1. Neutropenic Fever www.idsociety.org CID 2011; 52 (4):e56-e93

2. Learning Objectives Definition and classification – –Identify appropriate patient – –Classify risk and type Etiology / Microbiology – –Understand what you are evaluating for – –What “bugs” do you need to worry about Clinical evaluation Management – –Antibiotic selection, escalation, de-escalation – –Antibiotic duration

3. Definitions Fever: – Single oral temperature of ≥ 101°F (38.3°C) – Temperature ≥ 100.4°F (38.0°C) over 1 hour Neutropenia: –ANC < 500 cells/mm 3 –Expected ANC < 500 cells/mm 3 within the next 48 hours

4. Chemotherapy Induced Neutropenia

5. Risk Stratification High Risk ANC ≤ 100 anticipated > 7 days Hemodynamic instability Oral or GI mucositis interfering with swallowing or causing diarrhea Neurologic/MS changes – new onset Intravascular catheter infection New pulmonary infiltrate, hypoxemia or underlying chronic lung disease Hepatic or renal insufficiency MASCC < 21 Low Risk Neutropenia anticipated ≤ 7 days No active medical co-morbidity Adequate hepatic and renal function Multinational Assoc for Supportive Care in Cancer Risk-Index Score (MASCC) ≥ 21 of 26. Burden of febrile neutropenia 0,3,5 No hypotension 5 No COPD 4 Solid or Heme w/o fungus 4 No IVF 3 Outpatient 3 Age < 60 2

6. Classification Initial neutropenic fever – –Typically coincides with neutrophil nadir – –Standard protocol – concern for bacterial infection Persistent neutropenic fever – –Fever despite 5 days of broad-spectrum antibacterials – –Complex management – concern for fungal infection Recrudescent neutropenic fever – –Fever that recurs following initial response – –Wide differential

7. Etiology / Microbiology Infectious Bacterial translocation – –Intestinal – –Oropharyngeal Community-acquired – –Respiratory viruses Healthcare-associated – –MDR organisms – –C. diff Opportunistic – –Herpes virus reactivation – –Fungal Non-infectious Underlying malignancy Blood products Tumor lysis Hematoma Thrombosis Phlebitis Atelectasis Viscus obstruction Drug fever Myeloid reconstitution

8. Clinical Evaluation Symptoms and signs of inflammation may be minimal or absent in the severely neutropenic patient Cellulitis with minimal to no erythema Pulmonary infection without discernable infiltrate on radiograph Meningitis without pleocytosis in the CSF Urinary tract infection without pyuria Peritonitis - abdominal pain without fever or guarding Sickles, Arch Intern Med 1975; 135;715-9

9. The Work Up Physical Exam: PeriodontiumPalateLungAbdomenPerineumSkin Tissue around the nails BM biopsy site Blood cultures x2 UA and Urine Cx CXR Targeted workup –C.diff –Exit site cultures –Catheter tip cultures –CT Abdomen/Pelvis

10. Ecthyma Gangrenosum Bacteria: Pseudomonas GNR Staphylococcus aureus Fungus: Aspergillus Fusarium

11. Initial Neutropenic Fever Empiric antibiotics: –Pseudomonas and Streptococcus coverage Cefepime OR Zosyn OR Imipenem +/- Aminoglycoside +/- Vancomycin Coverage of bacteria –Gram-negative organisms Pseudomonas aeruginosa, E. coli, Klebsiella –Gram-positive organisms (60%) Coag neg Staph, Viridans Streptococcus, MRSA Corynebacterium jeikeium

12. Empiric Vancomycin

13. Management Algorithm 65 AML s/p induction chemotherapy – HD 12 neutropenic fever. Physical exam unremarkable. Vitals = SIRS. CXR negative. HD 13 – Remains febrile. Clinically stable. Cultures negative. Start Vanco/Cefepime/Amikacin Blood Culture x2 Any Change in Management?

14. Management Algorithm 65 AML s/p induction chemotherapy – HD 12 neutropenic fever. Physical exam unremarkable. Vitals = SIRS. CXR negative. HD 13 – Remains febrile. Clinically stable. Cultures negative. Start Vanco/Cefepime/Amikacin Blood Culture x2 Continue Vanco/Cefepime/Amikacin HD 14 – Afebrile. Cx negative.HD 14 – Cx E.coli (pan-S)

15. Management Algorithm 65 AML s/p induction chemotherapy – HD 12 neutropenic fever. Physical exam unremarkable. Vitals = SIRS. CXR negative. HD 13 – Remains febrile. Clinically stable. Cultures negative. Start Vanco/Cefepime/Amikacin Blood Culture x2 Continue Vanco/Cefepime/Amikacin HD 14 – Afebrile. Cx negative.HD 14 – Afebrile. Cx E.coli (pan-S) CefepimeCefazolin Continue antibiotics until ANC > 500.

