0314_IDSA FN _CID 和訳表紙

Clinical

Infectious

Diseases

Reprinted from

15 February 2011

Volume 52

pp. e56-e93

Alison G. Freifeld, Eric J. Bow, Kent A. Sepkowitz,

Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad,

Kenneth V. Rolston, Jo-Anne H. Young, and John R. Wingard

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients with

Cancer: 2010 Update by the Infectious Diseases

Society of America

好中球減少を呈する癌患者に対する

抗微生物薬の使用に関する

実践的臨床ガイドライン：

米国感染症学会による 2010 年改訂版

監訳：自治医科大学附属さいたま医療センター 血液科

神田 善伸 先生

Oxford OX2 6DP, UK

Tel: +44 (0) 1865 353827

[email protected]

Japanese Version



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目次

エグゼクティブサマリー 1 発熱性好中球減少症を呈する患者の評価および 治療に関するガイドライン推奨事項 2 Ⅰ． 発熱性好中球減少症を呈する患者におけるリスクアセスメント の役割は?そして、低リスクと高リスク患者はどのように鑑別 するか? 2 　　推奨事項 2 Ⅱ．初期アセスメントとして、 　　どのような検査および培養を行えばよいか？ 2 　　推奨事項 2 Ⅲ．発熱を呈する好中球減少患者にはどのような経験的抗菌薬 　　療法が適切か？また、どのような治療設定で行えばよいか？ 2 　　推奨事項 2 Ⅳ．発熱性好中球減少症期間中、 　　抗菌薬はいつどのように変更すればよいか？ 3 　　推奨事項 3 Ⅴ．経験的抗菌薬療法はいつまで継続すればよいか？ 3 　　推奨事項 3 Ⅵ．予防的抗菌薬療法はどのような場合に行えばよいか？　 　　また、どの薬剤を使用すればよいか？ 3 　　推奨事項 3 Ⅶ．真菌感染症に対する経験的または先制攻撃的治療の役割は？　 　　また、どの抗真菌薬を使用すればよいか？ 4 　　推奨事項 4 Ⅷ．真菌感染症に対する予防投与はどのような場合に 　　行えばよいか？また、どの抗真菌薬を使用すればよいか？ 4 　　推奨事項 4 Ⅸ．予防的抗ウイルス療法の役割は？　 　　また、抗ウイルス治療が必要なウイルス感染症は？ 4 　　推奨事項 4 Ⅹ．発熱性好中球減少症の管理における 　　造血因子（G−CSFまたはGM−CSF）の役割は？ 5 　　推奨事項 5 Ⅺ．好中球減少患者に対しカテーテル関連感染症は 　　どのように診断・管理するのか？ 5 　　推奨事項 5 Ⅻ．発熱性好中球減少症患者の管理において、 　　どのような環境予防策を実践すればよいか？ 5 　　推奨事項 5 緒　言 5 発熱：原因および疫学 5 定　義 6 改訂方法 7 　　委員会の構成 7 　　プロセスの概要 7 　　文献のレビューおよび分析 7 　　ガイドラインと利益相反 7 　　エビデンスに基づくコンセンサスの形成 7 　　改訂日 8 発熱性好中球減少症を呈する患者の評価および 治療に関するガイドライン推奨事項 8 Ⅰ．発熱性好中球減少症を呈する患者における 　　リスクアセスメントの役割は?　 　　そして、低リスクと高リスク患者はどのように鑑別するか? 8 　　推奨事項 8 　　エビデンスの要約 8 　　高リスク患者 9 　　低リスク患者 10 Ⅱ．初期アセスメントとして、 　　どのような検査および培養を行えばよいか？ 10 　　推奨事項 10 　　エビデンスの要約 10 　　培養 10 　　放射線画像検査 11 　　その他の臨床検査 11 　　炎症の血清マーカー 11 Ⅲ．発熱を呈する好中球減少患者にはどのような経験的抗菌薬 　　療法が適切か？また、どのような治療設定で行えばよいか？ 11 　　推奨事項 11 　　エビデンスの要約 12 Ⅳ．発熱性好中球減少症期間中、 　　抗菌薬はいつどのように変更すればよいか？ 15 　　推奨事項 15 　　エビデンスの要約 16 Ⅴ．経験的抗菌薬療法はいつまで継続すればよいか？ 18 　　推奨事項 18 　　エビデンスの要約 18 Ⅵ．予防的抗菌薬療法はどのような場合に行えばよいか？　 　　また、どの薬剤を使用すればよいか？ 19 　　推奨事項 19 　　エビデンスの要約 19 Ⅶ．真菌感染症に対する経験的または先制攻撃的治療の役割は？　 　　また、どの抗真菌薬を使用すればよいか？ 20 　　推奨事項 20 　　エビデンスの要約 21 Ⅷ．真菌感染症に対する予防投与はどのような場合に 　　行えばよいか？また、どの抗真菌薬を使用すればよいか？ 24 　　推奨事項 24 　　エビデンスの要約 24 　　　　Candida感染症 24 　　　　Aspergillus感染症 24 　　　　AML患者 24 　　　　同種HSCT施行患者 25 Ⅸ．予防的抗ウイルス療法の役割は？　 　　また、抗ウイルス治療が必要なウイルス感染症は？ 25 　　推奨事項 25 　　エビデンスの要約 26 Ⅹ．発熱性好中球減少症の管理における 　　造血因子（G−CSFまたはGM−CSF）の役割は？ 26 　　推奨事項 26 　　エビデンスの要約 26 Ⅺ．好中球減少患者においてカテーテル関連感染症は 　　どのように診断・管理されるのか？ 27 　　推奨事項 27 　　エビデンスの要約 27 Ⅻ．発熱性好中球減少患者の管理において、 　　どのような環境予防策を実践すればよいか？ 28 　　推奨事項 28

