全套MRSA-指南.ppt

Liu et al.Clin Infect Dis 2011 Jan 4最新美国最新美国IDSA MRSA 感染治疗指南解读感染治疗指南解读制定指南的背景-MRSA持续增高自1961年发现第一株对甲氧西林耐药的菌株,MRSA流行率就一直在稳定升高12005:在美国发生将近 94,360 侵袭性疾病1.Klevens RM,et al.JAMA 2007;298:1763-71.2.Herold BC,et al.JAMA 1998;279:593-8.制定指南的背景-万古霉素敏感性在下降1.Klevens RM,et al.JAMA 2007;298:1763-71.2.Herold BC,et al.JAMA 1998;279:593-8.万古霉素对MRSA的MIC值随着时间在飘移Steinkraus G et al.J Antimicrobial Chemother 2007;60:7887940.125 0.19 0.25 0.38 0.5 0.7 1.0 1.5 2.0 3.0 4.0Vancomycin MIC(g/ml)80 7060 5040 3020 100Isolates(%)200120032005Susceptibility breakpointMICs measured by EtestMRSA isolates(n=662)measured in a single US tertiary care institution万古霉素耐药性万古霉素耐药性1997 1997 日本首次报道日本首次报道 VISA VISA 20022002年美国首次报道年美国首次报道 VRSAVRSAMMWR July 2002MMWR July 20021 1stst 例例 Michigan Michigan 导管及糖尿病溃疡培养导管及糖尿病溃疡培养2 2ndnd 例例 Pennsylvania Pennsylvania Tenover et al 2004Tenover et al 2004足跟溃疡足跟溃疡先前无万古霉素暴露先前无万古霉素暴露Whitener et al 2004Whitener et al 2004USAUSA：迄今，临床已发现：迄今，临床已发现9 9株株VRSAVRSA6目前目前hVISA在中国的发生情况在中国的发生情况Sun W,AAC 2009;53(9):3642-910121012株株MRSAMRSA于于2002-72002-7年（主要为年（主要为05-0705-07）分离自）分离自1414个城市个城市检测方法：含药平皿及检测方法：含药平皿及METMET初筛，菌群分析策略初筛，菌群分析策略-曲线下面积方法曲线下面积方法确认确认n nhVISA hVISA 血培养血培养20020013.113.1(26/199)(26/199)VISA 1(VISA 1(万古万古 MIC 4mg/L)MIC 4mg/L)非血培养非血培养81281215.715.7（128/812128/812）o20072007年分离自年分离自1414个城市个城市315315株株MRSAMRSA，hVISA hVISA 9.59.5(30/315)(30/315)(陈宏斌，陈宏斌，中华检验医学杂志中华检验医学杂志 2009;32(11):1223-7)2009;32(11):1223-7)万古霉素万古霉素MIC值越高临床成功率越低值越高临床成功率越低Vancomycin MICAdapted from Sakoulas,et.al.,2004 JCM 42:2398;Moise-Broder et al.2004 CID 38:1700-5;Hidayat et al.2006 Arch Intern Med 166:2138-2144;Moise wt al.2007 AAC 51:2582-6Percent Success万古霉素治疗失败万古霉素治疗失败与与MIC增高呈正相关增高呈正相关Vancomycin MICStevens.CID 2006;42:S517The numbers on the plot are the%failure rates增加万古霉素剂量能增加疗效？增加万古霉素剂量能增加疗效？万古霉素杀菌活性与万古霉素杀菌活性与AUCAUC0-240-24/MIC/MIC 相关相关谷浓度谷浓度10mg/ml10mg/ml可能防止可能防止MICMIC增高和出现增高和出现hVISA,VISAhVISA,VISAAUC/MIC400ug.h/mlAUC/MIC400ug.h/ml，谷浓度，谷浓度15-20ug/ml 15-20ug/ml 疗效疗效良好良好 (ATS/IDSA Guidelines for management of adults with HAP,VAP,HCP)(ATS/IDSA Guidelines for management of adults with HAP,VAP,HCP)近期研究万古近期研究万古MIC 2MIC 2 ug/ml ug/ml 疗效减低疗效减低剂量增加导致肾毒性增加剂量增加导致肾毒性增加高剂量和低剂量万古霉素达到高剂量和低剂量万古霉素达到 AUC/MIC 400的可能性的可能性Mean TroughMean AUC低剂量(troughs 15 g/mL)9.43.2*318111*高剂量(troughs 15 g/mL)20.43.2*418152*P40010075502500.250.524MIC(g/mL)P=.04021高高剂剂量万古霉素量万古霉素低低剂剂量万古霉素量万古霉素如果肾功能正常（即如果肾功能正常（即CLcr为为70100 mL/min）的患者中万古霉素的）的患者中万古霉素的MIC2 