Chang Gung Memorial Hospital Antimicrobial stewardship program 邱政洵 教授 Department of Pediatrics Chang Gung Children’s Hospital Taoyuan, Taiwan

Chang Gung Memorial Hospital Antibiotic Stewardship 抗生素管理 2 透過管理的力量與方法，整合不同 專業 ( 醫師 藥事 醫檢 護理 感控 資 訊 ) ，將抗生素的使用最佳化，有效 治療病人之外，減少不必要的使用， 減少藥物可能造成的短期及長期的 傷害，維護病人與社會的健康。

Chang Gung Memorial Hospital Antibiotic stewardship programs are a “win ‐ win” for all involved: - A University of Maryland study showed one antibiotic stewardship program saved a total of $17 million over 8 years. - Antibiotic stewardship helps improve patient care and shorten hospital stays, thus benefiting patients as well as hospitals. 行政與管理的認知 : 抗生素管理 : 三贏 ( 病人 醫院 醫療人員 ) 3

Chang Gung Memorial Hospital Make appropriate antibiotic use a quality improvement and patient safety priority. Focus on reducing unnecessary antibiotic use, which can reduce antibiotic-resistant infections, Clostridium difficile infections, and costs, while improving patient outcomes. Emphasize and implement antibiotic stewardship programs and interventions for every facility – regardless of facility setting and size. Healthcare facility administrators and payers: ASP 行政與管理的認知 : 抗生素管理 4

Chang Gung Memorial Hospital Surveillance Infection Control Prudent antibiotics use Strategic plans against the spread of the resistance 5 Antibiotic stewardship (ABS)

Chang Gung Memorial Hospital StrategyMRSACoNSVREESBLMDR-AbMDR-Pa Hand-washing++ Contact isolation+/- +++/-++ Environmental cleaning+++++ Antibiotic stewardship++ C. difficile : antibiotic stewardship Reduction of resistance rate: antibiotic stewardship Common strategies to control the spread of different resistant bacteria: Hand washing and ABS are most crucial and universally important 6

Chang Gung Memorial Hospital Two key strategies to make ABS success Prospective audit of antimicrobial use with intervention and feedback to the prescriber (A-I) Formulary restriction and pre- authorization requirements for specific agents (B-II) CID 2007; 44:159 7

Chang Gung Memorial Hospital Supplemental strategies Guidelines & clinical pathway A-I Streamlining or de-escalation A-II Dose optimization A-II Education A-III IV to oral switch A-III Antimicrobial order form B-II Combination therapy C-II Antimicrobial cycling C-II CID 2007; 44:159 8

Chang Gung Memorial Hospital 症狀診斷 Surveys Empirical Tx prescription dispensing patients Front-end review Back-end review follow -up De-escalation Shift to oral agents Modify regimen? Yes No Infection Control Process and outcome measurements Agree or suggest to modify Antimicrobial Stewardship: a complex process in a simplified scheme 9

Chang Gung Memorial Hospital Fishman N. Am J Med 2006 Streamlinin g = de- escalation The “backbone’ for the ASP infrastructure: 1, 2, 3, 4 (6) = de- escalation 10

Chang Gung Memorial Hospital Interventions in ABS ID approval for restricted antibiotics CPOE (computerized prescriber order entry) warning system Medication profile and prescription review mechanism Front-end approach Re-evaluation after culture PD/PK consideration ADR report Monitor and feedback Back-end approach 11 Debra A. Goff, Pharm.D

Chang Gung Memorial Hospital Interventions in ABS ID approval for restricted antibiotics CPOE warning system Medication profile and prescription review mechanism Front-end approach Back-end approach 12

Chang Gung Memorial Hospital A hospital-wide computerized antimicrobial approval system (HCAAS) in CGMH (>3,500 beds) set up to guide antibiotic use since late

Chang Gung Memorial Hospital Antimicrobials under stewardship General hospitalized patient The 2 nd and 3 rd line antimicrobials Intensive care units All intravenous antimicrobials One patient who received 3 and more intravenous antimicrobials 14