I D S A G U I D E L I N E S

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients

with Cancer: 2010 Update by the Infectious

Diseases Society of America

Alison G. Freifeld,1_{Eric J. Bow,}9_{Kent A. Sepkowitz,}2_{Michael J. Boeckh,}4_{James I. Ito,}5_{Craig A. Mullen,}3_{Issam I. Raad,}6

Kenneth V. Rolston,6_{Jo-Anne H. Young,}7_{and John R. Wingard}8

1_{Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska;}2_{Department of Medicine, Memorial Sloan-Kettering Cancer}

Center, New York;3_{Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;}4_{Vaccine and Infectious Disease Division,}

Fred Hutchinson Cancer Research, Seattle, Washington;5_{Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California;} 6_{Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;} 7_{Department of Medicine, University of Minnesota, Minneapolis, Minnesota;}8_{Division of Hematology/Oncology, University of Florida, Gainesville,}

Florida; and9_{Departments of Medical Microbiology and Internal Medicine, the University of Manitoba, and Infection Control Services, Cancer Care}

Manitoba, Winnipeg, Manitoba, Canada

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia.

Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.

What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens.

Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care–associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

EXECUTIVE SUMMARY

Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection, because signs and symptoms of inflammation typically are attenuated. Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorith-mic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been

Received 29 October 2010; accepted 17 November 2010.

Correspondence: Alison G. Freifeld, MD, Immunocompromised Host Program, Dept of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400 ([email protected]).

Clinical Infectious Diseases 2011;52(4):e56–e93

� The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]. 1058-4838/2011/524-0001$37.00 DOI: 10.1093/cid/cir073 E\JXHVWRQ-DQXDU\  FLGR[IRUGMRXUQDOVRUJ 'RZQORDGHGIURP 

