1. MANAGEMENT OF NEUTROPENIC FEVERS IN CANCER PATIENTS Jerry Yu

2. Objective 1. Identify neutropenic fevers 2. Risk stratify patients with neutropenic fevers 3. Selecting the appropriate antibiotics for neutropenic fevers

3. 64 y/o M with hx of oral squamous cell carcinoma with local invasion into the neck s/p chemotherapy infusion 8 days prior via a R subclavian portacath, DM, HTN who presented with chief complaint of fatigue. In the ED, found to have WBC 0.1 (ANC 15). Observed to have temperature 38.4 with blood pressure 103/77 and pulse 88. CXR and U/A was normal. Medicine was called to admit patient.

4. Definition Fever: IDSA guidelines: single oral temperature > 38.3 C (101 F) or 38.0 C sustained for > 1 hour AND Neutropenia: ANC <1500, severe neutropenia ANC <500 Most commonly observed in leukemia undergoing induction therapy and less commonly seen in solid tumor receiving standard dose chemotherapy

5. Risk Assessment High Risk patients: Anticipated prolonged neutropenia (>7 days) ANC <100 cells/mm3 Significant medical comorbidities: HTN, PNA, abdominal pain, neurologic changes Low risk patients are eligible for oral empirical therapy Can use Multinational Association for Supportive Care in Cancer (MASCC) score: http://www.qxmd.com/calculate- online/hematology/febrile-neutropenia-mascchttp://www.qxmd.com/calculate- online/hematology/febrile-neutropenia-mascc MASCC >21 = low risk; may be eligible for oral/outpatient empirical antibiotic treatment MASCC<21= high risk; need inpatient hospitalization

7. T> 38.3 + ANC <1500 Start anti-gram (-) abx w/ pseudomonas coverage Risk factors for gram (+)? Hemodynamically stable? Start gram (+) and anaerobic coverage NoYes Start vancomycin Suspect anaerobic infections? Start anaerobic coverage No Yes Source Search Start anti-fungal treatment if persistent Fevers after 4-7 days

8. Antibiotic selection Initial regimen: First line treatment is gram (-) antibiotic that covers pseudomonas Antipseudomonal monotherapy: cefepime, meropenem, imipenem, zosyn *Avoid ceftazidime monotherapy due to rising resistance

9. Empiric Gram (+) coverage Not proven to improve survival Vancomycin is NOT recommended as part of initial therapy unless you suspect: Catheter related infection Soft tissue/skin infection Pneumonia Hemodynamic instability Positive blood cultures MRSA colonization Other alternatives: linezolid, daptomycin (if no evidence of pulmonary source)

10. Anaerobic treatment Specific anaerobic coverage NOT included in initial empiric therapy unless you suspect: necrotizing mucositis Sinusitis periodontal cellulitis perirectal cellulitis intraabdominal infection pelvic infection

11. Anti-fungal treatment NOT included in initial empiric coverage Persistent fevers after 4-7 days in high risk patients without clearly defined source Candida is most common organism Amphotericin, caspofungi, voriconazole, itraconazole

12. Modifying your antibiotic regimen No need to modify initial coverage if only persistent fever in a patient who is hemodynamically stable If vancomycin or empiric gram (+) was started, may be stopped after 2-3 days if no evidence of gram positive infection If patient is hemodynamically unstable after initial empiric abx, increase to cover gram (+), anaerobes, and fungi

13. How long to give antibiotics for? With clinically or microbiologically diagnosed infection, treat for full course of the infection In unexplained fever, continue antibiotics for the duration of neutropenia until ANC >500

14. Colony stimulating factors No survival benefit in routine administration. Administer only if high risk: prolonged (>10 day) neutropenia profound (<100 cells/microL) neutropenia age >65 uncontrolled primary disease Pneumonia hypotension multiorgan dysfunction invasive fungal infection being hospitalized at the time of the development of fever.

15. Neutropenic Precautions Hand Hygiene- most effective means of preventing transmissions Standard barrier precautions for all neutropenic patients HSCT recipients should be placed in private rooms Plants and dried or fresh flowers should not be allowed into patient rooms

16. Our patient Patient was started on vancomycin + cefepime. Blood cultures drawn from portacath were positive for MRSA. Line was removed by IR. Patient’s antibiotics were narrowed to vancomycin only. Patient received vancomycin for a total of 2 weeks with repeat blood cultures negative for further infections.

17. Summary Neutropenic fever: T38.3 + ANC <1500 Empirically start broad spectrum antibiotics for with anti- gram (-)pseudomonas regimen In an otherwise hemodynamically stable patient, no immediate indication to start gram (+) or anti-fungal coverage Proper antibiotic use requires aggressive source searching

18. References Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant. UpToDate Jan 2015 Greifeld AG, Wingard, JR. Clinical Practice Guideline for the Use of antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the infectious Disease Society of America. IDSA guidelines. 2011; 52(4): e56- e93