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1 파워포인트문서의제목

2 Reference 1. IDSA GUIDELINES. Clinical Practice Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Disease Society of America. Clinical Infectious Diseases 2011;52(4):e56-e NCCN Guidelines. Version Prevention and Treatment of Cancer-Related Infections. 3. NCCN Guidelines. Version Myeloid Growth Factors 4. NCCN Guidelines. Version Myelodysplastic Syndromes 5. NCCN Guidelines. Version Acute Myeloid Leukemia Update of Recommendations for the Use of White Blood cell Growth Factors: An Evidence-Based Clinical Practice Guidelines. J Clin Oncol 2006;24(19): Impact of Primary Prophylaxis With Granulocyte Colony-Stimulating Factor on Febrile Neutropenia and Mortality in Adult Cancer Patients Receiving Chemotherapy: A Systemic Review. J Clin Oncol 2007;25: The role of granulocyte transfusions in neutropenic patients. British Journal of Haematology 2004;127:

3 Ready to answer the questions? Seven days after completing chemotherapy, B.C developed a fever of 102 F (orally). Vital signs are blood pressure, 109/70 mmhg; pulse, 102 beats/min; and respirations, 25 breaths/min. physical examination demonstrate a clear oropharynx without exudates or plaques. Chest and cardiac examination are normal. The exit site for the Hickman catheter is clean and nontender without signs of erythema or induration./ the perineum and rectum are nontender, and no masses are noted. Lab data; Hct 20%, Hbg 7g/dL, WBC 1,400 cells/mm3 with polymorphonuclear leukocytes, 1% band forms, 70% lymphocytes, 22% monocytes, PLT17,000 cells/l, blood glucose 160 mg/dl, serum creatinine 1.1 mg/dl, BUN 24 mg/dl What are the signs & symptoms of infection in B.C? What are the most common sites & sources of infection in patients such as B.C? Should B.C be started on antibiotic therapy immediately? What would be a reasonable initial empiric antibiotic regimen for B.C? Can any of the more potent, extended spectrum beta-lactams be used as monotherapy in febrile neutropenic patients? What is the rationale for adding vancomycin to the regimen? How should therapy be modified? For how long should antibiotics be continued? What is the significance of fungal infections in neutropenic cancer patients? Is there any way to facilitate marrow recovery and reduce the duration of neutropenia?

4 Overview Neutropenia : < 500 neutrophils/mcl or < 1,000 neutrophils/mcl and a predicted decline to 500/mcl over the next 48 h Fever : 38.3 C orally or 38.0 C over 1 h Major dose-limiting toxicity of chemotherapy Prolonged hospitalization Increase diagnostic and treatment costs Broad-spectrum antibiotic use Compromise clinical outcomes Prompt dose reduction or treatment delays in subsequent chemotherapy cycles

5 Management of neutropenic fever Principles for initial management of fever Antibiotic regimens for fever and infection Outpatient therapy Role of colony-stimulating factors Granulocyte transfusions Management of persistent fever Empiric fungal therapy Other causes of persistent fever and their management

6 Role of risk assessment Determine the type of empirical antibiotic therapy (oral vs intravenous) venue of treatment (inpatient vs outpatient) duration of antibiotic therapy Distinguish high-risk and low-risk patients with fever and neutropenia High risk patients Anticipated prolonged (> 7 days) & profound neutropenia (ANC < 100 cells/mm 3 ) Significant co-morbid conditions (hypotension, pneumonia, new-onset abdominal pain or neurologic changes) Inpatient status Hepatic insufficiency (> 5times ULN for aminotransferases) Renal insufficiency (CCR < 30 ml/min) Uncontrolled/progressive cancer Pneumonia or other complex infections at clinical presentation) Alemtuzumab Mucositis grade 3-4 Poor performancs status (ECOG 2)

7 Role of risk assessment The Multinational Association for Supportive Care in Cancer Risk-Index Score (MASCC) Burden of febrile neutropenia with no or mild symptoms No hypotension (systolic blood pressure >90 mmhg) No chronic obstructive pulmonary disease Solid tumor or hematologic malignancy with no previous fungal infection No dehydration requiring parenteral fluids Burden of febrile neutropenia with moderate symptoms Outpatient status Age <60 years High-risk patients ; MASCC score <21 Initially admitted to the hospital for empirical antibiotic therapy Low-risk patients ; MASCC score 21 Candidates for oral and/or outpatient empirical antibiotic therapy

