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中华重症医学电子杂志

中华重症医学电子杂志 ›› 2024, Vol. 10 ›› Issue (01) : 16 -24. doi: 10.3877/cma.j.issn.2096-1537.2024.01.003

临床研究

CAZ-AVI与多黏菌素B治疗重症CRKP肺炎患者的效果及安全性比较
石颖1, 胡静2, 刘佩本2, 王婷婷2, 左祥荣2, 曹权2,†()   
  1. 1. 225002　江苏扬州，江苏省苏北人民医院重症医学科;210029　江苏南京，南京医科大学第一附属医院重症医学科
    2. 210029　江苏南京，南京医科大学第一附属医院重症医学科
  • 收稿日期:2023-02-06 出版日期:2024-02-28
  • 通信作者: 曹权
  • 基金资助:
    江苏省“青年医学人才”项目(QNRC2016557); 江苏省第五期“333高层次人才培养工程”第三层次人才项目; 江苏省高层次卫生人才“六个一工程”拔尖人才科研项目(LGY2019067); 江苏省苏北人民医院青年托举专项基金项目(SBQN22025)

Ceftazidime-Avibactam versus polymyxin B in the treatment of pneumonia caused by carbapenem-resistant Klebsiella pneumoniae pneumonia

Ying Shi1, Jing Hu2, Peiben Liu2, Tingting Wang2, Xiangrong Zuo2, Quan Cao2,†()   

  1. 1. Department of Critical Care Medicine, Northern Jiangsu People's Hospital of Jiangsu Province, Yangzhou 225002, China;Department of Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
    2. Department of Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
  • Received:2023-02-06 Published:2024-02-28
  • Corresponding author: Quan Cao
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石颖, 胡静, 刘佩本, 王婷婷, 左祥荣, 曹权. CAZ-AVI与多黏菌素B治疗重症CRKP肺炎患者的效果及安全性比较[J]. 中华重症医学电子杂志, 2024, 10(01): 16-24.

Ying Shi, Jing Hu, Peiben Liu, Tingting Wang, Xiangrong Zuo, Quan Cao. Ceftazidime-Avibactam versus polymyxin B in the treatment of pneumonia caused by carbapenem-resistant Klebsiella pneumoniae pneumonia[J]. Chinese Journal of Critical Care & Intensive Care Medicine(Electronic Edition), 2024, 10(01): 16-24.

目的

比较以头孢他啶-阿维巴坦（CAZ-AVI）与多黏菌素B为基础的抗感染治疗策略在重症耐碳青霉烯类肺炎克雷伯杆菌（CRKP）肺炎患者中的效果与安全性。

方法

回顾性分析2019年6月至2020年9月在南京医科大学第一附属医院ICU诊断为CRKP相关肺炎并接受CAZ-AVI（46例）或多黏菌素B（40例）为基础治疗的86例患者的临床资料，比较CAZ-AVI组和多黏菌素B组的临床治愈率、微生物清除率、28 d生存率和安全性等情况。

结果

86例研究对象中，CAZ-AVI组CRKP清除率为71.7%（33/46），多黏菌素B组为45.0%（18/40），2组比较，差异有统计学意义（χ2=6.338，P=0.012）。CAZ-AVI组临床治愈率为52.2%（24/46），28 d生存率为69.6%（32/46），多黏菌素B组分别为32.5%（13/40）、75.0%（30/40），2组比较，差异均无统计学意义（χ2=3.378，P=0.066；χ2=0.314，P=0.575）。应用多因素logistic回归分析和倾向性评分（PS）回归调整法发现，CAZ-AVI组患者临床治愈率比多黏菌素B组高（P值分别为0.017、0.025），校正ORs和95%CIs分别为3.550（1.250~10.078）、3.062（1.150~8.149）；CAZ-AVI组患者微生物清除率亦比多黏菌素B组高（P值分别为0.012、0.015），校正ORs和95%CIs分别为3.320（1.308~8.427）、3.297（1.259~8.637）；2组28 d生存率差异无统计学意义（P值分别为0.990、0.850）。CAZ-AVI组不良反应发生率低于多黏菌素B组，差异有统计学意义（8.7% vs 30.0%，χ2=6.413，P=0.011）。

结论

对于CRKP引起的肺炎，CAZ-AVI治疗效果可能优于多黏菌素B。

关键词: 耐碳青霉烯类肺炎克雷伯杆菌, 头孢他啶-阿维巴坦, 多黏菌素B, 临床结果, 安全性评价
Objective

To assess the efficacy and safety of Ceftazidime-Avibactam (CAZ-AVI) versus polymyxin B-based anti-infective therapy in patients with severe carbapenem-resistant Klebsiella pneumoniae (CRKP) pneumonia.