監訳のことば

このたび、2002 年に公表されていた米国感染症学会（IDSA：Infectious Disease Society

of America）の「好中球減少を呈する症例に対する抗微生物薬の使用に関する実践的臨床ガ

イドライン」が改定された。発熱性好中球減少症（FN）治療のガイドラインは、初版が 1997

年に公表され、2002 年に初回改定が行われた。今回はそれをさらに更新・拡充するもので

ある。その構成は、発熱性好中球減少症に関し、あらかじめ 12 項目の質問を設け、その質

問に回答する形で 52 の推奨事項が記述されている。

本ガイドラインの特徴の一つとして、最初に患者をリスクによって分類して管理するこ

とが重要であると記されている。好中球減少中の発熱に対しては迅速な抗菌薬による経験

的治療の実施が重要であるという点については従来のガイドラインと同様であり、広域な

スペクトルを有する抗菌薬が推奨されている。発熱がなくとも感染症を疑う症状が出現し

た好中球減少患者も高リスク患者として扱い、迅速な治療を開始する。一方、持続あるい

は再燃する発熱に対して真菌感染を考慮する場合においては、昨今の検査技術の向上によっ

て侵襲性真菌感染症の早期検出が可能になったことから、経験的治療に加えて先制攻撃的

治療についての記述が新たに追加された。しかし、真菌感染症に対する経験的治療あるい

は先制攻撃的治療のいずれが適しているかに関しては議論が残されている。また、経験的

真菌感染治療を行う場合には、予防を目的として投与した抗糸状菌薬とは異なる系統の注

射用抗糸状菌薬を推奨する「クラススイッチ」の考え方が示されている。さらに、経験的抗

菌薬投与の初期レジメンとして単剤投与が推奨されたこと、高リスク患者に対する抗菌薬、

抗真菌薬の予防投与がより積極的が推奨がされたということも今回の改訂について特筆す

べき点である。

本ガイドラインは米国のガイドラインであるため、効能・効果や用法・用量が本邦とは

異なる記載や、本邦では未発売の薬剤の記載がなされている箇所がある。また、日米では

スタッフ数や病院へのアクセスなどの医療資源の違いに加えて、気候、耐性菌の出現状況、

文化、医療経済を含めた様々な環境が異なることを念頭におきながら解釈する必要がある。

特に低リスク群患者の外来での管理の適応は日米で大きく異なる可能性がある。しかし、

日本の診療に適合するように調整しながら読み解いていけば、本ガイドラインは好中球減

少患者の診療現場において確かに役立つものとなるはずである。

自治医科大学附属さいたま医療センター　血液科

教授

　神田　善伸

I D S A G U I D E L I N E S

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients

with Cancer: 2010 Update by the Infectious

Diseases Society of America

Alison G. Freifeld,1_{Eric J. Bow,}9_{Kent A. Sepkowitz,}2_{Michael J. Boeckh,}4_{James I. Ito,}5_{Craig A. Mullen,}3_{Issam I. Raad,}6

Kenneth V. Rolston,6_{Jo-Anne H. Young,}7_{and John R. Wingard}8

1_{Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska;}2_{Department of Medicine, Memorial Sloan-Kettering Cancer}

Center, New York;3_{Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;}4_{Vaccine and Infectious Disease Division,}

Fred Hutchinson Cancer Research, Seattle, Washington;5_{Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California;} 6_{Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;} 7_{Department of Medicine, University of Minnesota, Minneapolis, Minnesota;}8_{Division of Hematology/Oncology, University of Florida, Gainesville,}

Florida; and9_{Departments of Medical Microbiology and Internal Medicine, the University of Manitoba, and Infection Control Services, Cancer Care}

Manitoba, Winnipeg, Manitoba, Canada

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia.

Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.

What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens.

Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care–associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

EXECUTIVE SUMMARY

Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection, because signs and symptoms of inflammation typically are attenuated. Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorith-mic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been

Received 29 October 2010; accepted 17 November 2010.

Correspondence: Alison G. Freifeld, MD, Immunocompromised Host Program, Dept of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400 ([email protected]).

Clinical Infectious Diseases 2011;52(4):e56–e93

� The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected].