Chang Gung Memorial Hospital IT-Infrastructure implemented HIS (Hospital Informatics System): electronic chart record system LIS (Laboratory Informatics System): Microbiology, hematology, biochemistry, all other lab data PACS: an integrated image system for X-ray, CT, MRI, and others 15

Chang Gung Memorial Hospital Front-end approach Computerized Antimicrobial Approval System 2010 March Approve PrescriberID PhysicianPharmacist Provide necessary clinical data by the prescriber Modify the regimens by the prescribers Submit a consultation sheet Prescribe antimicrobials recommended by ID physician Generate request message to ID physician through hospital Informatics system ID consultation Recommend appropriate antimicrobial regimens Online review in 48 hours Prescribing restricted antimicrobial through CPOE system Dispensing Disapprove Microbiologist Positive blood culture results with sensitivity results 2010 March 16 Positive sterile site culture results with sensitivity results (CSF/DTS/PC) 2014 August

Chang Gung Memorial Hospital Online Review Interface ID physician Individual Patient information Patient with (+) blood culture result 17

Chang Gung Memorial Hospital Integrated Health Information System Infection Source Rationale on Antimicrobial agent selection Temperature Blood Pressure Biochemistry Lab Data Chart Overview Microbiologic and Susceptibility Results Current Medications CT, PET, X-ray, Echo TPR, BP, I/O 18

Chang Gung Memorial Hospital Bidirectional Communication Platform Review Results Recommend Regimen, Treatment Duration Disapproval Reason 19

Chang Gung Memorial Hospital Front-end approach ID consult and feedback record link to the pharmacy system 20 Electronic chart front page in CGMH

Chang Gung Memorial Hospital Patient-centered Care Medical Chart Lab Data TPR, BP, I/O PAC Microbiology Medication 21

Chang Gung Memorial Hospital CPOE and medication delivery system in CGMH 22

Chang Gung Memorial Hospital Front-end approach Medication profile reviewing system in Pharmacy 23 Pharmacist review system in CGMH Allergy history Renal function Diagnosis High-alert medication warning

Chang Gung Memorial Hospital Front-end approach Prescribing error reporting system 24 Medication error reporting system in CGMH 24

Chang Gung Memorial Hospital Evaluation of prescribing error in antibiotics 25

Chang Gung Memorial Hospital Front-end approach Allergy history and adverse drug reaction chart warning system 26 Electronic chart front page in CGMH

Chang Gung Memorial Hospital Interventions in ABS ID approval for restricted antibiotics CPOE warning system Medication profile and prescription review mechanism Front-end approach Re-evaluation after positive culture PD/PK consideration ADR report Monitoring and feedback Back-end approach 27

Chang Gung Memorial Hospital 1. Ensure all orders have dose, duration, and indications 2. Get cultures before starting antibiotics 3. Take an “antibiotic timeout,” reassessing antibiotics after hours; not “reflex” style for prescription Promote antibiotic best practices – a first step in antibiotic stewardship: 28

Chang Gung Memorial Hospital Back-end approach Re-evaluation after positive blood and sterile site culture 29 Computerized Antimicrobial Approval System in CGMH

Chang Gung Memorial Hospital 30 Wang SY, et al. Int J Antimicrob Agents 2014

Chang Gung Memorial Hospital 31 Wang SY, et al. IJAA 2014

Chang Gung Memorial Hospital 32 Wang SY, et al. IJAA 2014

Chang Gung Memorial Hospital 33 JAC 2014

Chang Gung Memorial Hospital 34 JAC 2014

Chang Gung Memorial Hospital Back-end approach Clinical Pharmacokinetics Monitoring (CPM) System 35 susceptibility Monitor items Lab data Medication profile CPM System in CGMH

Chang Gung Memorial Hospital Back-end approach— ADR reporting system ADR reporting System in CGMH 36

