多黏菌素B治疗药物监测专家共识：中国药理学会治疗药物监测研究专业委员会及上海市医学会感染与化疗专科分会发起制定

Chinese consensus guidelines for therapeutic drug monitoring of polymyxin B, endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society 多黏菌素B治疗药物监测专家共识：中国药理学会治疗药物监测研究专业委员会及上海市医学会感染与化疗专科分会发起制定 1 first-author 2 3 3 2 1 4 1 1 5 6 7 8 6 9 1 10 9 11 12 10 13 14 15 2 corresp Liyan MIAO, miaolysuzhou@163.com Liyan MIAO, miaolysuzhou@163.com miaolysuzhou@163.com https://orcid.org/0000-0001-8481-0630 1 16 corresp Jing ZHANG, zhangj_fudan@aliyun.com Jing ZHANG, zhangj_fudan@aliyun.com zhangj_fudan@aliyun.com https://orcid.org/0000-0003-2966-9149 复旦大学附属华山医院抗生素研究所， 卫健委抗生素临床药理重点实验室， 国家老年医学研究中心， 中国上海， 200040 复旦大学附属华山医院抗生素研究所， 卫健委抗生素临床药理重点实验室， 国家老年医学研究中心， 中国上海， 200040 Institute of Antibiotics, Huashan Hospital, Fudan University / Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission of the People’s Republic of China / National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China Institute of Antibiotics, Huashan Hospital, Fudan University / Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission of the People’s Republic of China / National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China 苏州大学第一附属医院， 中国苏州， 215000 苏州大学第一附属医院， 中国苏州， 215000 Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University / Institute for Interdisciplinary Drug Research and Translational Sciences, College of Pharmaceutical Science, Soochow University, Suzhou 215000, China Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University / Institute for Interdisciplinary Drug Research and Translational Sciences, College of Pharmaceutical Science, Soochow University, Suzhou 215000, China 澳大利亚莫纳什大学， 墨尔本， VIC 3800 澳大利亚莫纳什大学， 墨尔本， VIC 3800 Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, VIC 3800, Australia Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, VIC 3800, Australia 陆军军医大学西南医院， 中国重庆， 400038 陆军军医大学西南医院， 中国重庆， 400038 The Southwest Hospital of Army Medical University, Chongqing 400038, China The Southwest Hospital of Army Medical University, Chongqing 400038, China 南昌大学第一附属医院， 中国南昌， 330006 南昌大学第一附属医院， 中国南昌， 330006 The First Affiliated Hospital of Nanchang University, Nanchang 330006, China The First Affiliated Hospital of Nanchang University, Nanchang 330006, China 东南大学附属中大医院， 中国南京， 210009 东南大学附属中大医院， 中国南京， 210009 Zhongda Hospital Southeast University, Nanjing 210009, China Zhongda Hospital Southeast University, Nanjing 210009, China 长沙市第三医院， 中国长沙， 410035 长沙市第三医院， 中国长沙， 410035 The Third Hospital of Changsha, Changsha 410035, China The Third Hospital of Changsha, Changsha 410035, China 福建医科大学附属协和医院， 中国福州， 350001 福建医科大学附属协和医院， 中国福州， 350001 Fujian Medical University Union Hospital, Fuzhou 350001, China Fujian Medical University Union Hospital, Fuzhou 350001, China 郑州大学第一附属医院， 中国郑州， 450052 郑州大学第一附属医院， 中国郑州， 450052 The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China 中南大学湘雅二医院， 中国长沙， 410011 中南大学湘雅二医院， 中国长沙， 410011 The Second Xiangya Hospital of Central South University, Changsha 410011, China The Second Xiangya Hospital of Central South University, Changsha 410011, China 四川省人民医院， 中国成都， 610072 四川省人民医院， 中国成都， 610072 People’s Hospital of Sichuan Province, Chengdu 610072, China People’s Hospital of Sichuan Province, Chengdu 610072, China 浙江大学附属医院邵逸夫医院， 中国杭州， 310020 浙江大学附属医院邵逸夫医院， 中国杭州， 310020 Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310020, China Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310020, China 南京大学医学院附属鼓楼医院， 中国南京， 210008 南京大学医学院附属鼓楼医院， 中国南京， 210008 Nanjing Drum Tower Hospital, Nanjing 210008, China Nanjing Drum Tower Hospital, Nanjing 210008, China 中南大学湘雅三医院， 中国长沙， 430100 中南大学湘雅三医院， 中国长沙， 430100 The Third Xiangya Hospital of Central South University, Changsha 430100, China The Third Xiangya Hospital of Central South University, Changsha 430100, China 天津市第一中心医院， 中国天津， 300190 天津市第一中心医院， 中国天津， 300190 Tianjin First Central Hospital, Tianjin 300190, China Tianjin First Central Hospital, Tianjin 300190, China 复旦大学附属华山医院研究型病房， 中国上海， 200040 复旦大学附属华山医院研究型病房， 中国上海， 200040 Research Ward of Huashan Hospital, Fudan University, Shanghai 200040, China Research Ward of Huashan Hospital, Fudan University, Shanghai 200040, China Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use. 