1058-4838/2011/524-0001$37.00 DOI: 10.1093/cid/cir073

e56 d CID 2011:52 (15 February) d Freifeld et al

E\JXHVWRQ-DQXDU\  FLGR[IRUGMRXUQDOVRUJ 'RZQORDGHGIURP 

I D S A G U I D E L I N E S

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients

with Cancer: 2010 Update by the Infectious

Diseases Society of America

Alison G. Freifeld,1_{Eric J. Bow,}9_{Kent A. Sepkowitz,}2_{Michael J. Boeckh,}4_{James I. Ito,}5_{Craig A. Mullen,}3_{Issam I. Raad,}6

Kenneth V. Rolston,6_{Jo-Anne H. Young,}7_{and John R. Wingard}8

1_{Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska;}2_{Department of Medicine, Memorial Sloan-Kettering Cancer}

Center, New York;3_{Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;}4_{Vaccine and Infectious Disease Division,}

Fred Hutchinson Cancer Research, Seattle, Washington;5_{Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California;} 6_{Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;} 7_{Department of Medicine, University of Minnesota, Minneapolis, Minnesota;}8_{Division of Hematology/Oncology, University of Florida, Gainesville,}

Florida; and9_{Departments of Medical Microbiology and Internal Medicine, the University of Manitoba, and Infection Control Services, Cancer Care}

Manitoba, Winnipeg, Manitoba, Canada

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia.

Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.

What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens.

Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care–associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

EXECUTIVE SUMMARY

Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection, because signs and symptoms of inflammation typically are attenuated. Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorith-mic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been

Received 29 October 2010; accepted 17 November 2010.

Correspondence: Alison G. Freifeld, MD, Immunocompromised Host Program, Dept of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400 ([email protected]).

Clinical Infectious Diseases 2011;52(4):e56–e93

� The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected].

1058-4838/2011/524-0001$37.00 DOI: 10.1093/cid/cir073

e56 d CID 2011:52 (15 February) d Freifeld et al

E\JXHVWRQ-DQXDU\



FLGR[IRUGMRXUQDOVRUJ

'RZQORDGHGIURP



Clinical Practice Guideline • CID 2011:52 (15 February) • 1

好中球減少を呈する癌患者に対する抗微生物薬の

使用に関する実践的臨床ガイドライン：

米国感染症学会による2010年改訂版

The IDSA wishes to express its gratitude to Dr Yoshinobu Kanda for his careful supervision of this translation. The IDSA wishes to express its gratitude to Dr Hiroo Toyoda for his careful review of this translation.

　本稿は、米国感染症学会（Infectious Diseases Society of America；IDSA）が1997年に公表し、2002年に 初回改訂を行った最初の発熱性好中球減少患者に対するガイドラインを更新・拡充するものである。化学療 法により引き起こされた発熱性好中球減少症を呈する癌患者の管理の際の抗微生物薬の使用指針として活用 されることを意図している。 　本稿に示す戦略および推奨事項には、抗微生物薬の開発と技術の最近の進歩、臨床試験結果および豊富な 臨床経験が反映されている。我々は、2002年に行った本ガイドラインの前回の改訂以降、癌患者のうち抗菌 薬、抗真菌薬および抗ウイルス薬の予防投与の有益性が最も期待されるのはどんな患者集団かという点に関 して、より明確な定義を打ち出した。また、好中球減少患者を徴候・症状、基礎にある癌、治療のタイプお よび併存病態に応じて感染症のリスクが高い患者と低い患者に分類することが、治療アルゴリズムの中で極 めて重要となっている。リスク分類は、発熱性好中球減少症を呈する患者の管理の最初に行うこととして推 奨されている。さらに、侵襲性真菌感染症の早期検出が可能になったことから、真菌感染症に対する経験的 治療あるいは先制的攻撃的治療のいずれが最適か、に関して議論が生じているが、その治療アルゴリズムは まだ発展段階である。 　変更がないのは、迅速な経験的抗菌薬による治療の適応である。発熱性好中球減少症を呈しているすべて の患者には、グラム陽性菌およびグラム陰性菌のいずれにも抗菌活性を有する抗菌薬を用いて迅速かつ広範 囲に治療することは、依然として正しい。 　最後に、注意すべき点として、本ガイドライン作成に寄与したメンバーはいずれも米国またはカナダの施 設に所属する者であるため、本ガイドラインは北米の医療習慣を背景に作成されている。地域によって使用 可能な抗菌薬、主要な病原体、医療関連の経済状況などが異なるため、一部の推奨事項は北米以外の地域に は適用できない可能性がある。しかし、地域にかかわらず、臨床症状の注意深い監視と迅速な治療は、発熱 および/または感染症を発現した好中球減少患者の管理において普遍的に重要である。

