FEVER AND NEUTROPENIA

1. FEVER AND NEUTROPENIA AZIZA SHAD, MD LOMBARDI CANCER CENTER GEORGETOWN UNIVERSITY HOSPITAL

2. INTRODUCTION • Febrile neutropenia and infections are expected treatment-related sequelae in childhood cancer • Increased use of dose-intensive combinations of chemotherapeutic agents • Fewer dosage modifications are being made for myelosuppression

3. DEFINITIONS Fever • Single oral temperature of > 38.30C (1010F) or • A temperature of 38.00C (100.40F) for > 1 hour Neutropenia • A neutrophil count of < 500 cells/cumm3 or • A count of < 1000 cells/cumm3 with a predicted decrease to <500 cells/cumm3

4. FACTORS CONTRIBUTING TO THE RISK OF INFECTION • Degree and duration of neutropenia • Single, most important risk factor associated with infection • ANC < 1000/mm3, risk with an ANC <100/mm3, • Protracted neutropenia • ANC < 500/mm3 for more than 10 days –   risk • At least 50% of febrile neutropenic patients will have an established or occult infection • 20% patients with ANC < 100/cumm3 have bacteremia at presentation

5. FACTORS CONTRIBUTING TO THE RISK OF INFECTION • Abnormalities in mucosal and integumentary physical defense barriers • Chemotherapy and radiation therapy • Implanted intravascular devices • Altered nutrition • Decrease in phagocyte number and function • Alteration in cellular and humoral immunity • Alteration in the endogenous microbial flora • colonization with aerobic gm –ive bacteria and fungi • Hospitalization

6. EVALUATION OF THE NEUTROPENIC PATIENT • Signs and symptoms of inflammation may be minimal or absent • Sites that deserve attention during the physical exam • Oral cavity and pharynx • Lungs • Perineum, including the anus • Fundi • Skin, including the bone marrow aspiration sites, central line exit site and tissue around the nails

7. EVALUATION OF THE NEUTROPENIC PATIENT • Laboratory tests • CBC and complete chemistry panels • At least 1 set of blood cultures from the central line and / or peripheral vein • Urine analysis • Chest X-Ray? • Respiratory signs / symptoms • If out-patient management is being planned • Gram stain and cultures of catheter exit site, urine, stool, CSF, skin biopsy, radiological studies as dictated by signs / symptoms

8. EVALUATION OF THE NEUTROPENIC PATIENT • Routine cultures from anterior nares, oropharynx, urine and rectum are not useful in the absence of a disease process • Infection control purposes • Nasal cultures: methicillin resistant Staph Aureus, penicillin resistant Pneumococcus, Aspergillus • Rectal cultures: Pseudomonas aeruginosa, multi-drug resistant gm-ive bacilli, VRE • Candida tropicalis in surveillance cultures has been associated with an  risk for subsequent infection

9. WHO QUALIFIES FOR INITIAL EMPERICAL ANTIBIOTIC THERAPY? • All neutropenic patients at the onset of fever • Afebrile, neutropenic patients with signs / symptoms compatible with infection

10. Treatment Guidelines For Fever and Neutropenia • 2002 Guidelines for the use of Antimicrobial Agents in Neutropenic Patients with Cancer • Infectious Diseases Society of America • Antimicrobial Therapy of Unexplained Fever in Neutropenic Patients • 2003 Guidelines of the Infectious Diseases Working Party of the German Society of Hematology Oncology, German Cancer Society

11. Treatment Guidelines For Fever and Neutropenia These are only General guidelines • Variation in individual patients and types of infections • Settings in which patients are being treated • Anti-microbial susceptibility patterns • Underlying causes of neutropenia • No specific combination of drugs or period of treatment can be applied universally to all febrile neutropenic patients

12. CHOOSING THE INITIAL ANTIBIOTIC THERAPY • Consider the type, frequency and antibiotic susceptibility of bacterial isolates recovered from other patients at the same hospital • Drug allergy, hepatic or renal dysfunction may limit the use of certain antibiotics • Cisplatin, amphotericin B, cyclosporine, vancomycin and aminoglycosides should be avoided in combination, if possible, because of additive renal toxicity • Monitor drug plasma levels wherever possible

13. COMMON BACTERIAL CAUSES OF FEBRILE EPISODES • Gram-positive bacteria - 60-70% of positive cultures • Incidence of gram-negative infections is  in some centers • Common gram-positive bacteria • Fulminant infections: Staph aureus, strep viridans, pneumococci • Indolent infections: coagulase neg staph,VRE, corynebacterium jeikeium • Common gram-negative bacteria • P. aeruginosa, E. coli, Klebsiella species • Fungal infections usually super infections • Candida species may cause primary infections

14. ALGORITHM FOR INITIAL MANAGEMENT OF FEBRILE NEUTROPENIC PATIENTS

15. 2003 Guidelines of the AGIHO of the German Society of Hematology Oncology • 3 risk groups based on duration of neutropenia • Low risk: < 5 days • Intermediate risk: 6-9 days • High risk: > 10 days