Chang Gung Memorial Hospital The most ADR-inducing antibiotics 37

Chang Gung Memorial Hospital “Low-Hanging Fruits” Antimicrobial Stewardship Initiatives ASP ActivityReferenceSettingDescription of ASP InterventionCost Savings/Avoidance Intravenous-to- oral conversion Davis et al 2005 [10] Detroit Receiving Hospital and University Health Center Prospective pharmacy intervention involving sequential intravenous/oral therapy for patients with pneumonia Drug acquisition cost savings of $110/patient Lau et al 2011 [18] Johns Hopkins HospitalEvaluated budget impact of voriconazole, pantoprazole, chorothiazide, levetiracetam in patients eligible for oral medication Potential annual cost reduction of $ Therapeutic substitution 2010The Ohio State University Wexner Medical Center Substituted brand-name vancomycin capsules for flavored vancomycin solution compounded by pharmacy Annual cost savings of $ Batching IV antimicrobials 2010The Ohio State University Wexner Medical Center Maintenance doses of daptomycin were made from single-use 500-mg vials by batching orders at standardized times 370 vials saved over 4 months ($83 991) Annual cost savings of $ Formulary restriction White et al 1997 [22] Ben Taub General Hospital Houston Prior ID authorization required for restricted antimicrobials Total intravenous antimicrobial expenditures decreased by 32% ($ ) Antibiotic cost per patient- day decreased from $18.00 to $12.90 Po et al 2012 [3]Banner Estrella Medical Center Implemented computer physician order entry ASP restrictive template for linezolid Linezolid use fell from 28 defined daily doses/1000 patient-days to 7 defined daily doses/1000 patient- days over 25 months; cost data not reported Abbreviations: ASP, antimicrobial stewardship program; ID, infectious diseases; VA, Veterans Affairs. CID

Chang Gung Memorial Hospital ICHE 2011; 32 (4): 367 Low hanging fruits 39

Chang Gung Memorial Hospital Back-end approach Monitoring and feedback 40

Chang Gung Memorial Hospital CGMH ASP Team and Responsibility 41

Chang Gung Memorial Hospital Outcome Measurements 1.Process measurements - Consumption of a specific antimicrobial or class of antimicrobials - Cost change 2.Outcome measurements - Clostridium difficile infection - Reduce or prevent resistance or other unintended consequences of antimicrobial use IDSA Guidelines

Chang Gung Memorial Hospital 1. 理念的澄清 2. 資源的分配要在重點上 3. 勿焦點模糊 4. 目標不可偏差 5. 實務面的障礙： - 人力與人才 - 缺乏Computer-assisted system - 缺乏大規模與第一線開方醫師全面互動的 實戰經驗 結論 43

Chang Gung Memorial Hospital 行政與管理的支持 人才 人力 2. 系統 建立流程 投入必需之軟硬 體 3. 經費 4. 高階主管全力支持 SAS EG system

Chang Gung Memorial Hospital Decrease antibiotic resistance Decrease C. difficile infections Decrease costs Increase good patient outcomes Antibiotic stewardship in your facility will: 45

Chang Gung Memorial Hospital Thank you

抗生素管理： 長庚經驗分享 黃景泰 醫師 林口長庚紀念醫院 內科部感染醫學科主任 廈門長庚紀念醫院 內科部感染醫學科召集人

大綱 抗生素發展的現況 2. 抗生素管理計劃 3. 目標導向的抗生素管理 4. 抗生素處方能見度 5. 抗生素處方基本管理 6. 抗生素使用的升階與降階 7. 抗生素的降階治療 8. 特定診斷之抗生素使用 9. 微生物學檢查 10. 抗生素的副作用 11. 期程管制 12. 長庚醫院的抗生素管理平台 13. 抗生素的使用文化 14. 良好的抗生素管理

1. 抗生素發展的現況

 1940 ~ 1962  > 20 new classes of antibiotics marketed  1962~  Only 2 new classes reached the market 抗生素發展的現況 50 Br J Pharmacol May;163(1):184-94

抗生素發展的現況 51 Clin Infect Dis May 1;38(9):

2. 抗生素管理計劃

Clin Infect Dis 2007; 44: 機構之抗生素管理計劃 INSTITUTIONAL ABS PROGRAM 53

Crit Care Med 2010; 38(Suppl.):S315-S323 抗生素管理計劃的組成 54

Optimize Patient Safety Decrease or Control Costs Reduce Resistance 抗生素管理 (ASP, Antimicrobial Stewardship Program) 55