エグゼクティブサマリー

化学療法により引き起こされる好中球減少症中の 発熱は、炎症の徴候・症状が一般的に弱いため、内 在する重症感染症を示す唯一の所見となり得る。医 師は、好中球減少期の発熱患者の管理に際し、感染 症のリスク、診断法および抗微生物薬による治療を

I D S A G U I D E L I N E S

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients

with Cancer: 2010 Update by the Infectious

Diseases Society of America

Alison G. Freifeld,1_{Eric J. Bow,}9_{Kent A. Sepkowitz,}2_{Michael J. Boeckh,}4_{James I. Ito,}5_{Craig A. Mullen,}3_{Issam I. Raad,}6

Kenneth V. Rolston,6_{Jo-Anne H. Young,}7_{and John R. Wingard}8

1_{Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska;}2_{Department of Medicine, Memorial Sloan-Kettering Cancer}

Center, New York;3_{Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;}4_{Vaccine and Infectious Disease Division,}

Fred Hutchinson Cancer Research, Seattle, Washington;5_{Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California;} 6_{Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;} 7_{Department of Medicine, University of Minnesota, Minneapolis, Minnesota;}8_{Division of Hematology/Oncology, University of Florida, Gainesville,}

Florida; and9_{Departments of Medical Microbiology and Internal Medicine, the University of Manitoba, and Infection Control Services, Cancer Care}

Manitoba, Winnipeg, Manitoba, Canada

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia.

Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.

What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens.

Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care–associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

EXECUTIVE SUMMARY

Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection, because signs and symptoms of inflammation typically are attenuated. Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorith-mic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been

Received 29 October 2010; accepted 17 November 2010.

Correspondence: Alison G. Freifeld, MD, Immunocompromised Host Program, Dept of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400 ([email protected]).

Clinical Infectious Diseases 2011;52(4):e56–e93

� The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]. 1058-4838/2011/524-0001$37.00 DOI: 10.1093/cid/cir073 E\JXHVWRQ-DQXDU\  FLGR[IRUGMRXUQDOVRUJ 'RZQORDGHGIURP 

I D S A G U I D E L I N E S

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients

with Cancer: 2010 Update by the Infectious

Diseases Society of America

Alison G. Freifeld,1_{Eric J. Bow,}9_{Kent A. Sepkowitz,}2_{Michael J. Boeckh,}4_{James I. Ito,}5_{Craig A. Mullen,}3_{Issam I. Raad,}6

Kenneth V. Rolston,6_{Jo-Anne H. Young,}7_{and John R. Wingard}8

1_{Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska;}2_{Department of Medicine, Memorial Sloan-Kettering Cancer}

Center, New York;3_{Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;}4_{Vaccine and Infectious Disease Division,}

Fred Hutchinson Cancer Research, Seattle, Washington;5_{Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California;} 6_{Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;} 7_{Department of Medicine, University of Minnesota, Minneapolis, Minnesota;}8_{Division of Hematology/Oncology, University of Florida, Gainesville,}

Florida; and9_{Departments of Medical Microbiology and Internal Medicine, the University of Manitoba, and Infection Control Services, Cancer Care}

Manitoba, Winnipeg, Manitoba, Canada

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia.

Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.

What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens.

Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care–associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

EXECUTIVE SUMMARY

Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection, because signs and symptoms of inflammation typically are attenuated. Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorith-mic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been

Received 29 October 2010; accepted 17 November 2010.

