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 Engels EA (1999). Clin Infect Dis No Abx IV Abx PO Cipro IV Abx + PO Cirpo

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 InfectionCount VRE8 Aspergillus4 CMV4 RSV3 BK2 Influenza A1 Adenovirus1 Non-infectious8

29. VRE Among SCCA Patients Jul Aug Sep Oct NovDec Jan FebMar Apr May Jun Jul Aug Sep Oct NovDec Jan FebMar Apr May Jun Jul Aug Sep Oct NovDec Jan FebMar Apr May Jun Jul Aug Sep Oct NovDec Jan FebMar Apr May Jun Jul Aug Sep Oct 20012002200320042005200620072008

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 AntibioticLimitation (s) LinezolidBacteriostatic Bone marrow suppression Quinupristin/Dalfopristin (Synercid) Bacteriostatic Only active against E. faecium Relatively poor penetration to urine Infusional Toxicity DaptomycinPoor alveolar penetration Resistance relatively easy to engender TigecyclineQuestionable efficacy in bacteremia Significant toxicities / drug-drug interactions

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 [ ] Adult Sepsis Protocol Standard  Imipenem 500 mg IVPB STAT over 20 minutes  Tobramycin 80 mg IVPB STAT over 20 minutes  Linezolid 600 mg IVPB STAT over 30 minutes [ ] Adult Sepsis Protocol PENICILLIN ALLERGIC  Aztreonam 2 gm IVPB STAT over 20 minutes  Tobramycin 80 mg IVPB STAT over 20 minutes  Linezolid 600 mg IVPB STAT over 30 minutes

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) InfectionCount VRE8 Aspergillus4 CMV4 RSV3 BK2 Influenza A1 Adenovirus1 Non-infectious8

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