Febrile neutropenia. Febrile neutropenia. Febrile neutropenia. Febrile neutropenia 1/30/2019. Infection in patients with cancer

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1 Manit Sae-teaw B.Pharm, BCP, BCOP Glad dip in pharmacotherapy Faculty of pharmaceutical sciences Ubon Ratchathani University Fever Oral temperature measurement of 38.3 C (101.0 F) single 38.0 C (100.4 F) sustained over 1-h period Use of axillary temperature is discouraged Not reflect core body temperature Rectal temperature is avoided Prevent gut organisms Absolute neutrophil count (ANC) Neutropenia ANC < 500 cells/mm3 Expected to decrease to < 500 cells/mm3 during next 48 h Seg : Segmented neutrophil Band : Band form neutrophil Profound neutropenia : ANC < 100 cells/mm 3 Functional neutropenia : qualitative defects of circulating neutrophil Infection in patients with cancer Quantitative relationship between circulating leukocytes and infection in patients with acute leukemia Enrolled 52 patients with leukemia 34 patients were diagnosed ALL 18 patients were diagnosed AML All patients receive chemotherapy treatment 34 patients receive 6-mercaptopurine+prednosilone Ref : Turvey S E et al. Postgrad Med J 2009;85: Ref : Bodey GP, et al. Ann Intern Med. 1966;64:

2 Fever occurs frequently during neutropenia % Solid tumor >80% hematologic malignancy Infectious source can be indentified ~30% 2 Bacteria always identified 85-90% 80% identified pathogen are patients normal flora 3 Common sites of tissue-based infection Respiratory tract, urinary tract, skin, gastrointestinal tract 1 Klastersky J, et al. Clin Infect Dis. 2004;39:S Pizzo PA, et al. N Engl J Med. 1993;328: Schimpff SC, et al. Ann Interm Med 1972;77: Infectious Diseases Society of America (IDSA) Guideline Published in st update nd update 2010 Ref : Freifeld AG, et al. Clin Infect Dis. 2011;52:e Risk assessment of febrile neutropenia To determine The type of empirical antibiotic therapy (IV or Oral) Venue of treatment (Inpatient vs Outpatient) Duration of antibiotic therapy Classification into High risk group and Low risk group MASCC criteria Clinical criteria MASCC : Multinational Association for Supportive Care in Cancer MASCC criteria Charactieristic Weight No or mild symptoms 5 No hypotension (SBP>90 mmhg) 5 No COPD 4 No previous fungal infection 4 No dehydration required parenteral 3 fluids Moderate symptoms 3 Outpatient status 3 Age < 60 years 2 High risk patient defined as MASCC < 21 points Clinical criteria High risk : IV antibiotic in hospital Profound (ANC 100 cells/mm3) and Prolong (anticipated to extend > 7 days) neutropenia Hepatic insufficiency (Aminotransferase >5 ULN) Renal insufficiency (CrCl <30 ml/min) Clinical criteria High risk : IV antibiotic in hospital Presence co-morbid medical problems Hemodynamic instability Mucositis interfere swallowing or severe diarrhea Gastrointestinal symptoms : Abdominal pain Neurologic or mental status change Intravascular catheter infection New pulmonary infiltrate or hypoxemia (or chronic lung disease) 2

3 Clinical criteria High risk : IV antibiotic in hospital Prolong neutropenia is expected as a consequence of HSCT preparation Induction chemotherapy for AML Risk assessment of febrile neutropenia Low risk : Oral antibiotic, Outpatient treatment MASCC score 21 points Neutropenia expected resolved within 7 days and no active medical co-morbidity Prolong neutropenia as a consequence of (MASCC 21 points) Autologous HSCT Consolidation therapy for leukemia Initial assessment Physical examination Signs and symptoms of inflammation are often attenuated Fever is often only sign of infection Assessment should evaluated carefully in most common site of infection Skin, orophalynx, alimentary tract, lung, perinium Initial assessment Laboratory Blood cultures At least 2 sets of blood culture specimens Set : ~20 ml of blood divided into 1 aerobic and 1 anaerobic blood culture In patients weight < 40 kg blood culture should limit to <1% of total blood volume (70 ml/kg) A set collected from each lumen 1 Central 1 peripheral 2 separate venopuncture Optimal testing parameters for blood culture To determine effect of volume of blood, number of cultures, incubation time 37,568 blood cultures tested Number of cultures Pathogen detection 1 set 65.1% 2 sets 80.4% 3 sets 95.7% Ref : Cockerill FR 3rd, et al. Clin Infect Dis. 2004;38: Initial assessment Laboratory Specific site cultures Site Indication Detection Stool Diarrhea C.Difficile toxin Urine UTI symptoms, Urine culture Catheter, Abnormal UA CSF Meningitis Spinal fluid culture Skin Skin lesion Skin biopsy or aspiration Respiratory Productive cough Sputum culture Nasal wash or BAL BAL : Bronchoalveolar lavage 3

