone access Uzun O and Anaizzie E.J. J Antimicrob Chemother 1999;43(3):317-320

  12. Advantages of Outpatient Therapy • Improved quality of life • Lower incidence of nosocomial infections • Simplification of antimicrobial therapy • Lower cost Uzun O and Anaizzie E.J. J Antimicrob Chemother 1999;43(3):317-320

  13. Febrile NeutropeniaEmpiric Therapy

  14. Febrile NeutropeniaEmpiric Monotherapy • Third generation cephalosporin • Ticarcillin + Clavulanic acid • Piperacillin + Tazobactam • Imipenem • Meropenem • Cefepime

  15. Febrile NeutropeniaEmpiric Monotherapy • Ceftazidime is no longer reliable as monotherapy decreasing potency against gram (-) ves poor activity against gram (+)ves(streptococci) • Aminoglycosides not to be used as monotherapy empirically due to rapid emergence of resistance Freifeld et al. Clin Infect Dis 2011;52:427-31

  16. Febrile NeutropeniaEmpiric Combination Therapy Third generation cephalosporin + aminoglycoside (gold standard) • Two beta-lactams Ticarcillin / Clavulanic Piperacillin / Tazobactam +3rd gen. cephalosporin • Carbapenem + Aminoglycosides • Quinolone + 3rd gen. cephalosporin • No combination is clearly superior to the rest Peacock J.E. et al Ann Intern Med 2002;137:77 Bliziotis I.A. et al. Mayo Clin Proc 2005;80:1146

  17. Febrile NeutropeniaEmpiric Combination Therapy • Prospective, non randomized study • 285 febrile neutropenia episodes, 235 patients • Solid tumor and hematologic malignancies • High baseline antimicrobial resistance prevalence Ceftazidime + Levofloxacin = Ceftazidime + Amikacin Samonis G et al Eur j Clin Microbiol Infect Dis 2012;31(7):1389-98

  18. Febrile NeutropeniaEmpiric Therapy Freifeld et al. Clin Infect Dis 2011;52:427-31

  19. Febrile NeutropeniaGram positive antimicrobial coverage Freifeld et al. Clin Infect Dis 2011;52:427-31

  20. Febrile NeutropeniaGram positive antimicrobial coverage Gram Positive organisms Increasing in frequency Central Venous Catheters (?) Antimicrobial Chemotherapy • vancomycin • linezolid • quinopristin - dalfopristin • tigecycline • daptomycin • Discontinuation of empiric gram(+)ve Rx post 72 hours if susceptible bacteria are not isolated from the patient Freifeld et al. Clin Infect Dis 2011;52:427-31 Hughes at al. Clin Infect Dis 2002;34:730

  21. MultiDrug Resistant (MDR) organisms Risk Factors • Previous infection • Colonization • Admission in hospital with endemic resistant bacteria • MRSA: vancomycin, linezolid, daptomycin • VRE: linezolid, daptomycin • ESBLs: carbapenem • KPCs: colistin, tigecycline

  22. Antibiotic Therapy in Cancer Patients: Challenges • Duration of treatment • Addition of gram(+)ve coverage • Addition of antifungal agents • Addition of antimicrobial agents against unusual or suspected specific bacteria • Use of G-CSF • Ongoing research

  23. Duration of antimicrobial therapy • Clinically or microbiologically documented infection: Rx at least till ANC ≥ 500 cells / mm 3 • Unexplained fever Rx till signs of marrow recovery (ANC ≥ 500 cells / mm 3) • Appropriate Rx completed, all signs and symptoms of a documented infection are resolved and patient remains neutropenic oral fluoroquinolone till marrow recovery (ANC ≥ 500 cells / mm 3) Freifeld et al. Clin Infect Dis 2011;52:427-31

  24. Fungal pathogens Major Candida spp. Aspergillus spp. Mucor spp. Cryptococcus neoformans Emerging Fusarium spp. Scedosporium spp. Trichosporon spp. Rhodotorula spp. Malassezia spp.

  25. Fungal Infections • More frequent in AML patients • Candida spp. more likely pathogen in the first days of neutropenia if no administered prophylaxis • If fluconazole prophylaxis then more likely • fluconazole resistant Candida (C. krusei, C. glabrata) • Mold (Aspergillus spp., Zygomyces spp. , Fusarium spp.) • Invasive mold infections in patients with severe (ANC ≤ 100 cells/mm 3) and prolonged (>10-15 days) neutropenia Freifeld et al. Clin Infect Dis 2011;52:427-31

  26. Antifungal Therapy • Added on the 5th - 7th day of fever and neutropenia • Increased incidence of fungal infection post day 7 of fever and neutropenia • 40% - 50% of patients will defervesce post initiation of antifungal chemotherapy Freifeld et al. Clin Infect Dis 2011;52:427-31

  27. Febrile NeutropeniaEmpirical Antifungal Therapy • Liposomal amphotericin B • Azoles (with mold activity) Itraconazole Voriconazole • Micafungin • Caspofungin Freifeld et al. Clin Infect Dis 2011;52:427-31

  28. CVC related infections • Diagnosis and treatment is a challenge • Usual microorganisms: CNS, S. aureus, Candida spp., gram (-)ve • Local and disseminated complications (septic thrombophlebitis, endocarditis) • Challenging question: Catheter removal • Prevention is feasible

  29. Major viral pathogens in immunocompromised hosts • HSV-1 • HSV-2 • VZV Herpesviridae • EBV • CMV • RSV • Adenoviruses

  30. Viral diseases in immunocompromised hosts Herpesviridae • Local infections • Generalized infections -Encephalitis - Pneumonia - Hepatitis - Colitis - Retinitis

  31. Viral diseases in immunocompromised hosts • RSV Pneumonia Generalized infection • Adenoviruses Gastroenteritis Pneumonia Cystitis Generalized infection

  32. Antiviral agents • Acyclovir (HSV 1, 2 andVZV) • Gancyclovir (CMV) • Foscarnet (CMV) • Ribavirin (RSV) • Adenoviruses (??)

  33. Infections in the Immunocompromised Host Challenges • Emerging pathogens • Emerging resistance • Changes in the flora • New antineoplastic agents • New antineoplastic strategies

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