Correspondence: Alison G. Freifeld, MD, Immunocompromised Host Program, Dept of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400 ([email protected]).

Clinical Infectious Diseases 2011;52(4):e56–e93

� The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected].

1058-4838/2011/524-0001$37.00 DOI: 10.1093/cid/cir073

e56d CID 2011:52 (15 February) d Freifeld et al

E\JXHVWRQ-DQXDU\  FLGR[IRUGMRXUQDOVRUJ 'RZQORDGHGIURP 

I D S A G U I D E L I N E S

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients

with Cancer: 2010 Update by the Infectious

Diseases Society of America

Alison G. Freifeld,1_{Eric J. Bow,}9_{Kent A. Sepkowitz,}2_{Michael J. Boeckh,}4_{James I. Ito,}5_{Craig A. Mullen,}3_{Issam I. Raad,}6

Kenneth V. Rolston,6_{Jo-Anne H. Young,}7_{and John R. Wingard}8

1_{Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska;}2_{Department of Medicine, Memorial Sloan-Kettering Cancer}

Center, New York;3_{Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;}4_{Vaccine and Infectious Disease Division,}

Fred Hutchinson Cancer Research, Seattle, Washington;5_{Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California;} 6_{Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;} 7_{Department of Medicine, University of Minnesota, Minneapolis, Minnesota;}8_{Division of Hematology/Oncology, University of Florida, Gainesville,}

Florida; and9_{Departments of Medical Microbiology and Internal Medicine, the University of Manitoba, and Infection Control Services, Cancer Care}

Manitoba, Winnipeg, Manitoba, Canada

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia.

Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.

What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens.

Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care–associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

EXECUTIVE SUMMARY

Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection, because signs and symptoms of inflammation typically are attenuated. Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorith-mic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been

Received 29 October 2010; accepted 17 November 2010.

Correspondence: Alison G. Freifeld, MD, Immunocompromised Host Program, Dept of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400 ([email protected]).

Clinical Infectious Diseases 2011;52(4):e56–e93

� The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected].

1058-4838/2011/524-0001$37.00 DOI: 10.1093/cid/cir073

e56 CID 2011:52 (15 February) Freifeld et al

E\JXHVWRQ-DQXDU\



FLGR[IRUGMRXUQDOVRUJ

'RZQORDGHGIURP

I D S A G U I D E L I N E S

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients

with Cancer: 2010 Update by the Infectious

Diseases Society of America

Alison G. Freifeld,1_{Eric J. Bow,}9_{Kent A. Sepkowitz,}2_{Michael J. Boeckh,}4_{James I. Ito,}5_{Craig A. Mullen,}3_{Issam I. Raad,}6

Kenneth V. Rolston,6_{Jo-Anne H. Young,}7_{and John R. Wingard}8

1_{Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska;}2_{Department of Medicine, Memorial Sloan-Kettering Cancer}

Center, New York;3_{Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;}4_{Vaccine and Infectious Disease Division,}

Fred Hutchinson Cancer Research, Seattle, Washington;5_{Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California;} 6_{Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;} 7_{Department of Medicine, University of Minnesota, Minneapolis, Minnesota;}8_{Division of Hematology/Oncology, University of Florida, Gainesville,}

Florida; and9_{Departments of Medical Microbiology and Internal Medicine, the University of Manitoba, and Infection Control Services, Cancer Care}

Manitoba, Winnipeg, Manitoba, Canada

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia.

Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.

What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens.

Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care–associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

EXECUTIVE SUMMARY

Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection, because signs and symptoms of inflammation typically are attenuated. Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorith-mic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been

Received 29 October 2010; accepted 17 November 2010.

Correspondence: Alison G. Freifeld, MD, Immunocompromised Host Program, Dept of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400 ([email protected]).