mg/L，按常规用药方案无法达到，按常规用药方案无法达到AUC/MIC400的目标，因此，的目标，因此，应考虑用其他方法治疗应考虑用其他方法治疗万古霉素的肾毒性随着谷浓度的增加而增加万古霉素的肾毒性随着谷浓度的增加而增加Lodise TP,et al.Clin Infect Dis.2009;49(4):507-514Single-Center,Retrospective StudyStratified Kaplan-Meier Analysis of Time to NephrotoxicityInitial Vancomycin Trough Value and the Rate of NephrotoxicityRate of Nephrotoxicity(%)010204030Probability of Remaining Nonnephrotoxic00.20.40.81.00.6Initial Trough Value(mg/L)101520Days209/445/953/154/12215203305101520 mg/LP.01P1 个恰当的随即对照试验的证据II来自 1 设计良好的临床试验,非随机;组群或者病例对照；多重时间序列及非对照试验，但有引人注目的结果等证据III来自作者的观点、基于临床经验、描述性研究、或者专家组的报告等证据1.Liu C,Bayer A,Cosgrove SE et al.Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.Clin Infect Dis.2011 Jan 4 Epub ahead of print推荐的强度和证据等级推荐的强度和证据等级Clinical Topics Addressed1.皮肤及软组织感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以及心内膜炎4.MRSA 肺炎5.MRSA 骨和关节感染6.MRSA 中枢神经感染7.联合治疗或辅助治疗8.万古霉素的剂量和检测9.万古霉素的敏感性试验10.持续性血流感染以及万古霉素治疗失败的管理11.MRSA 新生儿感染Clinical Topics Addressed1.皮肤及软组织感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以及心内膜炎4.MRSA 肺炎5.MRSA 骨和关节感染6.MRSA 中枢神经感染7.联合治疗或辅助治疗8.万古霉素的剂量和检测9.万古霉素的敏感性试验10.持续性血流感染以及万古霉素治疗失败的管理11.MRSA 新生儿感染Clinical Topics Addressed1.皮肤及皮肤及软组织感染感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以及心内膜炎4.MRSA 肺炎5.MRSA 骨和关节感染6.MRSA 中枢神经感染7.联合治疗或辅助治疗8.万古霉素的剂量和检测9.万古霉素的敏感性试验10.持续性血流感染以及万古霉素治疗失败的管理11.MRSA 新生儿感染MRSA 指南:对于住院的cSSTI成年患者的建议1cSSTI 包括:深层软组织感染、手术/创伤性伤口感染、严重脓肿、蜂窝织炎和溃疡及烧伤感染cSSTI的治疗包括:手术清创+广谱抗生素(覆盖MRSA)建议治疗7-14天,具体时间根据个人疗效决定 住院的住院的MRSA cSSTI成年患者的抗生素选择成年患者的抗生素选择药物成人用量等级*万古霉素15-20 mg/kg/剂 IV 每8-12小时一次A-I利奈唑胺600 mg PO/IV 每日两次A-I达托霉素4 mg/kg/剂 IV 每天一次A-I替拉万星10 mg/kg/剂 IV 每天一次A-I克林霉素600 mg PO/IV 每日三次A-III*推荐强度和证据质量的分级推荐强度和证据质量的分级由于由于FDA警告指出，临床试验汇总分析显示，和对照药相比，使用替加环素后各种原因的死亡风险增加，警告指出，临床试验汇总分析显示，和对照药相比，使用替加环素后各种原因的死亡风险增加，所以虽然所以虽然FDA许可替加环素用于许可替加环素用于cSSTI，这些指南也不推荐使用。，这些指南也不推荐使用。MRSA=耐甲氧西林的金黄色葡萄球菌;cSSTIs=复杂的皮肤和软组织感染1.Liu C,Bayer A,Cosgrove SE et al.Clinical practice guidelines by the Infectious Diseases Society of America for the 药剂 of methicillin-resistant Staphylococcus aureus infections in 成人s and children.Clin Infect Dis.2011 Jan 4 Epub ahead of printClinical Topics Addressed1.皮肤及软组织感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以血流感染以及心内膜炎及心内膜炎4.MRSA 肺炎5.MRSA 骨和关节感染6.MRSA 中枢神经感染7.联合治疗或辅助治疗8.万古霉素的剂量和检测9.万古霉素的敏感性试验10.持续性血流感染以及万古霉素治疗失败的管理11.MRSA 新生儿感染MRSA 指南:患有菌血症或自体瓣膜感染性心内膜炎的成人1推荐的治疗持续时间非复杂性菌血症 至少 2 周复杂性菌血症 4-6 周自体瓣膜感染性心内膜炎 6 周患有患有菌血症或自体瓣膜感染性心内膜炎的成人的抗菌治疗选择汇总治疗治疗成人用量成人用量等级等级*评论评论万古霉素15-20 mg/kg/剂 IV q8-12hA-II不建议在万古霉素中加入庆大霉素(A-II)或利福平(A-I)达托霉素6 mg/kg/剂 IV QDA-I一些专家建议使用更高剂量，8-10 mg/kg/天 IV QD(B-III)*推荐度和证据等级分类1.Liu C,Bayer A,Cosgrove SE et al.Clinical practice guidelines by the Infectious Diseases Society of America for the 药剂 of methicillin-resistant Staphylococcus aureus infections in 成人s and children.Clin Infect Dis.2011 Jan 4 Epub ahead of print万古霉素是此类感染的主要治疗药物达托霉素是万古霉素的替代治疗药物Clinical Topics Addressed1.皮肤及软组织感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以及心内膜炎4.MRSA 肺炎肺炎5.MRSA 骨和关节感染6.MRSA 中枢神经感染7.联合治疗或辅助治疗8.万古霉素的剂量和检测9.万古霉素的敏感性试验10.持续性血流感染以及万古霉素治疗失败的管理11.MRSA 新生儿感染MRSA 指南:MRSA肺炎的治疗 经验性治疗MRSA感染只推荐用在严重CAP(ICU 患者,necrotizingor cavitary infiltrates,脓胸)如果培养没有MRSA则停止经验性治疗疗程:7-21 天，根据感染程度调整 治疗药物成人儿童证据等级万古霉素15-20 mg/kg IV Q8-1215 mg/kg IV Q6 AII利奈唑胺600 mg PO/IV BID10 mg/kg PO/IV Q8AII克林霉素600 mg PO/IV TID10-13 mg/kg PO/IV Q6-8BIII/AII*Note:达托霉素不能应用于治疗肺炎，因其可被肺表面活性物质灭活，但有证据证实达托霉素不能应用于治疗肺炎，因其可被肺表面活性物质灭活，但有证据证实可用于血行感染性肺栓塞。可用于血行感染性肺栓塞。Clinical Topics Addressed1.皮肤及软组织感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以及心内膜炎4.MRSA 肺炎5.MRSA 骨和关骨和关节感染感染6.MRSA 中枢神经感染7.联合治疗或辅助治疗8.万古霉素的剂量和检测9.万古霉素的敏感性试验10.持续性血流感染以及万古霉素治疗失败的管理11.MRSA 新生儿感染外科清创术和引流是软组织脓肿的主要治疗手段(A-II)理想的抗生素给药的路径尚未被建立:根据个体情况使用肠道外的，口服的，或者先用肠道外在使用口服序贯的抗生素治疗(A-III)MRSA 指南:MRSA骨和关节感染的治疗 胃肠外给药的抗生素胃肠外给药的抗生素治疗药物剂量万古霉素(B-II)考虑谷浓度为15-20mcg/mL*达托霉素(B-II)6 mg/kg once dailyMRSA 指南:MRSA骨和关节感染的治疗*Not in this guideline.See Rybak M et al.Clin Infect Dis.2009 Aug 1;49(3):325-7 肠道外以及口服给药抗生素肠道外以及口服给药抗生素治疗药物剂量TMP/SMX+利福平4 mg/kg/dose(TMP component)BID600 mg once daily(B-II)利奈唑胺600 mg BID(B-II)克林霉素600 mg every 8 hours(B-III)Some experts recommend addition of rifampin 600 mg daily or 300-450 mg PO twice daily to above regimens(B-III).If bacteremia,start after bacteremia has cleared.MRSA 指南:骨和关节感染的治疗 骨髓炎和脓毒性关节炎1骨髓炎 伴发脓肿的手术清创和引流(A-II)使用抗生素 8周(A-II)一些专家建议添加利福平(B-III)如果同时出现菌血症,菌血症治愈后添加利福平一些专家建议添加1-3月以上的以利福平为主的口服联合治疗(C-III)脓毒性关节炎 关节间隙的清创或引流(A-II);使用3-4周的抗生素(A-III)31治疗治疗 MRSA 骨髓炎或者脓毒性关节炎的抗生素总结骨髓炎或者脓毒性关节炎的抗生素总结药剂药剂成人用量成人用量等级等级*评论评论万古霉素15-20 mg/kg/剂 IV 每8-12小时B-II一些专家建议添加使用600 mg QD或300-450 mg BID的利福平治疗骨髓炎达托霉素6 mg/kg/剂 IV 每天一次B-II利奈唑胺600 mg PO/IV 每日两次B-II克林霉素600 mg PO/IV 每日三次B-IIITMP-SMX+利福平3.5-4.0 mg/kg/剂 PO/IV 每8-12小时B-II如果是脓毒性关节炎(B-III)，就只使用TMP-SMXMRSA=methicillin-resistant Staphylococcus aureus;TMP-SMX=trimethoprim-sulfamethoxazole1.Liu C,Bayer A,Cosgrove SE et al.Clinical practice guidelines by the Infectious Diseases Society of America for the 药剂 of methicillin-resistant Staphylococcus aureus infections in 成人s and children.Clin Infect Dis.2011 Jan 4 Epub ahead of print治疗骨髓炎的理想疗程未能确定指南推荐至少8周(A-II)一些专家推荐要额外增加1-3个月(尤其对于慢性感染或者未进行清创手术可能需延长疗程)的口服治疗，以利福平为基础联合应用TMP/SMX,多西环素-米诺环素,克林霉素或者敏感的氟喹诺酮(C-III)ESR 和/或CRP 可能对治疗应答有帮助(B-III)MRSA 指南:骨和关节感染的治疗 骨髓炎和脓毒性关节炎1Clinical Topics Addressed1.皮肤及软组织感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以及心内膜炎4.MRSA 肺炎5.MRSA 骨和关节感染6.MRSA 中枢神中枢神经感染感染7.联合治疗或辅助治疗8.万古霉素的剂量和检测1.万古霉素的敏感性试验2.持续性血流感染以及万古霉素治疗失败的管理3.MRSA 新生儿感染万古霉素注射治疗2 周(B-II)一些专家建议增加利福平600 mg/天或者300-450 mg 每天2次(B-III)替代治疗利奈唑胺 600 mg PO/IV twice daily(B-II)or TMP/SMX 5 mg/kg/dose IV every 8-12 hours(C-III)If shunt infection,removal recommendedDo not replace until CSF cultures repeatedly negative(A-II)MRSA 指南:MRSA脑膜炎的治疗神经外科评估开颅引流(A-II)抗感染治疗MRSA 指南:MRSA 脑脓肿,硬膜下积脓及硬膜下脓肿的治疗治疗药物治疗药物剂量剂量/疗程疗程等级等级*万古霉素4-6 weeksB-II一些专家建议增加利福平600 mg daily or300-450 mg BID B-III替代治疗利奈唑胺600 mg PO/IV BIDB-IITMP/SMX5 mg/kg/dose IV every 8-12 hoursC-III*Classification of the strength of recommendation and quality of evidenceNote：也有一些个案报告达托霉素成功治疗 MRSA CNS 感染Clinical Topics Addressed1.皮肤及软组织感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以及心内膜炎4.MRSA 肺炎5.MRSA 骨和关节感染6.MRSA 中枢神经感染7.联合治疗或辅助治疗8.万古霉素的万古霉素的剂量和量和检测9.万古霉素的敏感性试验10.持续性血流感染以及万古霉素治疗失败的管理11.MRSA 新生儿感染MRSA Guidelines:How Should Vancomycin MICs be Used to Guide Therapy?1如果万古霉素的MIC 2 g/ml(eg,VISA or VRSA),必须使用万古霉素的替代治疗(A-III)MRSA=methicillin-resistant Staphylococcus aureus1.Liu C,Bayer A,Cosgrove SE et al.Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.Clin Infect Dis.2011 Jan 4 Epub ahead of print37Clinical Topics Addressed1.皮肤及软组织感染2.周期性复发的皮肤及软组织感染3.MRSA血流感染以及心内膜炎4.MRSA 肺炎5.MRSA 骨和关节感染6.MRSA 中枢神经感染7.联合治疗或辅助治疗8.万古霉素的剂量和检测9.万古霉素的敏感性试验10.持持续性血流感染以性血流感染以及万古霉素治及万古霉素治疗失失败的管理的管理11.MRSA 新生儿感染MRSA Guidelines:持续的菌血症&万古霉素治疗失败的治疗策略1由于MRSA菌血症的细菌清除中位时间是7-9 天,大多数专家建议考虑在7天左右根据临床表现决定是否改变治疗：改变治疗的考虑因素:总体的临床反应万古霉素的谷浓度药敏结果感染病灶是否可以移除在以下情况下可以更早换药尽管已经做了足够的清创或者感染病灶的移除，患者的临床反应很糟万古霉素的MIC是 2 g/mlMRSA=methicillin-resistant Staphylococcus aureus1.Liu C,Bayer A,Cosgrove SE et al.Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.Clin Infect Dis.2011 Jan 4 Epub ahead of printMRSA Guidelines:持续的菌血症&万古霉素治疗失败的治疗策略(continued)140治疗药物治疗药物成人剂量成人剂量如果达托霉素敏感如果达托霉素敏感高剂量的达托霉素+庆大霉素或者利福平 或者加上两者,或者利奈唑胺,或者TMP-SMX,或者-内酰胺类抗生素10 mg/kg/day 1 gm IV q8h(5 mg/kg QD as alternative)600 mg PO/IV QD or 300-450 mg PO/IV BID 600 mg PO/IV BID 5 mg/kg IV BID dose not given如果万古霉素以及达托霉素敏感性降低如果万古霉素以及达托霉素敏感性降低奎奴普丁/达福普汀7.5 mg/kg/dose IV q8hTMP-SMX5 mg/kg/dose IV BID利奈唑胺600 mg PO/IV BID替拉万星10 mg/kg/dose IV QDMRSA=methicillin-resistant Staphylococcus aureus1.Liu C,Bayer A,Cosgrove SE et al.Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.Clin Infect Dis.2011 Jan 4 Epub ahead of print专家组建议改变治疗而非在万古霉素的基础上增加其它药物Research Gaps血流感染与心内膜炎 心动超声图起到什么样的作用，对于治疗结果的改善是否有作用?How extensive should the work-up be to identify occult foci of metastatic infection?What is the optimal initial therapyWhat is the optimal therapy once susceptibility results are available?What regimens should be used in treating persistent or relapsing infection?What is the optimal duration of therapy?骨髓炎What is optimal therapy?Importance of bactericidal therapy?Importance of bone penetration?Oral vs.parenteral therapy?What is optimal management of hardware-associated infectionsWhat is the optimal duration?Research Gaps皮肤及软组织感染What is optimal management of nonpurulent cellulitis?What is the optimal management of abscesses?What s optimal management of recurrent infection?Research GapsTHANK YOU!BACK UP SLIDESMRSA Guidelines:Recommendations for the Management of 脓肿1皮肤脓肿 Primary treatment is I&D(A-II)Simple abscess or boilsI&D alone is likely adequate Benefit of antibiotics is marginalhigh cure rates(85-90%)whether or not an active antibiotic is usedPossible short-term prevention of new lesions/improved cure ratesAntibiotics recommended after I&D,due to CA-MRSA,for(A-III):Severe or extensive disease(e.g.,involves multiple sites)or rapid progression in presence of associated cellulitisSigns&symptoms of systemic illnessAssociated with comorbidities or immunosupression(DM,HIV/AIDS,neoplasm)Extremes of ageAbscess in area difficult to drain completely(e.g.,face,hand,genitalia)Associated septic phlebitisLack of response to I&D aloneMRSA=methicillin-resistant Staphylococcus aureus;I&D=incision&drainage;CA-MRSA=community-associated MRSALiu C,et al.Clin Infect Dis.2011;52:1-38Purulent Cellulitis(eg,cellulitis with purulent drainage or exudate in the absence of a drainable abscess)empiric coverage of CA-MRSAMRSA Guidelines:Recommendations for the Outpatient Management of Cellulitis5-10 days of therapy is recommended,individualized based on responseTreatmentAdult DoseClindamycin300-450 mg PO TIDTMP-SMX1-2 DS tab PO BIDDoxycycline100 mg PO BIDMinocycline200 mg x1,then 100 mg PO BIDLinezolid600 mg PO BIDStrength of recommendation and quality of evidence is A-II for all the aboveNonpurulent cellulitis(eg,cellulitis