Methods

From June 2019 to September 2020, the data from patients in ICU of the First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed. These patients were diagnosed with pneumonia caused by CRKP and were treated with either CAZ-AVI or polymyxin B-based anti-infective therapy. Clinical and microbiologic cure rates, 28-day survival, and safety evaluation were compared between patients in two groups.

Results

Among the 86 subjects, CRKP clearance was 71.7% (33/46) in the CAZ-AVI group and 45.0% (18/40) in the polymyxin B group, there was significant difference between two groups (χ2=6.338, P=0.012). The clinical cure rate was 52.2% (24/46), the 28-day survival rate was 69.6% (32/46) in the CAZ-AVI group while 32.5% (13/40) and 75.0% (30/40) in polymyxin B group, there were no significant difference between two groups (χ2=3.378, P=0.066; χ2=0.314, P=0.575). The multivariate logistic regression analysis and propensity score (PS) regression adjustment method were employed. The results indicated that the clinical cure rate was significantly higher in the CAZ-AVI group compared to the polymyxin B group (P values of 0.017 and 0.025, respectively). The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 3.550 (1.250-10.078) and 3.062 (1.150-8.149), respectively. The microbial clearance in CAZ-AVI patients was significantly higher relative to the polymyxin B group (P values: 0.012, 0.015, respectively), adjusted ORs and 95% CIs were 3.320 (1.308-8.427), 3.297 (1.259-8.637). There was no significant difference in 28-day survival between the 2 groups (P values were 0.990 and 0.850, respectively). The CAZ-AVI group had a lower incidence of adverse reactions when compared with the polymyxin B group (8.7% vs 30.0%, χ2=6.413, P =0.011).

Conclusion

CAZ-AVI be a reasonable alternative to polymyxin B in the treatment of pneumonia caused by CRKP.