多黏菌素B是治疗广泛耐药革兰氏阴性细菌感染的最后“一道防线”，但因剂量限制性肾毒性及低剂量可能出现治疗失败和耐药性，临床上迫切需要通过治疗药物监测（TDM）优化其使用。多黏菌素B TDM专家共识以及规范操作程序的制定将有助于确保TDM的准确性并为其合理使用提供依据。中国药理学学会治疗药物监测研究专业委员会及上海医学会感染与化疗专科分会共同发起制定多黏菌素B的TDM专家共识。共识小组由来自中国不同省份的临床药学、临床医学和临床微生物学专家，及两位澳大利亚莫纳什大学专家组成，就多黏菌素B进行TDM的目标浓度、样本采集、测定、报告和TDM结果解释提出了建议。该指南共识的制定旨在指导多黏菌素B的个体化精准治疗。 多黏菌素B 治疗药物监测（TDM） 药动学 临床疗效 Polymyxin B Therapeutic drug monitoring (TDM) Pharmacokinetics Clinical efficacy 1 Introduction 1 Increasing multidrug-resistant and extensively drug-resistant Gram-negative bacteria in clinics now pose a great therapeutic challenge worldwide. Data from the Chinese Antimicrobial Surveillance Network (CHINET; https://www. https://www. ‍chinets.‍com) show that carbapenem-resistant Acinetobacter baumannii (CRAB) and Klebsiella pneumoniae (CRKP) increased from 32.9% and 3.0% in 2005 to 66.5% and 21.9% in 2021, respectively. However, new antibacterial drug development is slow ( Theuretzbacher et al., 2019 Theuretzbacher et al., 2019 ; Behzadi et al., 2021 Behzadi et al., 2021 ) and available clinical treatment options for carbapenem-resistant organisms are extremely limited. Polymyxin antibiotics were approved in the late 1950s but were subsequently replaced by “less toxic” antibiotics. However, they retain substantial activity against many problematic Gram-negative pathogens ( Gales et al., 2012 Gales et al., 2012 ; Jones et al., 2013 Jones et al., 2013 ) and have since appeared in clinics again to treat these difficult infections. The currently available parenterally administered polymyxins are polymyxin B (sulphate) and colistin; the latter is available as both colistin sulphate (in China) and the inactive prodrug colistimethate (sodium) ( Li et al., 2006 Li et al., 2006 ; Cai et al., 2015 Cai et al., 2015 ; Nang et al., 2021 Nang et al., 2021 ). Although antibiotics such as ceftazidime/avibactam have recently become available, polymyxins are still considered last-line antibiotics for treatment of CRKP (e.g., New Delhi metallo-‍β‍-lactamase), as well as the multidrug-resistant A. baumannii (MDRAB) and Pseudomonas aeruginosa (MDRPA) ( CDC, 2019 CDC, 2019 ). Optimizing parenteral polymyxin therapy is challenging. Of great concern is that resistance to the polymyxins is emerging, with low polymyxin exposure a contributing factor ( Hermes et al., 2013 Hermes et al., 2013 ). Unfortunately, simple dose escalation is precluded due to nephrotoxicity, which occurs in up to 60% of patients receiving intravenous administration ( Azad et al., 2019 Azad et al., 2019 ; Pogue and Tam, 2019 Pogue and Tam, 2019 ). Therefore, therapeutic drug monitoring (TDM) of polymyxins is recommended to reduce both the emergence of resistance and adverse reactions, especially nephrotoxicity. TDM requires multidisciplinary cooperation between clinicians, nurses, testing technicians, and clinical pharmacists for dose optimization. It is necessary to standardize polymyxin TDM operating procedures and analyze the influential factors during the TDM process to ensure that it is conducted accurately and to provide evidence for the rationality of the operating procedures. Although both polymyxin B and colistin (the latter usually administered as colistimethate) are currently available in China for intravenous administration, the requirements for TDM are specific to each antibiotic. This is due in part to the different patient populations/indications for which they are generally recommended with colistimethate being advantageous in the treatment of urinary tract infections (where high colistin concentrations are achieved in urine due to active excretion of colistimethate by the kidneys) and polymyxin B being superior for treatment of serious systemic infections in critically ill patients (administered as an active component). They also have different chemical properties which necessitate different conditions for storage of TDM samples and transfer to testing laboratories (colistimethate is unstable and converted to colistin at room temperature), as well as different liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for detection of the active entity. Given these differences