16. 2003 Guidelines of the AGIHO of the German Society of Hematology Oncology • Low Risk group • Empirical mono or duo therapy IV • Oral therapy with cipro, levo or ofloxacin + Amoxicillin/clavulinic acid • Intermediate Risk and High Risk group • Empirical mono or duo therapy IV

17. TREATMENT WITH INTRAVENOUS ANTIBIOTICS - MONOTHERAPY • No difference between monotherapy and multi-drug combinations for uncomplicated F&N • 3rd or 4th generation cephalosporin, piperacillin - tazobactam or carbapenem – all effective • Extended spectrum and type 1 -lactamases have reduced the utility of ceftazidime • Cefepime, imipenem and meropenem - excellent activity against strep viridans and pneumococcus • Vancomycin less frequently required with cefepime monotherapy

18. INTRAVENOUS ANTIBIOTICS- 2 DRUG THERAPY WITHOUT VANCOMYCIN Different 2 drug combinations have similar results Advantages Potential synergistic effects against some gram-negative bacilli Minimal emergence of drug resistant strains during treatment Disadvantages Lack of activity against gram-positives Nephrotoxicity, hypokalemia, ototoxicity Single daily dose aminoglycoside with ceftrioxone as effective as monotherapy

19. CEFEPIME VS CEFTAZIDIME + AMIKACIN FOR FEVER AND NEUTROPENIA • Prospective randomized trial in children • 50 febrile neutropenic episodes • Results • Both equally effective regimens • Vancomycin and antifungal agents added more frequently to ceftazidime arm • Duration of fever, hospitalization, and length of antibiotic coverage longer in ceftazidime arm • Cefepime as first choice? • Shorter duration of fever, shorter hospital stay, lower treatment cost

20. VANCOMYCIN PLUS MONOTHERAPY OR DUO THERAPY • Vancomycin use should be limited to specific indications - emergence of VRE • May be incorporated into initial therapy of high risk patients at institutions where penicillin resistant strains of strep viridans are common • Discontinue within 24-48 hours if no infection is identified

21. INDICATIONS FOR VANCOMYCIN USE IN INITIAL EMPIRIC THERAPY • Serious catheter-related infections (cellulitis, bacteremia) • Known colonization with penicillin or cephalosporin resistant pneumococci or methicillin resistant staph aureus • Positive blood cultures for gram-positive bacteria before final identification • Hypotension, fever > 400C or other cardiovascular impairment • Quinolone prophylaxis in afebrile neutropenic patients before onset of fever (risk for strep viridans) • Mucositis

22. WHY ORAL ANTIBIOTICS AS INITIAL EMPIRIC THERAPY? • Comparable outcomes in low risk patients treated with oral antibiotics compared to similar groups treated with intravenous therapy • Reduced cost • Out-patient management • Avoidance of catheter use • Decreased risk for nosocomial infection • Better quality of life for patient (2004 JCO)

23. CHOICE OF ORAL ANTIBIOTIC THERAPY • Oral regimens that have been thoroughly evaluated • ofloxacin, ciprofloxacin, ciprofloxacin plus amoxicillin-clavulanate • Quinolones • Not as effective as cephalosporins or carbapenems in treating gram-positive infections • May predispose to development of strep viridans sepsis

24. LEVEL OF RISK FOR ORAL ANTIBIOTICS AND OUTPATIENT MANAGEMENT • Oral antibiotics alone appear to be feasible in carefully selected, febrile neutropenic patients • May only be considered for patients with no signs / symptoms or focus of bacterial infection • Vigilant observation and prompt access to medical care 24 hours / day must be available • Preferably initiated in an in-patient setting after a minimum of 48 hours of IV antibiotics

25. ASSESSMENT OF RISK IN CHILDREN WITH FEVER AND NEUTROPENIA • A few oral empiric trials have been conducted in children • Lowest risk for severe bacterial infections • Initial AMC >100 /cumm3 at presentation • No obvious signs / symptoms of illness • Normal CXR • Meet hospital criteria for discharge • Cancer is in remission

26. MANAGEMENT OF ANTIBIOTIC REGIMEN DURING THE FIRST WEEK OF THERAPY

27. GUIDE TO TREATMENT OF PATIENTS WITH PERSISTANT FEVER.

28. DURATION OF ANTIBIOTIC THERAPY

29. ROLE OF COLONY STIMULATING FACTORS IN FEVER AND NEUTROPENIA • Indications for use • Fever with ANC <100/mm3 • Sepsis • Invasive fungal infection • Primary prophylaxis for patients at high risk for developing fever with neutropenia based on prior treatment history • GCSF and GMCSF

30. DO COLONY STIMULATING FACTORS HELP IN FEBRILE NEUTROPENIA? • COG Study – April 2005 • Randomized study of antibiotics with/without GCSF in 67 patients (59 with ALL) • Results • GSCF significantly reduced duration of neutropenia (4 vs. 13 d) • Reduced days of in hospital (4 vs. 5 d) • No difference in resolution of fever, duration of IV or oral antibiotics, antifungal therapy or shock