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Infections in Oncology Patients: Febrile Neutropenia and Beyond

Infections in Oncology Patients: Febrile Neutropenia and Beyond. Corey Casper, MD MPH Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Division of Infectious Disease, University of Washington 9 July 2010. Overview. Febrile Neutropenia Epidemiology

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Infections in Oncology Patients: Febrile Neutropenia and Beyond

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  1. Infections in Oncology Patients: Febrile Neutropenia and Beyond Corey Casper, MD MPH Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Division of Infectious Disease, University of Washington 9 July 2010

  2. Overview • Febrile Neutropenia • Epidemiology • Microbiology • Evidence for Various Prophylactic Strategies • Controversies • VRE • Prevention and treatment of invasive fungal infections

  3. Incidence of Infection in Neutropenic Patients with Cancer • Prior to routine antibiotic prophylaxis, infection was a common complication of cancer therapy • Acute Leukemia • 20-40 infections per 1000 patient-days • Bodey GP (1966), Ann Intern Med • Transplant • 71-100 infections per 1000-patient days • Engels EA (1999), Clin Infect Dis • Infections frequently associated with high mortality • 75% of mortality in early era of chemotherapeutics was due to infection • Schimpff SC (1971). N Engl J Med

  4. Risk Factors for Infection in Patients with Neutropenia: Duration Viscoli C (2005), Clin Infect Dis

  5. Risk Factors for Infection in Patients with Neutropenia: Depth IV Abx PO Cipro IV Abx + PO Cirpo No Abx Engels EA (1999). Clin Infect Dis

  6. Risk Factors for Infection in Patients with Neutropenia: Other • Therapy • Type of chemotherapy • Corticosteroids • Breach of Physical Barriers to Infection • Skin / mucous membranes • Catheters • Malignancy • Those which impair Ig function • Multiple myeloma • CLL • Those associated with splenectomy Incidence of Febrile Neutropenia by Cancer Type

  7. Etiology of Fever in Neutropenia • Only 50% of patients with fever during neutropenia will have a documented infection • Of those 50%, only 20% have blood stream infection • Not all are bacterial

  8. Etiology of Bacteremia in Neutropenic Cancer Patients (1) Viscoli C (2005) Clin Infect Dis

  9. Etiology of Bacteremia in Neutropenic Cancer Patients (2) Wisplinghoff H (2003), Clin Infect Dis

  10. Sites of Infection in Cancer Patients Yadegarynia D (2003), Clin Infect Dis, MD Anderson

  11. Is Prophylaxis For Neutropenia Effective? • Landmark 1988 study at FHCRC looking at approach to prophylaxis in 342 MRD transplant patients • Control: standard care without antibiotics or rooms with laminar air flow (LAF) • Prophylactic systemic antibiotics, no LAF • LAF only, no antibiotics • LAF + Antibiotics Petersen F (1988), Infection But which general oncology patients should receive prophylaxis?

  12. Antibiotic Prophylaxis for General Oncology Patients with Short-Term Neutropenia (1) Cullen, et. al. NEJM 2005

  13. Antibiotic Prophylaxis for General Oncology Patients with Short-Term Neutropenia (2) P value for all comparisons <0.01, Cullen, et. al. NEJM 2005

  14. Antibiotic Prophylaxis for General Oncology Patients with Short-Term Neutropenia (3) Bucaneve NEJM 2005

  15. Antibiotic Prophylaxis for General Oncology Patients with Short-Term Neutropenia (4)

  16. …But Resistance to Fluoroquinolones is Increasing • Among 823 hematology/oncology patients receiving FQ pphx, risk of FQ resistant bacteremia was 3 fold higher among those receiving prophylaxis • Cattaneo J Antimicrob Chemother. 2008

  17. Prediction Model to Identify Neutropenic Patients Needing Pphx? Cullen, JCO 2007

  18. Predicting Risk of Infection During Neutropenia : Risk Groups NCCN, “Prevention and Treatment of Cancer-Related Infections”

  19. Principals of Antibiotics for Febrile Neutropenia • Antibiotics are not antipyretics • Look for sources • Risk factors • Exam • Studies • Know antibiotic resistance patterns at UWMC / FHCRC and inherent susceptibilities of organisms to antibiotics

  20. Evaluation of Patients with Febrile Neutropenia

  21. Empiric Therapy for Febrile Neutropenia

  22. Does Cefepime Kill People? The Story

  23. Cefepime Meta-analysis • Lancet meta-analysis indicated that use of Cefepime was associated with a 26% increased risk of death compared with other antibiotics • Not due to microbiologic failure • NCCN hired biostatistician to review data, found methodology to be sound

  24. Does Cefepime Kill People?The Data

  25. Cefepime FDA Re-review • FDA asked for additional primary data from company and found no increased risk for death • Quality / comprehensiveness of additional data provided? • Subgroup analysis found significantly increased risk of death in solid tumor patients (but small numbers) and trend in hematologic malignancy patients • My conclusion (only partially evidenced-based): use another agent in cancer patients when possible!