and the greater use of polymyxin B in China due to its pharmacokinetic advantages over colistimethate (which requires in vivo conversion to colistin), the TDM consensus guidelines in the present paper will focus on polymyxin B. This consensus is specified for the TDM of polymyxin B, and covers the whole process of conducting TDM (including the necessity; target patient population; the explanations and technical notes for target concentrations, sample collection, concentration measurements, and reporting; explanation of TDM results and dose adjustment; as well as quality control and quality assurance). The purpose of the consensus is to provide practical and operational guidelines to professionals such as physicians, clinical pharmacists, and testing laboratorians, for conducting TDM and precision dosing of polymyxin B. 2 Methods 1 This consensus was initiated by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of two clinicians, 21 pharmacists, and one microbiologist from ten provinces in China and Australia. Relevant professional issues were discussed in meetings, arising from a review of English and Chinese literature (conducted before May 10, 2022). The recommendations were developed based on the most up-to-date evidence from Chinese and international sources and were designed to meet existing clinical needs. The consensus was externally reviewed by independent experts: three clinicians, 17 pharmacists, and two microbiologists from 12 provinces in China. The external experts individually graded the strength of each recommendation as either strong, medium, weak, or not supported. The definitions for the recommendation grading are listed in Table 1 Table 1 . For each recommendation, the level chosen by the external experts is reported as the percentage of experts choosing each level. The expert group reviewed the external review results and revised recommendations where necessary to reach a final consensus. Strength category Definition Strong Strong evidence, and the external panel member agrees that the recommendation is beneficial for patients. Medium Less evidence, and the external panel member agrees that the recommendation is beneficial for patients. Weak Less evidence, and the external panel member considers that the recommendation is less beneficial for patients. Not supported No evidence, and the external panel member considers that the recommendation is not beneficial for patients. 3 Necessity for polymyxin B TDM 1 Polymyxin B is used as a “last-line” antibiotic for patients with severe systemic infection caused by extensively drug-resistant bacteria ( CDC, 2019 CDC, 2019 ). Polymyxin B exhibits concentration-dependent bacterial killing ( Li et al., 2001 Li et al., 2001 ; Tam et al., 2005 Tam et al., 2005 ; Bulitta et al., 2010 Bulitta et al., 2010 ; Bergen et al., 2011a Bergen et al., 2011a , 2011b 2011b ; Landersdorfer et al., 2018 Landersdorfer et al., 2018 ). The pharmacokinetic/pharmacodynamic (PK/PD) index most closely associated with polymyxin antimicrobial activity is the f AUC/MIC (the area under the unbound drug concentration curve to the minimum inhibitory concentrations (MICs)) ( Bergen et al., 2010 Bergen et al., 2010 ; Dudhani et al., 2010a Dudhani et al., 2010a , 2010b 2010b ; Deris et al., 2012 Deris et al., 2012 ; Cheah et al., 2015 Cheah et al., 2015 ; Landersdorfer et al., 2018 Landersdorfer et al., 2018 ). Intravenously administered polymyxin B has a narrow therapeutic window and dose-limiting nephrotoxicity. The frequent necessity for simultaneous use of various other drugs such as calcineurin inhibitors, acute loop diuretics, and vasopressors further increases the risk of nephrotoxicity ( Naesens et al., 2009 Naesens et al., 2009 ; Gul et al., 2016 Gul et al., 2016 ; Ciftci et al., 2018 Ciftci et al., 2018 ). The incidence of nephrotoxicity of intravenous polymyxin B globally is 20%‍–‍60% ( Javan et al., 2015 Javan et al., 2015 ; Zavascki and Nation, 2017 Zavascki and Nation, 2017 ; Azad et al., 2019 Azad et al., 2019 ; Pogue and Tam, 2019 Pogue and Tam, 2019 ; Wang et al., 2021 Wang et al., 2021 ). In Chinese patients over the last three years, the incidence of acute