抗生素管理醫師與抗生素處方醫師 56

抗生素管理醫師的角色  務必需要  像空服員一樣  和藹可親  像管家一樣  體貼入微  像侍酒師一樣  深得您心  萬萬不可  警察抓小偷  強力操控  監視 57

3. 目標導向的抗生素管理 Goal-Oriented Antibiotics Stewardship

 處方能見度  處方基本管理  降階治療  特定診斷之抗生素使用  微生物學檢查  抗生素的副作用  期程管制 抗生素管理的目標 59

4. 抗生素處方能見度 Visibility

 避免絕無必要之使用  處方要有一定的能見度 (Visibility)  審查  時機 (Timing)  穿透性 (Penetrance)  醫療記錄  完整的感染相關記錄 抗生素處方能見度 61

62 檢驗數 0 最佳者 總成本 檢驗成本 不良品耗費的成本

5. 抗生素處方基本管理

 劑量  給藥間隔  個別病患特殊考量  體重  腎臟功能  肝臟功能 抗生素的處方管理 64

6. 抗生素使用的升階與降階 Escalation & De-escalation

Host 細菌 Host 細菌 EscalationDe-escalation 抗生素的升階與降階 66

Host 細菌 Host 細菌 Escalation De-escalation 抗生素的升階與降階 67

Host 細菌 Host 細菌 EscalationDe-escalation 抗生素的升階與降階 68

7. 抗生素的降階治療 De-escalation

 先決條件  （ 1 ）病情已趨於穩定  （ 2 ）明確的微生物學證據  證實為敏感性細菌  血液培養  其他無菌部位培養  無法證實有抗藥性細菌  MRSA 抗生素的降階治療 70

8. 特定診斷之抗生素使用

 同時滿足  （ 1 ）沒有尿路症狀  （ 2 ）沒有全身症狀 無症狀膿尿菌尿 72

Prevalence 73 Clin Infect Dis. 2005:40 (1 March) 643

 不需要使用抗生素治療  例外  （ 1 ）孕婦  （ 2 ）泌尿道手術 無症狀膿尿菌尿 74 Clinical Infectious Diseases 2005; 40:643–54

 呼吸道感染  上呼吸道感染 (URI)  不需要使用抗生素  不能排除下呼吸道感染  (R/O Pneumonia)  下呼吸道感染 (Pneumonia)  上 / 下呼吸道感染 75

CPIS  Body Temperature  36.5°C≤BT≤38.4°C = 0 point  38.5°C≤BT≤38.9°C = 1 point  38.9°C≤BT or BT≤36.0°C = 2 points  WBC  11,000≥ WBC ≥ 4,000 = 0 point  >11,000 or <4,000 = 1 point  Band ≥ 50% + 1 point  Tracheal secretions  ( - ) = 0 point  Non-purulent = 1 point  Purulent = 2 points  Oxygenation: PaO 2 /FIO 2 (mm Hg)  > 240 or ARDS = 0 point  ≤ 240 and no ARDS = 2 points  Pulmonary Radiography  No infiltrate = 0 point  Diffuse/Patchy = 1 point  Localized = 2 points  Progression of Pulmonary Infiltrate  No = 0 point  Yes = 2 points (after CHF and ARDS excluded)  Culture of Tracheal Aspirate  ( - ) or rare or light = 0 point  Moderate or heavy = 1 point  Gram stain (+) +1 point Am Rev Respir Dis 1991;143: *ARDS defined as ： PaO2/FIO2≤200 PAWP ≤18 mm Hg Acute bilateral infiltrates 76

77 Am J Respir Crit Care Med 2000;162:

9. 微生物學檢查

 使用抗生素前必須進行  配合病情變化做為抗生素調整之基礎  血液培養  相關部位檢體培養 微生物學檢查 79

 相關部位檢體培養  沒有懷疑肺炎不得做痰液培養  沒有泌尿道症狀的小便培養  無症狀膿尿菌尿  留意避免追打不必要消滅之細菌 微生物學檢查 80 Am J Respir Crit Care Med 2005;171:

 檢查結果需要正確判讀  無菌位置 (Sterile Site) 檢體  血液  其他無菌位置  CSF 、 DTS 、 SY  非無菌位置 (Non-sterile Site) 檢體  Urine  Sputum  Skin 微生物學檢查 81