16. Management Algorithm 65 AML s/p induction chemotherapy – HD 12 neutropenic fever. Physical exam unremarkable. Vitals = SIRS. CXR negative. HD 13 – Remains febrile. Clinically stable. Cultures negative. Start Vanco/Cefepime/Amikacin Blood Culture x2 Continue Vanco/Cefepime/Amikacin HD 14 – Remains febrile. Clinically stable. Cultures negative. Any Change in Management?

17. Management Algorithm 65 AML s/p induction chemotherapy – HD 12 neutropenic fever. Physical exam unremarkable. Vitals = SIRS. CXR negative. HD 13 – Remains febrile. Clinically stable. Cultures negative. Start Vanco/Cefepime/Amikacin Blood Culture x2 Continue Vanco/Cefepime/Amikacin HD 14 – Remains febrile. Clinically stable. Cultures negative. Blood Culture x2Continue Cefepime HD 15 – Remains febrile. Clinically stable. Cultures negative. Any Change in Management?

18. Early Management Summary D/C vanco after 48 hours if no evidence of GP infection. No need to perform more BC after first 48-72 hours if patient clinically stable and no new symptoms. Can simplify regimen if organism isolated. No need to double cover Pseudomonas if sensitive to monotherapy. Median time to defervescence ~5 days. Treatment duration typically until ANC > 500. If clinical worsening: – –Aggressive diagnostics – –Modify antibiotics to cover for resistant organisms – –Start anti-Candida therapy

19. Persistent Neutropenic Fever 65 AML s/p induction chemotherapy – HD 12 neutropenic fever. Physical exam unremarkable. Vitals = SIRS. CXR negative. HD 17 – Remains febrile. Clinically stable. Cultures negative. Vanco/Cefepime/Amikacin HD 14 - Cefepime Any Change in Management?

20. Persistent Neutropenic Fever Persistent Neutropenic Fever Up to 1/3 of patients with persistent neutropenic fever after 7d Abx have invasive fungal infection. Most common: Candida & Aspergillus Look for a source: CT Chest and Sinus Fungal blood cultures Galactomannan or  -D-Glucan Biopsy suspicious skin lesions

21. Fungus 101 YEAST: Candida, Cryptococcus MOLD: Aspergillus, Mucor

22. Invasive Mold Aspergillus Zygomyces Mucor Rhizopus Absidia Fusarium Halo signAir crescent sign Halo sign, air crescent sign, cavitating nodule  Invasive mold Abnormal CT chest  BAL with biopsy or IR guided biopsy

23. Invasive Fungal Pneumonia

24. Anti-Fungal Therapy Empiric: –Normal CT chest and/or sinus –Non-specific infiltrate on CT chest –No other evidence of invasive fungus –USE: Caspofungin or Amphotericin Presumed or Definite Invasive Aspergillus: –Classic CT chest findings (no previous Voriconazole) –Positive culture or biopsy with typical hyphae –Positive Galactomannan –USE: Voriconazole

25. Persistent Fever 65 AML s/p induction chemotherapy – HD 12 neutropenic fever. Physical exam unremarkable. Vitals = SIRS. CXR negative. HD 17 – Remains febrile. Clinically stable. Cultures negative. Vanco/Cefepime/Amikacin Cefepime CT Chest & Sinus, GalactomannanContinue Cefepime. Start anti-mold. Consult ID Invasive mold infectionNo invasive mold infection Voriconazole / AmphotericinEchinocandin / Amphotericin

26. Case 65 M AML s/p induction chemotherapy with daunorubicin and cytarabine. Develops fever 12 days after completion of induction chemotherapy. He notes some non-specific abdominal pain and reports diarrhea x2 days (C.diff negative x1). Fever to 39 O C, HR 110, BP 90/50. Looks ill, diffuse mild abd tenderness

27. Next Steps Blood Cx x2 UA and Urine Cx PA/LAT CXR Empiric Abx – Vanco/Cefepime/Amikacin

28. Results Blood Cultures negative x 24 hours UA and Urine Cx negative CXR negative C.diff EIA negative He develops septic shock ~30 hours later

29. CT Abd/Pelvis Blood Cultures x2 – anaerobic bottle: Clostridium septicum

30. Neutropenic Colitis Typhlitis –ANC < 500, usually AML –Abdominal pain –Diarrhea initially, ileus later –CT or US with bowel wall thickening –Rule-out C.diff –Need anaerobic coverage: Zosyn, Imipenem, Cefepime + Flagyl

31. Summary Neutropenic fever – definition and classification – –High risk versus Low risk – –Initial, Persistent, Recrudescent Etiology / Microbiology – –Bacterial translocation, CAI, HAI, opportunistic Clinical evaluation – –Neutropenia = lack of inflammation Management – –Initial NF – need Pseudomonas and Strep coverage – –De-escalate empiric therapy after 48-72 hours – –Persistent/Recrudescent NF – think fungal infection – –Duration until ANC > 500