kidney injury (AKI) following intravenous administration of polymyxin B ranged from 21.7% to 32.9% in prospective studies ( Wang et al., 2021 Wang et al., 2021 ; Zhang et al., 2021 Zhang et al., 2021 ) and 19.0% to 38.7% in retrospective studies ( Jia et al., 2022 Jia et al., 2022 ; Wen et al., 2022 Wen et al., 2022 ). Risk factors for AKI include age, weight, chronic comorbidities, septic shock, hypoalbuminemia, and concomitant use of nephrotoxic drugs ( Phe et al., 2014 Phe et al., 2014 ; Deng et al., 2021 Deng et al., 2021 ). Although polymyxin B dose reduction reduces the risk of nephrotoxicity, it increases the likelihood of treatment failure and emergence of polymyxin resistance ( Hermes et al., 2013 Hermes et al., 2013 ; Olaitan et al., 2014 Olaitan et al., 2014 ). Moreover, the physiological and pathological changes in critically ill patients affect the pharmacokinetics of polymyxin B. Therefore, it is difficult to adjust the dosage regimen to achieve rapid attainment of effective polymyxin B concentrations; and dose adjustment based solely on clinical experience creates a risk of toxicity, treatment failure, and the emergence of resistance. There is thus an urgent clinical need to perform TDM of polymyxin B to optimize the use of this “last-line” therapy. 4 Recommendation of polymyxin B TDM in patient populations 1 It is recommended that critically ill patients, burn patients, neonates/children, the elderly (65 years or older), overweight or obese patients (body mass index (BMI)≥25 kg/m 2 ), underweight patients (BMI≤18.5 kg/m 2 ), those with an elevated risk of nephrotoxicity (such as those receiving concomitant treatment with other nephrotoxic drugs) or with augmented renal clearance, and those receiving renal replacement therapy or who are on a long course of treatment ( > 5 d) all receive polymyxin B TDM ( Wong et al., 2014 Wong et al., 2014 ; Lanckohr et al., 2021 Lanckohr et al., 2021 ). 5 Target concentrations, sample collection, concentration measurement, and reporting for polymyxin B TDM 1 5.1 TDM target for polymyxin B 2 Based on PK/PD studies undertaken in mouse thigh infection models employing A. baumannii , P. aeruginosa , and K. pneumoniae and in human patients ( Sandri et al., 2013 Sandri et al., 2013 ; Cheah et al., 2015 Cheah et al., 2015 ; Kubin et al., 2018 Kubin et al., 2018 ; Landersdorfer et al., 2018 Landersdorfer et al., 2018 ; Miglis et al., 2018 Miglis et al., 2018 ; Liu et al., 2021 Liu et al., 2021 ), an area under the total plasma concentration-time curve across 24 h (AUC 24 h ) of 50 mg·h/L was identified for colistin and polymyxin B as the lower limit for effective treatment of pathogens with MICs of ≤2 mg/L. Using data from 17 studies that examined the nephrotoxicity of intravenous polymyxin B and original Monte Carlo simulations, Lakota et al. (2018) Lakota et al. (2018) identified that an area under the plasma concentration-time curve across 24 h at steady state (AUC ss, 24 h ) of 100 mg·h/L resulted in mild nephrotoxicity, and ultimately proposed a target AUC ss, 24 h window of 50‍‒‍100 mg·h/L for polymyxin B, for pathogens with MICs of ≤2 mg/L. Wang et al. (2021) Wang et al. (2021) compared the population pharmacokinetic properties of polymyxin B in Chinese patients and concluded that the AUC ss, 24 h was significantly higher in patients that experienced AKI ((108±70) mg·h/L) compared to those without AKI ((66±34) mg·h/L). The 2019 International Consensus Guidelines for the Optimal Use of Polymyxins recommended that for polymyxin B the AUC ss, 24 h should be about 50 mg·h/L and possibly 50‍‒‍100 mg·h/L, with the latter corresponding to an average steady-state concentration across 24 h ( C ss, avg ) of 2‒4 mg/L ( Tsuji et al., 2019 Tsuji et al., 2019 ). The Chinese Consensus Guidelines proposed here specify a PK/PD therapeutic window of 50‒100 mg·h/L when making recommendations for clinical practice. Recommendation 1: The recommended TDM target of polymyxin B-treated systemic infections for clinical efficacy and safety is a C ss, avg of 2‍‒4 mg/L, corresponding to an AUC ss, 24 h of 50‒100 mg·h/L. Recommendation level as graded by external experts: strong (72.7%); medium (27.3%); weak (0%); not recommended (0%). 5.2 Recommended sampling time 2 For patients with severe infections, the International Consensus Guidelines for the Optimal Use of Polymyxins recommend a polymyxin B loading dose of 2.0‍–‍2.5 mg/kg total body weight (TBW) infused over 1 h, with subsequent 12-h maintenance doses of 1.25‍–‍1.50 mg/kg TBW infused over 1 h (1 mg is equivalent to 10 000 international units (IU) ( Tsuji et al., 2019 Tsuji et al., 2019 ). The peak concentration ( C max ) and trough concentration ( C trough ) are achieved at the end of the first infusion and immediately before the next infusion at steady state, respectively ( Liu et al., 2021 Liu et al., 2021 ). An approach requiring two samples is commonly applied in TDM, with the AUC calculated using a first-order elimination method ( Rybak et al., 2020 Rybak et al., 2020 ). Recommendation 2: For patients with normal renal function and in the absence of a loading dose, TDM samples should be collected before and after the fourth or fifth dose. If a loading dose is administered, samples can instead be collected before and after the second or third dose. Samples for trough concentrations should be collected no earlier than 0.5 h before the next infusion, and samples for peak concentrations should be collected within 0.5 h of the end of the infusion. Recommendation level as graded by external experts: strong (68.2%); medium (31.8%); weak (0%); not recommended (0%). Given the importance of early treatment, the target polymyxin B exposure should be achieved early in treatment (within the first 24‍–48 h). If a model-informed precision dosing (MIPD) and Bayesian estimation method is used to assist in individualized polymyxin B dosing, earlier concentrations before steady state can be collected to guide dose adjustment. In addition, MIPD offers opportunities for flexible sampling time during treatment (Wich et al., 2021). If dose adjustment is required after initial TDM, it is recommended to wait for two to three doses following the adjustment before TDM is repeated. As the time required to reach steady state may be longer in patients with renal insufficiency, attainment of steady state can be confirmed by performing additional trough sampling (with similar trough concentrations confirming steady state). For patients on long courses of treatment, hemodynamically unstable patients, or patients receiving renal replacement therapy, TDM could be conducted weekly to monitor whether dose adjustment is necessary. 5.3 Sample-collection tubes and transportation to laboratories 2 Sample-collection requirements are necessarily related to the analysis method. Prior communication with the testing laboratory is essential to ensure the appropriate choice of specimen-collection tube and collection of an adequate volume of blood. In whole blood, polymyxin B is stable in ethylenediaminetetraacetic acid (EDTA) or heparin tubes for at least 10 h at room temperature and for at least 19 h at (2‒6) ℃ ( Deng et al., 2021 Deng et al., 2021 ). In plasma, it is stable in EDTA or heparin tubes for at least 22 h at room temperature and at least 24 h in EDTA anticoagulant plasma when refrigerated at 2‍‒‍8 ℃ ( Liu et al., 2020 Liu et al., 2020 ). Polymyxin B samples in EDTA anticoagulant plasma are stable for at least 141 d at -‍20 or -70 ℃ and can be freeze-thawed at least three times ( Liu et al., 2020 Liu et al., 2020 ). Accordingly, data from the literature would suggest that blood samples containing polymyxin B (with EDTA or heparin as the anticoagulant) need to be transferred to testing laboratories at room temperature within 10 h of collection when stored at room temperature (25±5) ℃ and within 19 h of collection when stored on ice. Importantly, as the stability of the sample is dependent upon the storage tube, temperature, and composition (whole blood or plasma), the testing laboratory is still required to investigate the stability of TDM samples and provide information to clinicians and nurses for appropriate collection and transfer of samples ( Chinese Pharmacopoeia Commission, 2020 Chinese Pharmacopoeia Commission, 2020 ). 5.4 Analysis methods 2 5.4.1　Analytes 3 Analysis methods for polymyxin B include microbiological, high-performance liquid chromatography (HPLC), LC-MS/MS, and immunoassay methods, each of which has different sensitivity and suitability ( Sun et al., 2009 Sun et al., 2009 ; Thomas et al., 2012 Thomas et al., 2012 ; Wang et al., 2017 Wang et al., 2017 ; Burkin et al., 2021 Burkin et al., 2021 ). The most suitable method for the TDM requirements of polymyxin B is LC-MS/MS. It is important to recognize that polymyxin B sulfate is a fermented mixture produced by Paenibacillus polymyxa (previously known as Bacillus polymyxa ) that consists of more than 30 components, the two main components in commercial preparations being polymyxins B1 and B2 (which constitute more than 80% of the total polymyxin B) ( Zavascki et al., 2008 Zavascki et al., 2008 ; Wang et al., 2017 Wang et al., 2017 ; Liu et al., 2020 Liu et al., 2020 ; Tam et al., 2020 Tam et al., 2020 ; Deng et al., 2021 Deng et al., 2021 ). Previously published LC-MS/MS methods have focused on determining the concentrations of these two major components ( Liu et al., 2020 Liu et al., 2020 ; Wang et al., 2020 Wang et al., 2020 ; Deng et al., 2021 Deng et al., 2021 ). An in-house LC-MS/MS method developed for the detection of polymyxin B can be used for TDM once validated according to the Expert Consensus on Quality Assurance of Chromatographic Technology for Therapeutic Drug Monitoring (2021 Edition) (Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society et al., 2021) and the 9012 Guidelines for Validation of Quantitative Analysis Methods of Biological Samples ( Chinese Pharmacopoeia Commission, 2020 Chinese Pharmacopoeia Commission, 2020 ). After determination of the concentrations of polymyxins B1 and B2 via LC-MS/MS, the concentration of polymyxin B is calculated and reported in the TDM report. The calculation is based on the molar concentration of polymyxin B and its components according to the following Eq. (1) Eq. (1) : <math display="block" id="M1"><msub><mrow><mi>C</mi></mrow><mrow><mi mathvariant="normal">B</mi></mrow></msub><mo>=</mo><mo stretchy="false">(</mo><msub><mrow><mi>C</mi></mrow><mrow><mi mathvariant="normal">B</mi><mn mathvariant="normal">1</mn></mrow></msub><mo>/</mo><mi mathvariant="normal">M</mi><mi mathvariant="normal">o</mi><msub><mrow><mi mathvariant="normal">l</mi></mrow><mrow><mi mathvariant="normal">B</mi><mn mathvariant="normal">1</mn></mrow></msub><mo>+</mo><msub><mrow><mi>C</mi></mrow><mrow><mi mathvariant="normal">B</mi><mn mathvariant="normal">2</mn></mrow></msub><mo>/</mo><mi mathvariant="normal">M</mi><mi mathvariant="normal">o</mi><msub><mrow><mi mathvariant="normal">l</mi></mrow><mrow><mi mathvariant="normal">B</mi><mn mathvariant="normal">2</mn></mrow></msub><mo stretchy="false">)</mo><mo>×</mo><mi mathvariant="normal">M</mi><mi mathvariant="normal">o</mi><msub><mrow><mi mathvariant="normal">l</mi></mrow><mrow><mi mathvariant="normal">a</mi><mi mathvariant="normal">v</mi><mi mathvariant="normal">g</mi><mi mathvariant="normal">B</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=39691393&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=39691388&type= 60.70600128 4.48733330 , where C B is the total polymyxin B concentration; C B1 and C B2 are the concentrations of polymyxins B1 and B2, respectively; Mol B1 and Mol B2 are the molar weights of polymyxins B1 (1203.48 g/mol) and B2 (1189.45 g/mol), respectively; and Mol avgB is the average molar weight of polymyxin B, calculated based on the amounts of polymyxins B1 and B2 in each batch. It should be noted that this calculation underestimates the polymyxin B concentration by about 15%–20% given that polymyxins B1 and B2 comprise only about 80%–85% of total polymyxin B. 5.4.2　Analyte reference standard 3 It is essential to use qualified standard analytes for quantitative analysis. Due to access or price-limitation issues in obtaining pure standards of polymyxins B1 and B2, mixtures of polymyxin B standard with detailed composition and purity information are alternative choices. If only the polymyxin B sulfate content is indicated in the standard certificate of analysis (COA), concentrations of