  26. GNR Resistance at UWMC (2009) http://healthlinks.washington.edu/primeanswers/documents/antibiogram2009.pdf

  27. SCCA Febrile Neutropenia Empiric Treatment Algorithm

  28. Tally of Infection-Related Deaths in Transplant, Q1 2008

  29. Infectious Disease Surveillance Trends: Vancomycin Resistant Enterococcus 0.180 0.160 0.140 0.120 0.100 0.080 0.060 0.040 0.020 0.000 May May May May Dec Sep Nov Dec Sep Nov Dec Sep Nov Mar Mar Feb Feb Mar Mar Feb Feb Jan Jun Jan Jun Jan Jun Jan Jun Aug Aug Aug Oct Jul Oct Oct Jul Jul Apr Apr Apr Apr VRE Among SCCA Patients May May May May Sep Nov Dec Dec Sep Sep Nov Sep Mar Nov Mar Nov Dec Mar Dec Sep Mar Feb Feb Feb Feb Jun Jun Jan Jun Jan Jun Jan Jan Aug Aug Aug Aug Aug Oct Oct Jul Jul Jul Jul Oct Oct Oct Jul Apr Apr Apr Apr 2001 2002 2003 2004 2005 2006 2007 2008

  30. Prevalence / Significance of VRE Among SCCA Transplant Patients • All transplant patients receive “welcome” culture to survey for VRE • 25% of transplant patients arrive at SCCA colonized with VRE • Additional 25% of susceptible patients develop VRE over course of treatment at SCCA • Presence of VRE colonization predicts the development of bacteremia in up to 1/3rd of cancer patients. • Matar MJ, et. al.. Am J Infect Control 2006; Zaas AK, et. al. Clin Infect Dis 2002 • VRE bacteremia portends a poor prognosis in persons undergoing treatment of malignancies with a high mortality rate • Avery R, et. al.. Bone Marrow Transplant 2005; Bach PB, et. al.. Infect Control Hosp Epidemiol 2002

  31. Antimicrobials for VRE: No Magic Bullet

  32. New SCCA Strategy for VRE • Empiric use of daptomycin in all patients with known VRE colonization prior to or subsequent to transplant when vancomycin would ordinarily be used

  33. Sepsis Stat Pack - Rationale • Anecdotal observations found opportunities for improvement in providing antibiotics to septic patients with febrile neutropenia presenting to SCCA outpatient clinic • No antibiotics given in clinic because they would slow transfer to acute setting • Inappropriate antibiotics given in clinic • Convenience • Failure to appreciate spectrum of resistant organisms

  34. Sepsis Stat Pack - Implementation

  35. Improved Survival of Cancer Patients with Sepsis with Use of “Stat Pack” • Among patients meeting criteria for severe sepsis, 90% thirty-day survival • More than double compared with other published studies • No toxicities noted • 81% had follow-up ID consultation and tailoring of antibiotics Larche J, Intensive Care Med 2003 Pene F, Crit Care Med 2008

  36. Invasive Fungal Infections (IFI)

  37. IFI Prevention:New Triazole on the Block • Fluconazole • Cheap (<$1 per generic dose) • Effective against yeast • Safe • Voriconazole • Expensive ($68 per dose) • Increased toxicities / drug interactions • Effective against yeast and mould • Posaconazole • Expensive ($88 per dose) • Equally safe as fluconazole • Proven efficacy against IFI (and in vitro activity against Zygomycetes)

  38. Posaconazole:Acute Leukemia and MDS with Prolonged Neutropenia Cornely, NEJM 2007

  39. SCCA IFI Prophylaxis

  40. Reduction of Invasive Aspergillosis • Despite constant construction at SCCA Outpatient Clinic and UWMC, number of aspergillus cases has dropped nearly 5-fold over last 7 years • May be attributable to improved early diagnostics or prophylactic antifungal strategies

  41. Conclusions (1) • Infections are a significant cause of morbidity and mortality among neutropenic patients with cancer • Several well-defined risk factors help to identify neutropenic patients at highest risk of infection and death • Neutropenic patients are susceptible to many types of infection, including blood stream infections, pneumonia, urinary tract infections and intra-abdominal infections • Antibiotic prophylaxis significantly reduces infections in neutropenic patients

  42. Conclusions (2) • VRE is an increasing problem in cancer patients and aggressive empiric therapy is warranted • Prevention and treatment of mould infections is an emerging area of research • Rational use of antibiotics is essential to prevent toxicities, resistance and unnecessary costs • Understand antimicrobial spectrum • Change antibiotics for well-defined and validated reasons • Follow FHCRC Standard Practice Algorithms and consult FHCRC Infectious Disease attendings with questions

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