8 Initial therapy for febrile neutropenia Infection risk assessment Potential infecting organisms Colonization Site of infection Local antibiotics susceptibility patterns Organ dysfunction/ drug allergy Broad spectrum of activity Previous antibiotic therapy Antipseudomonal coverage Bactericidal

9 Empiric antibiotic therapy what? Initial Monotherapy with an antipseudomonal β-lactam agent : Cefepime or ceftazidime, carbapenem, piperacillin-tazobactam Added to aminoglycosides, fluoroquinolones, and/or vancomycin Considered for suspected catheter-related infections, skin or softtissue infection, pneumonia, or hemodynamic instability MRSA : early addition of vancomycin, linezolid, or daptomycin VRE : early addition of linezolid, or daptomycin ESBLs : early use of a carbapenem KPCs : early use of polymymix-colstin or tigecycline Modification Others Penicillin-allergic patients : ciprofloxacin + clindamycin or aztreonam Oral empirical regimen : ciprofloxacin + amoxicillin-clavulanate Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone.

10 Appropriate use of vancomycin Vancomycin should not be considered as a routine component of initial therapy for fever & neutropenia. Exception for serious infections Clinically apparent, serious, catheter-related infection Blood culture positive for G(+) bacteremia prior to final identification & susceptibility testing Known colonization with penicillin/cephalosporin-resistant pneumoccoci or MRSA Hypotension or septic shock without an identified pathogen Soft tissue infection Risk factors for viridans group streptococcal, bacteremia : severe mucositis & prophylaxis with quinolones or TMP-SMX Vancomycin should be discontinued in 2-3 days if a G(+) infection (eg, MRSA) is not identified. Linezolid, quinupristin/dalfopristin, and daptomycin may be used specifically for infections caused by documented VRE or in patients for whom vancomycin is not an option.

11 Empiric antibiotic therapy when, how? Guided by clinical & microbiologic data For the site & susceptibilities of any isolated organisms Unexplained persistent fever If hemodynamically unstable, coverage for resistant G(-), G(+), anaerobic fungi Vancomycin should be stopped after 2 days if no evidence for G(+) infection An IV-to-oral switch, if clinically stable & adequate gastrointestinal absorption If fever persists or recurs within 48 h in outpatients, hospital admission & with management as for high-risk patients Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4-7 days of a broad-spectrum antibacterial regimen & no identified fever source.

12 Empiric antibiotic therapy how long? Time to defervescence ranges from 2 to 7 days (median, 5 days) for febrile cancer patients with neutropenia who receive appropriate initial antibiotic therapy. With clinically or microbiologically documented infections Continue for at least the duration of neutropenia (until ANC is 500 cells/mm 3 ) A defined course of therapy appropriate for the specific infection With unexplained fever The traditional endpoint is an increasing ANC > 500 cells/mm 3 With resolved signs & symptoms, remained neutropenia Oral fluoroquinolone prophylaxis until marrow recovery The patient is clinically well and afebrile for at least 24 hours before antibiotic discontinuation. With persistent fever (clinically stable patient) Modification of initial empiric antibiotic therapy based on specific new clinical findings and/or new microbiologic results

13 Antibiotic prophylaxis when, what? Fluoroquinolone prophylaxis (levofloxacin ciprofloxacin) for high-risk patients with expected durations of prolonged & profound neutropenia (ANC 100 cells/mm 3 for >7 days). Addition of a G(+) active agent to fluoroquinolone prophylaxis is generally not recommended. Not routinely recommended for low-risk patients who are anticipated to remain neutropenic for <7 days. Routine antibacterial prophylaxis was not recommended in patients undergoing high-dose therapy & autologous HSCT.

14 Antibacterial agents

15 Antibacterial agents

16 Antibacterial agents

17 Antifungal therapy ; empirical or prophylaxis With persistent or recurrent fever after 4-7 days of antibiotics & expected overall duration of neutropenia (>7 days) Data are insufficient to recommended a specific empirical antifungal agent for a patient already receiving antimold prophylaxis Prophylaxis against Candida infection such as allogenic hematopoietic stem cell transplant (HSCT) recipients or those undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia. Fluconazole, itraconazole, voriconazole, posaconazole, micafungin, and caspofungin are all acceptable. In low-risk patients, routine use of empirical & prophylactic antifungal therapy is not recommended.

18 Antifungal agents

19 Antifungal agents

20 Antifungal agents

21 Antiviral therapy - prophylaxis Herpes simplex virus (HSV)-seropositive patients undergoing allogenic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis. Yearly influenza vaccination with inactivated vaccine is recommended for all patients being treated for cancer. Optimal timing of vaccination is not established, but serologic responses may be best between chemotherapy cycles (>7 days after the last treatment) or >2 weeks before chemotherapy starts.