Key words: Carbapenem-resistant Klebsiella pneumoniae, Polymyxin B, Ceftazidime-Avibactam, Clinical outcomes, Safety evaluation
表1 2组ICU患者基线资料及临床结局比较
基线资料及临床结局 CAZ-AVI组（46例） 多黏菌素B组（40例） 统计值 P值
男性[例（%）] 41（89.1） 27（67.5） χ2=6.049 0.014
年龄（岁，） 59.7±18.6 59.9±16.0 t=0.043 0.966
基础疾病[例（%）]
心血管疾病 30（65.2） 25（62.5） χ2=0.069 0.793
脑血管疾病 14（30.4） 8（20.0） χ2=1.224 0.269
慢性呼吸系统疾病 1（2.2） 1（2.5） - 1.000
糖尿病 15（32.6） 8（20.0） χ2=1.736 0.188
肿瘤 6（13.0） 2（5.0） - 0.275
慢性肝病 2（4.3） 1（2.5） - 1.000
慢性肾病 4（8.7） 2（5.0） - 0.681
Charlson指数[M（Q25，Q75）] 2.00（0，4.00） 1.00（0.25，3.00） Z=0.873 0.383
CRRT[例（%）] 20（43.5） 15（37.5） χ2=0.317 0.574
VAP[例（%）] 34（73.9） 27（67.5） χ2=0.427 0.514
感染时SOFA评分（分，） 7.0±3.8 6.4±2.8 t=0.951 0.344
感染时APACHEⅡ评分（分，） 14.3±5.8 13.4±3.7 t=0.945 0.348
合并的多部位感染[例（%）]
合并血流感染 6（13.0） 8（20.0） χ2=0.760 0.383
合并尿路感染 9（19.6） 4（10.0） χ2=1.526 0.217
合并皮肤软组织感染 4（8.7） 3（7.5） - 1.000
合并腹腔感染 3（6.5） 4（10.0） - 0.700
联合使用抗生素种类[例（%）]
联合碳青霉烯类 20（43.5） 20（50.0） χ2=0.366 0.545
联合阿米卡星 11（23.9） 8（20.0） χ2=0.190 0.663
联合氨曲南 2（4.3） 0 - 0.497
联合磷霉素 2（4.3） 2（5.0） - 1.000
联合替加环素 6（13.0） 10（25.0） χ2=2.020 0.155
单药治疗 9（19.6） 5（12.5） χ2=0.784 0.376
临床结局[例（%）]
临床治愈 24（52.2） 13（32.5） χ2=3.378 0.066
细菌清除 33（71.7） 18（45.0） χ2=6.338 0.012
28 d生存 32（69.6） 30（75.0） χ2=0.314 0.575
表2 2组患者临床治愈、细菌清除及28 d生存的单因素与多因素分析
因素 粗OR值（95%CI） P值 校正OR值a（95%CI） P值 B SE Wald
临床治愈b
CAZ-AVI治疗 2.266（0.941~5.456） 0.068 3.550（1.25~10.078） 0.017 1.267 0.532 5.663
肿瘤史 0.167（0.02~1.419） 0.101 0.126（0.014~1.158） 0.067 -2.017 1.131 3.351
CRRT 0.284（0.111~0.726） 0.009 0.378（0.123~1.158） 0.088 -0.973 0.571 2.902
感染时SOFA评分 0.760（0.645~0.896） 0.001 0.801（0.664~0.966） 0.020 -0.222 0.095 5.404
合并腹腔感染 0.199（0.023~1.731） 0.144 0.280（0.025~3.177） 0.305 -1.271 1.238 1.054
细菌清除c
CAZ-AVI治疗 3.103（1.269~7.588） 0.013 3.320（1.308~8.427） 0.012 1.200 0.475 6.379
感染时SOFA评分 0.927（0.814~1.055） 0.248 0.923（0.801~1.065） 0.272 -0.080 0.073 1.209
合并腹腔感染 0.245（0.045~1.343） 0.105 0.328（0.054~2.000） 0.227 -1.115 0.922 1.461
28 d生存d
CAZ-AVI治疗 0.762（0.294~1.974） 0.576 0.992（0.260~3.777） 0.990 -0.008 0.682 0.000
年龄 0.950（0.917~0.985） 0.006 0.925（0.871~0.982） 0.011 -0.078 0.031 6.459
心脏疾病 0.173（0.047~0.642） 0.009 0.189（0.028~1.265） 0.086 -1.663 0.969 2.949
Charlson指数 0.834（0.683~1.019） 0.076 1.090（0.789~1.505） 0.602 0.086 0.165 0.271
CRRT 0.366（0.139~0.962） 0.042 1.023（0.205~5.115） 0.978 0.023 0.821 0.001
VAP 0.390（0.118~1.291） 0.123 1.077（0.201~5.765） 0.931 0.074 0.856 0.007
感染时SOFA评分 0.670（0.551~0.814） <0.001 0.545（0.395~0.754） <0.001 -0.607 0.165 13.500
感染时APACHE评分 0.870（0.784~0.965） 0.009
表3 通过单因素分析、多因素分析及PS回归调整分析法研究CAZ-AVI治疗与临床结局关系
分析方法 临床治愈 细菌清除 28 d生存
OR（95% CI） P值 OR（95% CI） P值 OR（95% CI） P值
单因素分析 2.266（0.941~5.456） 0.068 3.103（1.269~7.588） 0.013 0.762（0.294~1.974） 0.576
多因素分析 3.550（1.250~10.078） 0.017 3.320（1.308~8.427） 0.012 0.992（0.260~3.777） 0.990
PS回归调整 3.062（1.150~8.149） 0.025 3.297（1.259~8.637） 0.015 0.906（0.326~2.517） 0.850
1
Potter RF, D'Souza AW, Dantas G. The rapid spread of carbapenem-resistant Enterobacteriaceae [J]. Drug Resist Updat, 2016, 29: 30-46.
2
Xu L, Sun X, Ma X. Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae [J]. Ann Clin Microbiol Antimicrob, 2017, 16(1): 18.
3
Agyeman AA, Bergen PJ, Rao GG, et al. A systematic review and meta-analysis of treatment outcomes following antibiotic therapy among patients with carbapenem-resistant Klebsiella pneumoniae infections [J]. Int J Antimicrob Agents, 2020, 55(1): 105833.
4
胡付品, 郭燕, 朱德妹, 等. 2018年CHINET中国细菌耐药性监测 [J]. 中国感染与化疗杂志, 2020, 20(1): 1-10.
5
Vincent JL, Sakr Y, Singer M, et al. Prevalence and outcomes of infection among patients in Intensive Care Units in 2017 [J]. JAMA, 2020, 323(15): 1478-1487.
6
Zuo Y, Zhao D, Song G, et al. Risk factors, molecular epidemiology, and outcomes of carbapenem-resistant Klebsiella pneumoniae infection for hospital-acquired pneumonia: a matched case-control study in Eastern China during 2015-2017 [J]. Microb Drug Resist, 2020, 27(2): 204-211.
7
Brinkworth AJ, Hammer CH, Olano LR, et al. Identification of outer membrane and exoproteins of carbapenem-resistant multilocus sequence type 258 Klebsiella pneumoniae [J]. PLoS One, 2015, 10(4): e0123219.
8
荣芳, 吴峰, 周俊. 耐碳青霉烯类肺炎克雷伯菌对替加环素的耐药机制研究进展 [J]. 实用临床医药杂志, 2022, 26(9): 134-138.
9
American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia [J]. Am J Respir Crit Care Med, 2005, 171(4): 388-416.
10
中华医学会呼吸病学分会感染学组. 中国成人医院获得性肺炎与呼吸机相关性肺炎诊断和治疗指南 (2018年版) [J]. 中华结核和呼吸杂志, 2018, 41(4): 255-280.
11
Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations [J]. Br J Clin Pharmacol, 2011, 72(3): 381-393.
12
Centers for Disease Control and Prevention. Facility guidance for control of carbapenem-resistant Enterobacteriaceae (CRE) 2015 update [Z]. 2021-08-12.
13
Kuang H, Zhong C, Wang Y, et al. Clinical characteristics and outcomes of patients with multidrug-resistant Gram-negative bacterial infections treated with Ceftazidime/Avibactam [J]. J Glob Antimicrob Resist, 2020, 23: 404-407.
14
Zalts R, Neuberger A, Hussein K, et al. Treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia [J]. Am J Ther, 2016, 23(1): e78-e85.
15
Lin QY, Tsai YL, Liu MC, et al. Serratia marcescens arn, a PhoP-regulated locus necessary for polymyxin B resistance [J]. Antimicrob Agents Chemother, 2014, 58(9): 5181-5190.
16
Liang Q, Huang M, Xu Z. Early use of polymyxin B reduces the mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection [J]. Braz J Infect Dis, 2019, 23(1): 60-65.
17
Lu Q, Zhu HH, Li GH, et al. A comparative study of the microbiological efficacy of polymyxin B on different carbapenem-resistant Gram-negative bacteria infections [J]. Front Med (Lausanne), 2021, 8: 620885.
18
Bergen PJ, Bulman ZP, Saju S, et al. Polymyxin combinations: pharmacokinetics and pharmacodynamics for rationale use [J]. Pharmacotherapy, 2015, 35(1): 34-42.
19
Sandri AM, Landersdorfer CB, Jacob J, et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens [J]. Clin Infect Dis, 2013, 57(4): 524-531.
20
Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients [J]. Antimicrob Agents Chemother, 2011, 55(7): 3284-3294.
21
Rahal JJ. Novel antibiotic combinations against infections with almost completely resistant Pseudomonas aeruginosa and Acinetobacter species [J]. Clin Infect Dis, 2006, 43 Suppl 2: S95-99.
22
Nang SC, Azad MAK, Velkov T, et al. Rescuing the last-line polymyxins: achievements and challenges [J]. Pharmacol Rev, 2021, 73(2): 679-728.
23
Bassetti M, Peghin M, Carnelutti A, et al. How should we treat HAP/VAP caused by carbapenemase-producing enterobacteriaceae? [J]. Semin Respir Crit Care Med, 2017, 38(3): 301-310.
24
Van Duin D, Lok JJ, Earley M, et al. Colistin versus Ceftazidime-Avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae [J]. Clin Infect Dis, 2018, 66(2): 163-171.
25
Shields RK, Nguyen MH, Chen L, et al. Ceftazidime-Avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia [J]. Antimicrob Agents Chemother, 2017, 61(8): e00883-17.
26
Karaiskos I, Daikos GL, Gkoufa A, et al. Ceftazidime/avibactam in the era of carbapenemase-producing Klebsiella pneumoniae: experience from a national registry study [J]. J Antimicrob Chemother, 2020, 76(3): 775-783.
27
Shields RK, Potoski BA, Haidar G, et al. Clinical outcomes, drug toxicity, and emergence of Ceftazidime-Avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections [J]. Clin Infect Dis, 2016, 63(12): 1615-1618.
28
Jorgensen SCJ, Trinh TD, Zasowski EJ, et al. Real-world experience with Ceftazidime-Avibactam for multidrug-resistant Gram-negative bacterial infections [J]. Open Forum Infect Dis, 2019, 6(12): ofz522.
29
Sousa A, Perez-Rodriguez MT, Soto A, et al. Effectiveness of Ceftazidime/Avibactam as salvage therapy for treatment of infections due to OXA-48 carbapenemase-producing Enterobacteriaceae [J]. J Antimicrob Chemother, 2018, 73(11): 3170-3175.
30
Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial [J]. Lancet Infect Dis, 2018, 18(3): 285-295.
31
Tsolaki V, Mantzarlis K, Mpakalis A, et al. Ceftazidime-Avibactam to treat life-threatening infections by carbapenem-resistant pathogens in critically ill mechanically ventilated patients [J]. Antimicrob Agents Chemother, 2020, 64(3): e02320-19.
32
Stachyra T, Pechereau MC, Bruneau JM, et al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor [J]. Antimicrob Agents Chemother, 2010, 54(12): 5132-5138.
33
Ehmann DE, Jahic H, Ross PL, et al. Kinetics of avibactam inhibition against class A, C, and D beta-lactamases [J]. J Biol Chem, 2013, 288(39): 27960-27971.
34
Vena A, Castaldo N, Bassetti M. The role of new beta-lactamase inhibitors in gram-negative infections [J]. Curr Opin Infect Dis, 2019, 32(6): 638-646.
35
Han R, Shi Q, Wu S, et al. Dissemination of carbapenemases (KPC, NDM, OXA-48, IMP, and VIM) among carbapenem-resistant Enterobacteriaceae isolated from adult and children patients in China [J]. Front Cell Infect Microbiol, 2020, 10: 314.
36
Zhang R, Liu L, Zhou H, et al. Nationwide surveillance of clinical carbapenem-resistant Enterobacteriaceae (CRE) strains in China [J]. Ebiomedicine, 2017, 19: 98-106.
37
Shaw E, Rombauts A, Tubau F, et al. Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/ CTX-M-15-producing Klebsiella pneumoniae infection [J]. J Antimicrob Chemother, 2018, 73(4): 1104-1106.
38
Hobson Ca, Bonacorsi S, Fahd M, et al. Successful treatment of bacteremia due to NDM-1-producing Morganella morganii with Aztreonam and Ceftazidime-Avibactam combination in a pediatric patient with hematologic malignancy [J]. Antimicrob Agents Chemother (Bethesda), 2019, 63(2): e02463-18.
39
Tsuji BT, Pogue JM, Zavascki AP, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP) [J]. Pharmacotherapy, 2019, 39(1): 10-39.
40
Rigatto MH, Behle TF, Falci DR, et al. Risk factors for acute kidney injury (AKI) in patients treated with polymyxin B and influence of AKI on mortality: a multicentre prospective cohort study [J]. J Antimicrob Chemother, 2015, 70(5): 1552-1557.
41
张少楠, 黄晓晖, 岳慧杰. 多黏菌素B相关皮肤色素沉着的研究进展 [J]. 药物不良反应杂志, 2020, 22(1): 38-41.
42
Mattos KP, Lloret GR, Cintra ML, et al. Acquired skin hyperpigmentation following intravenous polymyxin B treatment: a cohort study [J]. Pigment Cell Melanoma Res, 2016, 29(3): 388-390.
43
Mattos KPH, Cintra ML, Gouvea IR, et al. Skin hyperpigmentation following intravenous polymyxin B treatment associated with melanocyte activation and inflammatory process [J]. J Clin Pharm Ther, 2017, 42(5): 573-578.
44
Cheng K, Newell P, Chow JW, et al. Safety profile of Ceftazidime-Avibactam: pooled data from the adult phase Ⅱ and phase Ⅲ clinical trial programme [J]. Drug Saf, 2020, 43(8): 751-766.
45
刘佩本, 石颖, 左祥荣, 等. 头孢他啶/阿维巴坦治疗耐碳青霉烯类肠杆菌科细菌感染的研究进展 [J/OL]. 中华重症医学电子杂志, 2022, 8(1): 67-73.
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