 檢查結果需要正確判讀  無菌位置 (Sterile Site) 檢體  感染 vs 污染 (contamination)  非無菌位置 (Non-sterile Site) 檢體  感染 vs 移生 (colonization) 微生物學檢查 82

 血液培養的正確判讀  生長時間  快 vs 慢  陽性套數  一套 vs 多套  菌種  通常為污染  Coagulase(-) staphylococcus （ Non-aureus ）  Bacillus, Diphtheroid, or other GPB  Micrococcus 微生物學檢查 83

10. 抗生素的副作用

 過敏  藥物疹 (Drug rash)  嗜伊紅性白血球增加 (Eosinophilia)  藥物熱 (Drug fever)  Spiral escalation 抗生素的副作用 85

 抗生素相關腹瀉 Antibiotics associated diarrhea  艱難梭孢桿菌感染 C. difficile infection  偽膜性大腸炎 Pseudomembranous colitis 抗生素的副作用 86

 抗藥性細菌的出現  MDRAB  Candida and other yeasts  Enterococcus/VRE  Stenotrophomonas  KPC 抗生素的副作用 87

11. 期程管制

 使用期程鮮少需要超過 7-14 天  特別感染  骨骼  心臟血管  內臟膿瘍  特殊考量  宿主免疫功能  異物植入 抗生素使用之期程管制 89

12. 長庚醫院的抗生素管理平台

 建構在醫療照顧資訊系統之上  全面而完整的病人資料 長庚醫院的抗生素管理平台 91

 線上抗生素管理  效率  即時  新事證出現可再重新評估  臨床狀況的變化  檢驗檢查結果  培養結果、特別是血液培養結果  互動性與教育性 長庚醫院的抗生素管理平台 92

Since 2004 Review List Prescription of Sanctioned Regimens Pharmacist Review Providing information on clinical assessment 處方醫師 管理醫師管理 Online Stewardship Dispense 48 hr mercy period Dispensing cont ’ d OK Formal ID Consultation Request Bedside evaluation indicated ≦ 48 hr ID Consult with Bedside Evaluation Recommendation New Prescription 1. 2 nd line or above 2. Combination of ≧ 3 antibiotics *Text message *Dispensing DC in 48 hrs NOT OK 長庚醫院的抗生素管理平台 93

 病人安全為最高考量  處方權  所有醫師有所有抗生素藥物的處方權  抗生素管理的防呆機制  48 小時的免審空間  允許重新開立不被同意之抗生素處方 長庚醫院的抗生素管理平台 94

13. 抗生素的使用文化

 不是把病人身上的細菌殺乾淨  不是有細菌就是有感染  身上的細菌  永遠殺不完！  永遠殺不乾淨！ 抗生素的使用文化 96

Colon ： cfu/g -Anaerobes 99.9% -Aerobes *E. coli & other enteric rods cfu/g 抗生素的使用文化 97

 不需要用、不要用  要根據臨床判斷  不是有細菌就是有感染  不能根據細菌培養  盲目的尿液培養  無症狀菌尿  盲目的痰液培養  呼吸道內的移生菌 (colonization) 抗生素的使用文化 98

 能降階、趕快降階  臨床狀況改善  微生物證據支持  能停、趕快停  7-14 天的切實檢討 抗生素的使用文化 99

14. 良好的抗生素管理

 共識至上  處方醫師與抗生素管理醫師  病人安全  實證醫學 良好的抗生素管理 101

 動態管理  臨床病情演變  細菌培養結果 良好的抗生素管理 102

 要件  便利完善的工具平台  領導階層的全力支持  實質的誘因 良好的抗生素管理 103

 終極目標  動態、及時升階或降階讓抗生素使用最優化  最初的經驗性使用  有需要的話 “Hit right ! Hit hard!”  抗生素管理醫師及時檢視並且追蹤抗生素使用 的合理性  降階 De-escalation  升階 Escalation  良好的互動循環以達成對抗生素使用的共識  抗生素處方醫師  抗生素管理醫師 良好的抗生素管理 104

 更好的未來  外部稽核  抗生素管理計劃  國際合作 良好的抗生素管理 105

June 10,

敬請指教