Clinical Infectious Diseases 2011;52(4):e56–e93

� The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]. 1058-4838/2011/524-0001$37.00 DOI: 10.1093/cid/cir073 E\JXHVWRQ-DQXDU\  FLGR[IRUGMRXUQDOVRUJ 'RZQORDGHGIURP 

I D S A G U I D E L I N E S

Clinical Practice Guideline for the Use of

Antimicrobial Agents in Neutropenic Patients

with Cancer: 2010 Update by the Infectious

Diseases Society of America

Alison G. Freifeld,1_{Eric J. Bow,}9_{Kent A. Sepkowitz,}2_{Michael J. Boeckh,}4_{James I. Ito,}5_{Craig A. Mullen,}3_{Issam I. Raad,}6

Kenneth V. Rolston,6_{Jo-Anne H. Young,}7_{and John R. Wingard}8

1_{Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska;}2_{Department of Medicine, Memorial Sloan-Kettering Cancer}

Center, New York;3_{Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;}4_{Vaccine and Infectious Disease Division,}

Fred Hutchinson Cancer Research, Seattle, Washington;5_{Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California;} 6_{Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;} 7_{Department of Medicine, University of Minnesota, Minneapolis, Minnesota;}8_{Division of Hematology/Oncology, University of Florida, Gainesville,}

Florida; and9_{Departments of Medical Microbiology and Internal Medicine, the University of Manitoba, and Infection Control Services, Cancer Care}

Manitoba, Winnipeg, Manitoba, Canada

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia.

Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving.

What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens.

Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care–associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

EXECUTIVE SUMMARY

Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection, because signs and symptoms of inflammation typically are attenuated. Physicians must be keenly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for management of febrile patients through the neutropenic period. Accordingly, algorith-mic approaches to fever and neutropenia, infection prophylaxis, diagnosis, and treatment have been

Received 29 October 2010; accepted 17 November 2010.

Correspondence: Alison G. Freifeld, MD, Immunocompromised Host Program, Dept of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400 ([email protected]).

Clinical Infectious Diseases 2011;52(4):e56–e93

� The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]. 1058-4838/2011/524-0001$37.00 DOI: 10.1093/cid/cir073 E\JXHVWRQ-DQXDU\  FLGR[IRUGMRXUQDOVRUJ 'RZQORDGHGIURP  しっかりと認識していなければならない。そのため、過去 40 年の間、発熱・好中球減少に対するアルゴリズム的アプ ローチ、感染症予防、診断法および治療法が、長年にわた る臨床エビデンスと臨床経験に基づく実践と修正を経て確 立されてきた。 米国感染症学会の発熱・好中球減少ガイドラインは、い まだ発展段階にあるこれらのアルゴリズムの論理的根拠を 要約することを目的としている。2010 年ガイドライン改訂 において確定された推奨事項を以下に要約する。方法、背 景および各推奨事項を支持するエビデンスの要約の詳細は、 ガイドライン詳細版に記載されている。