4 General consideration Observational study observe > 2,000 febrile neutropenia pts reveals Only 23% associated with bacteremia Frequencies of bacteremia Gram-positive : 57% Gram-negative : 34% Polymicrobial : 9% Gram negative associated with greater mortality (esp. P. aeruginosa) High risk Require hospitalization for IV empirical antibiotic Monotherapy with anti-pseudomonal β-lactam agent Cefepime Carbapenem Piperacillin-tazobactam Other antimicrobials may be added to manage complication Hypotension, pneumonia Ref : Klastersky J, et al. Int J Antimicrob Agents. 2007;30:S51-9. Vancomycin Indication for addition antibiotic against Gram positive organism Hemodynamic instability Pneumonia documented radiographically Positive blood culture for Gram positive infection Serious catheter related infection Skin and soft tissue infection Colonization with MRSA, PRSP Severe mucositis, if previous fluoroquinolone prophylaxis and ceftazidime use for empirical therapy Penicillin allergy Most penicillin allergic patients can use cephalosporins Immediate type hypersensitivity reaction (hives and brochospasm) Avoid β-lactam antibiotic Ciprofloxacin plus clindamycin Aztreonam plus vancomycin Low risk Medication therapy include Ciprofloxacin plus amoxicillin-clavulanate Moxifloxacin Levofloxacin or ciprofloxacin monotherapy Ciprofloxacin plus clindamycin Previous quinolone prophylaxis should not receive oral empirical quinolone Modified antimicrobial Monitoring efficacy and safety should be evaluated Median time to defervescence Solid tumor : 2 days Hematologic malignancy (include HSCT) : 5 days Specific antimicrobial addition or change to initial regimen guide by clinical and culture result 4

5 Modified antimicrobial Should be guided by clinical and microbiologic data Unexplained persistent fever Clinical stable : Not require antibiotic change Clinical unstable : Broadened antimicrobial Vancomycin may be stopped after 2 days (If no gram positive infection) Low risk patients require hospitalized if fever persist >48 hours Empirical antifungal should be considered after 4-7 days of antibacterial treatment IV-to-Oral switch may be made if Clinically stable Gastrointestinal absorption is adequate Duration of antimicrobial treatment Clinical and microbiology documented Treatment until neutropenia resolved Clinically necessary Unexplained fever (No microbiological documented) Treatment until neutropenia resolved Alternatively if treatment course has been completed Patients who remain neutropenia may resume oral quinolone until marrow recovery Empirical antifungal High risk patient are risk for invasive fungal infection Manifested by persistent or recurrent fever in neutropenic patients Yeast infection Candida species (the most common) Can occur 4-7 days of neutropenia Invasive mold infection : Aspergillosis (the most common) Related to profound (ANC<100 cells/mm3), prolong (>10-15 days) neutropenia Empirical/Preemtive antifungal No antifungal prophylaxis patients Amphotericin B (conventional) Fluconazole Other antifungal Previous antifungal prophylaxis Fluconazole prophylaxis Amphotericin B (standard empirical) Alternative itraconazole, voriconazole, caspofungin Mold-active prophylaxis Switch to IV mold active agent in difference class s Recommended guideline American society of clinical oncology (ASCO) European organisation for research and treatment of cancer (EORTC) National comprehensive cancer network 3 Indication Primary prophylaxis Secondary prophylaxis Treatment during febrile neutropenia 1 Smiths TJ, et al. J Clin Oncol. 2015;33: Aapro MS, et al. Eur J Cancer. 2011;47: Available at : 5