22 Antiviral agents

23 Antiviral agents

24 Adjunctive therapies Adjunctive therapies Limited or anecdotal data are available to suggest that these interventions may be beneficial; GCSF or GMCSF should be considered in neutropenic patients with serious infectious complications, such as the following Pneumonia Invasive fungal infection Progressive infection (any type) Granulocyte transfusions Invasive fungal infection G(-) rod infection unresponsive to appropriate antimicrobial therapy Intravenous immunoglobulin Should be used in combination with ganciclovir for CMV pneumonia consider IV IgG for patients with profound hypogammaglobulinemia

25 Adjunctive therapies Prophylactic use of CSFs Risk assessment Evaluation of risk for chemotherapy-induced FN prior to the first cycle Disease type Chemotherapeutic regimen (high dose, dose dense or standard dose) Patients risk factors ; > 65 yrs, previous chemotherapy or radiotherapy, pre-existing neutropenia tumor involvement in the bone marrow, poor performance status comorbidities (renal or liver dysfunction) Treatment intent - curative/adjuvant - treatment directed toward prolongation of survival - symptom management therapy Based on the chemotherapy regimen & patient-related risk factors, the patient assigned to High risk group (< 20% ㅡ,risk of FN) Intermediate group (10-20% risk) Low risk group (< 10% risk)

26 Adjunctive therapies Efficacy of prophylactic CSFs

27 Adjunctive therapies Efficacy of prophylactic CSFs

28 Adjunctive therapies Efficacy of prophylactic CSFs

29 Adjunctive therapies Efficacy of prophylactic CSFs

30 Adjunctive therapies Apply prophylactic use of CSFs Risk of FN 20% (NCCN, ASCO, EORTC) Risk of < 20% + treatment intent chemotherapy or risky patient factors After the first cycle, patient evaluation should performed prior to each subsequent cycle to determine the risk categorization & treatment intent. If the patient experiences such as episode despite receiving CSF, recommends a chemotherapy dose reduction or change in treatment regimen unless there is an impact on patient survival. If the patient dose not develop FN or a dose-limiting neutropenic event and is thought to be benefiting from chemotherapy, the previous assessment should be repeated after each subsequent cycle.

31 Recommended for the prevention of FN in patients who have a high risk of FN based on age, medical history, disease characteristics, myelotoxicity of regimen Required and recommended for dose dense regimens Clinical trial data support the use of CSF when the risk of FN is in the range of 20% or higher Special circumstances often appropriate even with regimens with FN rates of < 20% Age > 65years / previous FN Poor performance status / poor nutritional status Open wounds or active infections More advanced cancer Cytopenias due to bone marrow involvement by tumor Extensive prior treatment Administration of combined chemoradiotherapy Other serious comorbidities

32 Examples of disease settings and chemotherapy regimens with a high risk febrile neutropenia (> 20%)

33 Examples of disease settings and chemotherapy regimens with a intermediate risk febrile neutropenia (10-20%)

34 Adjunctive therapies Therapeutic use of CSFs Compared to prophylactic use, there is less evidence supporting therapeutic use of CSFs for FN as an adjunctive to antibiotics. Patients with FN who are receiving prophylactic filgrastim or sargramostim should be continue with CSF therapy. Patients who have not received prophylactic CSFs, recommends an evaluation for risk factors for infection-related complications or poor clinical outcome. If risk factors are present, CSFs should be considered. Old age (> 65 years) Sepsis syndrome Severe (ANC < 100/mcl) or anticipated (> 10 days) neutropenia Pneumonia, invasive fungal infection, other clinically-documented infections Hospitalization Prior episode of FN

35 Should not be routinely used For patients with neutropenia who are afebrile As adjunctive treatment with antibiotic therapy for patients with fever and neutropenia Should be considered Patients with FN who are at high risk for infection-associated complications Patients who have prognostic factors that are predictive of poor clinical outcome High risk features Prolonged (> 10days) and profound neutropenia Age > 65 years Uncontrolled primary disease Pneumonia / Invasive fungal infection Sepsis syndrome (hypotension and multi-organ dysfunction) Being hospitalized at the time of fever development

36 Adjunctive therapies CSFs dosing & administration Severe chronic neutropenia : 6 mcg/kg bid non-myeloid malignancies At least 14 days between injection Insufficient evidence in use for primary prophylaxis