発熱性好中球減少症を呈する患者の評価および治

療に関するガイドライン推奨事項

Ⅰ．発熱性好中球減少症を呈する患者におけるリスクア セスメントの役割は?　そして、低リスクと高リスク患 者はどのように鑑別するか? 推奨事項 1．発熱症状がある場合、重症感染症合併のリスクアセス メントを行わなければならない（A−Ⅱ）。リスクアセスメン トに基づき、経験的抗菌薬療法のタイプ（経口か静注［IV］）、 治療の場（入院 か 外来）および抗菌薬の治療期間を決定でき る可能性がある（A−Ⅱ）。 2．ほとんどの専門家は、高リスク患者は遷延的（7 日間を 超える）で深刻な好中球減少（抗がん化学療法治療後の好中 球絶対数［ANC］が 100 個 /mm3_{以下）が予測され、かつ / ま} たは、重大な併存症（低血圧、肺炎、新たに出現した腹痛、 神経学的変化を含む）を有する患者である。このような患者 は経験的治療を行うために先ず入院すべきである（A−Ⅱ）。 3．低リスク患者とは、好中球減少の持続期間が短い（7 日 以下）と予測される患者や、併存病態がほとんどまたはまっ たくない患者であり、このような患者は経口剤による経験 的治療の適応となる（A−Ⅱ）。 4．形式的分類は、Multinational Association for Supportive Care in Cancer（MASCC）スコアリングシステムを用いて行 うことができる（B−Ⅰ）。 ⅰ．高リスク患者は MASCC スコアが 21 未満である（B− Ⅰ）。MASCC基準または臨床基準による高リスク患者は、 入院患者でなければまず入院させ、経験的抗菌薬療法を 行うべきである（B−Ⅰ）。 ⅱ．低リスク患者はMASCCスコアが21以上である（B−Ⅰ）。 慎重に選択された低リスク患者は、経口かつ/または外来 での経験的抗菌薬療法の対象となる可能性がある（B−Ⅰ）。 Ⅱ．初期アセスメントとして、どのような検査および培 養を行えばよいか？ 推奨事項 5．臨床検査として、白血球分画数および血小板数を含む 全血球計算（CBC）、血清クレアチニンおよび血中尿素窒素 の測定、ならびに電解質、肝トランスアミナーゼおよび総 ビリルビンの測定を行うべきである（A−Ⅲ）。 6．少なくとも血液サンプル 2 セット以上の血液培養が推 奨され、中心静脈カテーテル（CVC）を留置している場合各 ルーメンと末梢静脈からそれぞれ 1 セットのサンプルを同 時に採取する。中心カテーテルを留置していない場合は、 別々の静脈穿刺で得られた血液サンプル 2 セットを培養検 査に提出するべきである（A−Ⅲ）。体重 40 kg 未満の患者 の場合、血液培養サンプルの量は全血液量（一般的に約 70 mL/kg）の 1％未満とするべきである（C−Ⅲ）。 7．臨床的に必要であると判断される場合は、感染が疑 われる他の部位からも培養サンプルを採取するべきである （A−Ⅲ）。 8．呼吸器の徴候・症状が認められる患者には、胸部 X 線 検査が適応される（A−Ⅲ）。 Ⅲ．発熱を呈する好中球減少患者にはどのような経験的 抗菌薬療法が適切か？　また、どのような治療設定で行 えばよいか？ 推奨事項 概　論 9．高リスク患者は静注による経験的抗菌薬療法を行うた め入院の必要がある。セフェピム、カルバペネム系薬（メロ ペネムまたはイミペネム−シラスタチン）、ピペラシリン−タ ゾバクタムなどの抗緑膿菌活性を有するβ−ラクタム系薬を 用いた単剤療法が推奨される（A−Ⅰ）。合併症（低血圧、肺 炎など）の管理が必要な場合や、抗菌薬耐性が疑われるか確 定された場合は、初期レジメンに他の抗菌薬（アミノグリコ シド系薬、フルオロキノロン系薬および / またはバンコマ イシン）を追加してもよい（B−Ⅲ）。 10．バンコマイシン（または好気性グラム陽性球菌に活性 を有する他の薬剤）は、発熱性好中球減少症に対する初期抗 菌薬に加える標準薬としては推奨されない（A−Ⅰ）。これら の薬剤の使用は、カテーテル関連感染症、皮膚・軟組織感 染症、肺炎が疑われる場合や、血行動態が不安定な場合な ど、特定の臨床状態で考慮するべきである。 11．下記の抗菌薬耐性菌による感染症のリスクがある患 者、特に、状態が不安定な患者や、血液培養で耐性菌の疑 いを示す陽性結果が得られた患者では、経験的初期療法の 変更を考慮してもよい（B−Ⅲ）。耐性菌とは、メチシリン 耐性黄色ブドウ球菌（MRSA）、バンコマイシン耐性腸球菌 （VRE）、基質特異性拡張型βラクタマーゼ（ESBL）産生グ ラム陰性菌、カルバペネマーゼ産生菌（カルバペネマーゼ産 生Klebsiella pneumoniae［KPC］を含む）などである。リスク