6 Primary prophylaxis Chemotherapy FN risk > 20% American Society of Clinical Oncology (ASCO) guideline updates 2015 Chemotherapy with febrile neutropenia risk 20% Intensive chemotherapy regimen Dose-dense (increased frequency) Dose-intense (increased dose) High risk patient Type Breast Esophargeal H&N NHL Lung cancer Ovarian Regimen AC>D, TAC, TC, Doxetaxel+Cyclophosphamide TCF Paclitaxel+ifosfamide ESHAP, R-ICE Docetaxel+Carboplatin, Topotecan Topotecen, Docetaxel Primary prophylaxis High risk patient Age 65 years Advanced disease Previous chemotherapy and radiation therapy Preexisting neutropenia or bone marrow involvement with tumor Infection Open wound or recent surgery Poor performance status or poor nutritional status Poor renal function Liver dysfunction (most notable elevated bil) Cardiovascular disease Multiple comorbid conditions HIV infection Secondary prophylaxis Recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy Especially in reduced dose may compromise therapeutic outcome Treatment Restrict use in high risk FN patients Sepsis syndrome Age > 65 years Profound neutropenia (ANC < 100 cells/mm 3 ) Neutropenia expected to last > 10 days Pneumonia Invasive fungal infection Other clinically documented infections Hospitalization at time of fever Prior episode of febrile neutropenia Acute leukemia and Myelodysplastic syndromes Acute myeloid leukemia (AML) Not recommended in induction phase prophylaxis Recommended in consolidation phase prophylaxis Myelodysplastic syndromes (MDS) Recommended treatment intermittent in severe neutropenia and recurrent infection Acute lymphocytic leukemia (ALL) Recommended in induction phase prophylaxis Ref : Smiths TJ, et al. J Clin Oncol. 2006;24:

7 Compare colonystimulating factors s Filgrastim Lenograstim Sargamostim Pegfilgrastim Source E.Coli - Yeast Yeast Dose 5 mcg/kg/d 5 mcg/kg/d 250 mcg/m2/d 6 mcg single dose** Route SC, IV SC,IV SC,IV SC Half life 3.5 hr 3 hr 2 hr hr Eliminate Renal Renal - Neutrophil Adverse effect Bone pain, Bruising, diarrhea*, edema*, fatigue*, fever*, rash, injection site reaction Bone pain, injection site reaction, urticaria * Less frequent with filgrastim compare with sargamostim ** Do not used in infants and children and BW < 45 kg Ref : Molineux G. Current Pharmaceutical Design. 2004;10: s s Ref : Crawford J. Drugs. 2002;62: Ref : Holmes FA, et al. J Clin Oncol. 2002;20: Compare colonystimulating factors Filgrastim Lenograstim Sargamostim Pegfilgrastim Source E.Coli - Yeast Yeast Dose 5 mcg/kg/d 5 mcg/kg/d 250 mcg/m2/d 6 mg single dose** Route SC, IV SC,IV SC,IV SC Half life 3.5 hr 3 hr 2 hr hr Eliminate Renal Renal - Neutrophil Adverse effect Bone pain, Bruising, diarrhea*, edema*, fatigue*, fever*, rash, injection site reaction * Less frequent with filgrastim compare with sargamostim ** Do not used in infants and children and BW < 45 kg Bone pain, injection site reaction, urticaria Colonystimulating factor regimen Colonystimulating factor Filgrastim : 5 mcg/kg/day Lenograstim : 5 mcg/kg/day Pegfilgrastim : 6 mg Duration Should started 24 to 72 hours after chemotherapy Continued up to 14 days (prophylaxis) or until reaching ANC 3,000 cells/mm 3 for 2 consecutive days (treatment) Pegfilgrastim : single dose (only prophylaxis) 7

8 Von Minckwitz G, et al. 1 Compare G-CSF (5-10 days) vs Pegfilgrastim Out come : febrile neutropenia incidence G-CSF 18%, Pegfilgrastim 7% (P<0.001) Almenar D, et al 2 and Morrison VA, et al. 3 Study G-CSF used in real world practice Median number of daily G-CSF is 6-7 days More patients have febrile neutropenia compare with pegfilgrastim (41%) Environmental precautions Hand hygiene Isolation and barrier precustions HSCT should be placed in private room With > 12 air exchanged/hr HEPA filtration Plants and dried fresh flowers should not allowed Hospital work exclusion policies application 1 von Minckwitz G, et al. Ann Oncol. 2008;19: Almenar D, et al.eur J Cancer Care (Engl) 2009;18: Morrison VA, et al. J Manag Care Pharm. 2007;13: