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抗菌药物耐药性是一个全球性的公共卫生问题。碳青霉烯类抗生素被认为是治疗多重耐药菌感染的最后防线,但随着其在临床的广泛应用及不合理使用,导致耐碳青霉烯类肠杆菌(CRE)特别是耐碳青霉烯类肺炎克雷伯菌(CRKP)激增,给临床抗感染治疗带来巨大挑战。
头孢他啶/阿维巴坦(ceftazidime/avibactam,CAZ/AVI)是一种新型β-内酰胺类/β-内酰胺酶抑制剂,研究表明,阿维巴坦在体外可抑制Ambler分类中的A类、C类和某些D类酶的活性,由于缺乏活性位点丝氨酸残基,对B类金属酶没有活性[1]。阿维巴坦可重新环化恢复活性从而可长效抑制β-内酰胺酶[2],能够恢复或增强头孢他啶抗菌活性,CAZ/AVI组合具有广谱抗菌活性,对包括CRE在内的多重耐药革兰阴性杆菌(MDR-GNB)具有强有力的杀菌活性。CAZ/AVI于2015年在美国获批上市,随后在欧洲和中国获批上市。现已陆续被美国食品药品管理局(FDA)、欧洲药品管理局(EMA)和国家药品监督管理局(NMPA)批准用于成人治疗方案有限或无其他选择的G-菌感染的治疗。目前,有一些小样本的回顾性研究表明[3-7],CAZ/AVI可能是治疗CRE/CRKP的有效替代品,但没有关于CAZ/AVI与其他抗菌药物用于CRE/CRKP的疗效和安全性比较的系统评价,以至于无法客观的评估两者之间的差异。本研究拟采用Meta分析方法,对国内外公开发表的CAZ/AVI治疗碳青霉烯类耐药菌感染的疗效和安全性研究进行系统评价,以期为CAZ/AVI的临床选用提供循证依据。
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初筛得到相关文献564篇,其中,英文文献486篇(PubMed 315篇、Embase 83篇、Cochrane Library 88篇),中文文献78篇(CBM 28篇、CNKI 27篇、VIP 23篇)。剔除重复文献后获得248篇,阅读标题后排除与CAZ/AVI治疗CRE/CRKP/CPE感染不相关文献227篇。阅读剩余文献摘要,排除结局指标缺失或指标不相关文献33篇,得到文献11篇。阅读全文剔除样本量<10的文献后,最终纳入5篇英文文献[3-7]进入本研究。共计患者392例,其中,试验组110例,对照组282例。其中,1项为前瞻性研究,4项为回顾性研究。4项研究为CRE感染,1项研究为CRKP感染,4项CRE研究进行了碳青霉烯酶检测确定绝大部分菌株产KPC酶。纳入研究的基本信息见表1。
表 1 纳入研究基本信息
纳入研究 中心情况 研究类型 研究时间(年) 分组及样本量 平均年龄(岁) 男性(%) 致病菌 观察时间(t/d) 给药方案 伴随疗法 结局指标 Shields[3]
2017单中心
(美国)回顾性 2009-2017 T(13) 66 54 CRKP 90 CAZ/AVI GEN ①③④⑤⑥⑦ C(96) 59 (57.3) CB+AG,CB+COL,其他疗法 Castón[4]
2017多中心(西班牙、以色列) 回顾性 2012-2016 T(8) 61 50 CRE 30 CAZ/AVI AM,CB,FOS,TGC,COL ①③ C(23) 59 (65.2) CB,AG,
BLIBL,TGC,
FOS,COLDuin[5] 2018 多中心
(美国)前瞻性 2011-2016 T(38) 57 61 CRE 30 CAZ/AVI TIG,AG,GEN,CB,FOS,
SXT①②③⑥⑦ C(99) 63 (42) COL Alraddadi[6]2019 单中心(沙特阿拉伯) 回顾性 2017-2018 T(10) 59.5 80 CRE 30 CAZ/AVI - ①②③⑤ C(28) 61.5 (57.1) COL,CB,TGC,AM,QU,SXT,AZT Tsolaki[7]
2019多中心
(希腊)回顾性 40个月 T(41) 61.9 68.3 CRE 28 CAZ/AVI - ①③⑤ C(36) 59.1 (77.3) 适当抗生素
治疗注:T:试验组;C:对照组。结局指标:①临床治愈率;②临床缓解率;③28 d/30 d全因病死率;④感染复发率;⑤AEs;⑥SAEs。CAZ/AVI:头孢他啶/阿维巴坦;CB:碳青霉烯类;AG:氨基糖苷类;GEN:庆大霉素;COL:多粘菌素E;TGC:替加环素;BLIBL:β-内酰胺酶抑制剂;FOS:磷霉素;QU:喹诺酮类;SXT:复方磺胺甲唑;AZT:氨曲南。 -
依据NOS对5项观察性研究进行质量评价,NOS评分均为6颗星,符合纳入Meta分析标准。
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5项研究[3-7]报道了临床治愈率,各研究间无统计学异质性(I2=0%,P=0.40),选择固定效应模型分析,结果显示,CAZ/AVI组患者临床治愈率高于对照组,结果有统计学意义[OR=3.57,95% CI(2.03,6.26),P<0.00001],见图1。
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两项研究[5-6]报道了临床缓解率,各研究间无统计学异质性(I2=0%,P=0.45),选择固定效应模型分析,结果显示两组患者临床缓解率相当,结果无统计学意义[OR=1.92,95% CI(0.93,3.97),P=0.08]。
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5项研究[3-7]报道了28 d/30 d全因病死率,各研究间无统计学异质性(I2=0%,P=0.63),选择固定效应模型分析,结果显示CAZ/AVI组患者28 d/30 d全因病死率低于对照组,结果有统计学意义[OR=0.27,95% CI(0.14,0.50),P<0.0001],见图2。
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3项研究[3, 5-6]报道了感染复发率,各研究间有统计学异质性(I2=61%,P=0.08),选择随机效应模型分析,结果显示两组患者感染复发率相当,结果无统计学意义[OR=0.44,95% CI(0.11,1.85),P=0.26]。
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2项研究[3, 5]分别报道了不良事件(AEs)和严重不良事件(SAEs),各研究间均无统计学异质性(I2=0%,P=0.43)和(I2=0%,P=0.46),选择固定效应模型分析,结果显示,CAZ/AVI组患者AEs低于对照组,结果有统计学意义[OR=0.29,95% CI(0.10,0.80), P=0.02]。两组患者SAEs相当,结果无统计学意义[OR=0.33,95% CI(0.09,1.19), P=0.09],见图3。
The efficacy and safety of ceftazidime/avibactam therapy on carbapenem-resistant Enterobacteriaceae infections: a Meta-analysis
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摘要:
目的 系统评价头孢他啶/阿维巴坦(ceftazidime/avibactam,CAZ/AVI)治疗耐碳青霉烯类肠杆菌/肺炎克雷伯菌(CRE/CRKP)感染的疗效和安全性,以期为临床治疗提供循证依据。 方法 计算机检索PubMed、Embase、The Cochrane Library、CBM、CNKI、VIP电子数据库,收集从建库起至2020年5月公开发表的使用CAZ/AVI治疗CRE/CRKP感染的研究,由2名评价员独立按纳入与排除标准筛选文献、提取资料并评价纳入研究的方法学质量后,采用RevMan 5.3统计软件对结果进行分析。 结果 共纳入5篇英文文献,合计392例患者。结果显示有效性方面:CAZ/AVI组患者临床治愈率[OR=3.57, 95% CI(2.03, 6.26), P<0.00001]显著高于对照组。CAZ/AVI组患者28 d/30 d全因病死率[OR=0.27, 95% CI(0.14, 0.50), P<0.0001]显著低于对照组。两组患者临床缓解率[OR=1.92, 95% CI(0.93, 3.97), P=0.08]和感染复发率[OR=0.44, 95% CI(0.11, 1.85), P=0.26]无显著性差异。安全性方面:CAZ/AVI组患者不良事件(AEs) [OR=0.29, 95% CI(0.10, 0.80), P=0.02]显著低于对照组,两组患者严重不良事件(SAEs) [OR=0.33, 95% CI(0.09, 1.19), P=0.09]无显著性差异。 结论 当前证据表明,CAZ/AVI治疗碳青霉烯类耐药菌感染具有生存优势且并不增加SAEs,安全性好。受纳入研究质量和数量限制,上述结论有待更多高质量的RCT加以验证。 -
关键词:
- 头孢他啶/阿维巴坦 /
- 耐碳青霉烯类肠杆菌 /
- 耐碳青霉烯类肺炎克雷伯菌 /
- 系统评价 /
- 荟萃分析
Abstract:Objective To systematically evaluate the efficacy and safety of ceftazidime/avibactam(CAZ/AVI) in the treatment of carbapenem-resistant Enterobacteriaceae(CRE) or carbapenem-resistance Klebsiella pneumonia (CRKP), and to provide evidence-cased reference for clinic therapy. Methods A comprehensive literature search from PubMed, Embase, the Cochrane Library, CBM, CNKI and VIP database was conducted for the CAZ/AVI therapy on CRE/CRKP infections published before May.2020. Two reviewers independently screened literatures according to the inclusion and exclusion criteria, extracted data, and assessed the methodological quality of the included studies. The results were analyzed by RevMan 5.3 statistical software. Results Five studies in English involving 392 patients were included for the analysis. In terms of effectiveness, the results showed CAZ/AVI group significantly increased the clinical cure rate[OR=3.57, 95% CI (2.03, 6.26), P<0.00001] compared with the control group. Also CAZ/AVI group significantly decreased the 28/30 day all-cause mortality [OR=0.27, 95% CI (0.14, 0.50), P<0.0001]. There were no significant difference between the two groups in the clinical remission rate [OR=1.92, 95% CI (0.93, 3.97), P=0.08] and the infection recurrence rate [OR=0.44, 95% CI (0.11, 1.85), P=0.26]. In terms of safety, the incidence of adverse events in CAZ/AVI group were lower than those in control group [OR=0.29, 95% CI (0.10, 0.80), P=0.02]. There was no significant difference between two groups in the incidence of serious adverse events[OR=0.33, 95% CI (0.09, 1.19), P=0.09]. Conclusion The current evidence shows that CAZ/AVI therapy has advantage in survival rate for the treatment of CRE/CRKP infections without increase of SAEs. Limited by the quality and quantity of the included studies, the above conclusions need to be verified with more high-quality RCTs. -
表 1 纳入研究基本信息
纳入研究 中心情况 研究类型 研究时间(年) 分组及样本量 平均年龄(岁) 男性(%) 致病菌 观察时间(t/d) 给药方案 伴随疗法 结局指标 Shields[3]
2017单中心
(美国)回顾性 2009-2017 T(13) 66 54 CRKP 90 CAZ/AVI GEN ①③④⑤⑥⑦ C(96) 59 (57.3) CB+AG,CB+COL,其他疗法 Castón[4]
2017多中心(西班牙、以色列) 回顾性 2012-2016 T(8) 61 50 CRE 30 CAZ/AVI AM,CB,FOS,TGC,COL ①③ C(23) 59 (65.2) CB,AG,
BLIBL,TGC,
FOS,COLDuin[5] 2018 多中心
(美国)前瞻性 2011-2016 T(38) 57 61 CRE 30 CAZ/AVI TIG,AG,GEN,CB,FOS,
SXT①②③⑥⑦ C(99) 63 (42) COL Alraddadi[6]2019 单中心(沙特阿拉伯) 回顾性 2017-2018 T(10) 59.5 80 CRE 30 CAZ/AVI - ①②③⑤ C(28) 61.5 (57.1) COL,CB,TGC,AM,QU,SXT,AZT Tsolaki[7]
2019多中心
(希腊)回顾性 40个月 T(41) 61.9 68.3 CRE 28 CAZ/AVI - ①③⑤ C(36) 59.1 (77.3) 适当抗生素
治疗注:T:试验组;C:对照组。结局指标:①临床治愈率;②临床缓解率;③28 d/30 d全因病死率;④感染复发率;⑤AEs;⑥SAEs。CAZ/AVI:头孢他啶/阿维巴坦;CB:碳青霉烯类;AG:氨基糖苷类;GEN:庆大霉素;COL:多粘菌素E;TGC:替加环素;BLIBL:β-内酰胺酶抑制剂;FOS:磷霉素;QU:喹诺酮类;SXT:复方磺胺甲唑;AZT:氨曲南。 -
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