37 Adjunctive therapies Toxicity risks of CSFs

38 Adjunctive therapies Scheduled dose delivery of CSFs

39 CSF in older patients 65 years, diffuse aggressive lymphoma, curative chemotherapy Prophylactic CSF CSF in the pediatric population Primary prophylaxis with a likelihood of FN Secondary prophylaxis or therapeutic CSF should be limited to high-risk patients ALL children should be considered with caution CSF in patients with acute leukemia and myelodysplastic syndromes AML & ALL after the completion of the initial induction or first post-remission course MDS : in case of severe neutropenia & recurrent infection AML in relapse should be used judiciously, or not at all, in patients with refractory or relapsed myeloid leukemia since the expected benefit is only a few days of shortened neutropenia

40 CSF to increase chemotherapy dose-intensity and dose-density should only be used within an appropriately designed clinical trial CSF as adjuncts to progenitor-cell transplantation after autologous, but not allogenic, PBPC transplant is the current standard of care CSF in patients receiving radiotherapy with/without concurrent chemotherapy Chemoradiotherapy : should be avoided (particularly involving the mediastinum) Radiotherapy : in the absence of chemotherapy, therapeutic use of CSF may be considered Special comment (growth factors as treatment for radiation injury) patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury other organs, should receive prompt administration of CSF or pegylated GCSF Impact of CSF on quality of life and health care costs ; further research

41 Summary (ASCO 2006) Setting/indication Recommended Not recommended General FN risk in the range of 20% or higher circumstances Special circumstances Secondary prophylaxis Therapy of AFN Clinical factors dictate use Based on chemotherapy reaction among other factors Not to be used routinely Therapy of FN AML If high-risk for complications or poor clinical outcomes Following induction therapy, patients > 55years old most likely to benefit After the completion of consolidation chemotherapy Not to be used routinely as adjunctive treatment with antibiotic therapy Not to be used for priming effects ALL MDS Radiotherapy Older patients Pediatric population Radiation injury After the completion of initial chemotherapy or first post remission course Consider if receiving radiation therapy alone and prolonged delays are expected If 65 years old with diffuse aggressive lymphoma and treated with curative chemotherapy For the primary prophylaxis with a likelihood of FN & secondary prophylaxis or Tx for high-risk patients Prompt administration of CSF or pegylated G-CSF if exposed to lethal doses of total body radiotherapy Intermittent administration for a subset of patients with severe neutropenia & recurrent infection G-CSF use in children with ALL should be considered carefully

42 Adjunctive therapies Granulocyte transfusions One of the earliest approaches used to boost the patient s defense against infections was the transfusion of WBCs. In the 1970s, granulocyte transfusions were used adjunctively in patients with persistent neutropenia & documented infections who, despite appropriate antibiotics, failed to respond after 24 to 48 hours. This approach had limited value because of the difficulties in obtaining adequate cells for transfusion, as well as the problems with alloimmunization and risk of infection transmission. In addition, the questionable efficacy of WBC transfusions has decreased the use of this strategy. Therefore, granulocyte transfusions are not routinely indicated in this population. However, patients with progressive bacterial of fungal infections unresponsive to appropriate antimicrobial therapy may be considered as candidates.

43 Ready to answer the questions? Seven days after completing chemotherapy, B.C developed a fever of 102 F (orally). Vital signs are blood pressure, 109/70 mmhg; pulse, 102 beats/min; and respirations, 25 breaths/min. physical examination demonstrate a clear oropharynx without exudates or plaques. Chest and cardiac examination are normal. The exit site for the Hickman catheter is clean and nontender without signs of erythema or induration./ the perineum and rectum are nontender, and no masses are noted. Lab data; Hct 20%, Hbg 7g/dL, WBC 1,400 cells/mm3 with polymorphonuclear leukocytes, 1% band forms, 70% lymphocytes, 22% monocytes, PLT17,000 cells/l, blood glucose 160 mg/dl, serum creatinine 1.1 mg/dl, BUN 24 mg/dl What are the signs & symptoms of infection in B.C? What are the most common sites & sources of infection in patients such as B.C? Should B.C be started on antibiotic therapy immediately? What would be a reasonable initial empiric antibiotic regimen for B.C? Can any of the more potent, extended spectrum beta-lactams be used as monotherapy in febrile neutropenic patients? What is the rationale for adding vancomycin to the regimen? How should therapy be modified? For how long should antibiotics be continued? What is the significance of fungal infections in neutropenic cancer patients? Is there any way to facilitate marrow recovery and reduce the duration of neutropenia?

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