associated with no purulent drainage or exudate and no associated abscess)empiric coverage of-hemolytic streptococciMRSA Guidelines:Recommendations for the Outpatient Management of CellulitisTreatmentAdult Dose-lactam(eg,cephalexin&dicloxacillin)500 mg PO QIDClindamycin300-450 mg PO TID-lactam(eg,amoxicillin)&/or TMP-SMX or a tetracyclineAmoxicillin:500 mg PO TID(TMP-SMX&tetracycline dosing above)Linezolid600 mg PO BIDStrength of recommendation and quality of evidence is A-II for all the above5-10 days of therapy is recommended,individualized based on responsePersonal hygiene and appropriate wound care:Keep draining wounds covered,clean with dry bandages(A-III)Maintain good personal hygiene(Bathing,hand washing)(A-III)Avoid reusing/sharing personal items that have contacted infected skin(A-III)Environmental hygieneFocus on high-touch surfaces(counters,door knobs,toilet seats)that come into contact with bare skin(C-III)Commercial cleaners/detergents used according to instructions on label for that surface(C-III)MRSA Guidelines:Recommendations for management of recurrent MRSA SSTIsConsider decolonization if:Recurrent SSTI despite optimizing wound care and hygiene measures(C-III)Ongoing transmission among close contacts despite optimizing wound care/hygiene measures(C-III)Decolonization should be in conjunction with ongoing reinforcement of hygiene measuresMRSA Guidelines:Recommendations for management of recurrent MRSA SSTIs(ConDecolonization optionsNasal decolonization with mupiricin BID for 5-10 days(C-III)Mupiricin as above and topical body decolonization with skin antiseptic(chlorhexidine)5-14 days or dilute bleach baths(1 teaspoon per gallon of water or cup per tub or 13 gallons of water)given for 15 minutes twice weekly for 3 months(C-III)MRSA Guidelines:Recommendations for management of recurrent MRSA SSTIs(cont)Note:Oral antimicrobial therapy for active infection only,not decolonization(A-III)Oral agent plus rifampin(if susceptible)may be considered for decolonization if infections recur despite measures mentioned aboveSurveillance cultures following decolonization regimen not routinely recommended in absence of active infection(B-III)MRSA Guidelines:Recommendations for management of recurrent MRSA SSTIs(cont)MRSA Guidelines:Adults with Infective Endocarditis,Prosthetic ValveEarly evaluation for valve replacement surgery is also recommended(A-II)*Classification of the strength of recommendation and quality of ev