polymyxin B base should be employed, not the sulphate form. 5.4.3　Self-developed LC-MS/MS method notes 3 Because polymyxins are complex mixtures with similar structures, developing an analysis method is challenging. First, precursor ions with two or three charges are observed in LC-MS/MS for polymyxins B1 and B2. As the intensity responses of polymyxins B1 and B2 with three charges are different from the responses of those with two charges, it is necessary to monitor suitable ion pairs according to the sensitivity of the instrument ( Covelli et al., 2017 Covelli et al., 2017 ; Liu et al., 2020 Liu et al., 2020 ). Second, the high cost of an isotopic internal standard of a single component of synthetic polymyxin B means that structural analogs of polymyxin B, or pure polymyxin E1 or polymyxin E2, are often used as internal standards in reported methods ( Covelli et al., 2017 Covelli et al., 2017 ). However, it should be noted that if a patient is concurrently receiving either colistin sulfate (also known as polymyxin E) or colistimethate—which would generally be administered via nebulization when given concurrently with intravenous polymyxin B—polymyxin E1 or E2 cannot be used as an internal standard and another polymyxin (e.‍g., polymyxin D1) should be used. Finally, the following must be avoided: adsorption of polymyxin B onto glass tubes or plastic products ( Meng et al., 2016 Meng et al., 2016 ); interference (or cross-talk) in ion transitions between polymyxins B1, B2, or the internal standard in LC-MS/MS ( Song, 2011 Song, 2011 ; Covelli et al., 2017 Covelli et al., 2017 ); and carryover from high-concentration (e.g., 10 mg/L) to low-concentration (e.‍g., 0.05 mg/L) samples. Notably, blood samples from patients with baseline diseases and complex concomitants may bring unexpected matrix effects that require attention during analysis ( Furey et al., 2013 Furey et al., 2013 ; Panuwet et al., 2016 Panuwet et al., 2016 ). When matrix effects are observed, the method needs to be re-evaluated and measures need to be taken to minimize these effects, such as optimizing the sample preparation process, optimizing the chromatograph conditions, or applying an isotopic internal standard. 5.5 Calculation of AUC ss, 24 h and C ss, avg 2 After determination of polymyxin B concentrations in blood samples, the TDM target (AUC ss, 24 h or C ss, avg ) can be calculated in either of the following two ways. (1) First-order elimination-based equation method Once the steady-state polymyxin B concentrations immediately before ( C trough ) and after ( C max ) infusion have been received from the testing laboratory, the infusion time ( t infusion ) and dosing interval ( τ ) can be used to calculate the elimination constant ( k e ) using the following Eq. (2) Eq. (2) ( Begg et al., 1995 Begg et al., 1995 ; Pai et al., 2014 Pai et al., 2014 ): <math display="block" id="M2"><msub><mrow><mi>k</mi></mrow><mrow><mi mathvariant="normal">e</mi></mrow></msub><mo>=</mo><mfrac><mrow><mi mathvariant="normal">l</mi><mi mathvariant="normal">n</mi><msub><mrow><mi>C</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">a</mi><mi mathvariant="normal">x</mi></mrow></msub><mo>-</mo><mi mathvariant="normal">l</mi><mi mathvariant="normal">n</mi><msub><mrow><mi>C</mi></mrow><mrow><mi mathvariant="normal">t</mi><mi mathvariant="normal">r</mi><mi mathvariant="normal">o</mi><mi mathvariant="normal">u</mi><mi mathvariant="normal">g</mi><mi mathvariant="normal">h</mi></mrow></msub></mrow><mrow><mi>τ</mi><mo>-</mo><msub><mrow><mi>t</mi></mrow><mrow><mi mathvariant="normal">i</mi><mi mathvariant="normal">n</mi><mi mathvariant="normal">f</mi><mi mathvariant="normal">u</mi><mi mathvariant="normal">s</mi><mi mathvariant="normal">i</mi><mi mathvariant="normal">o</mi><mi mathvariant="normal">n</mi></mrow></msub></mrow></mfrac></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=39691404&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=39691398&type= 32.08866501 8.29733276 . The AUC ss, 24 h is then calculated using either Eq. (3) Eq. (3) or Eqs. 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It should be noted that AUC ss, 24 h estimations based on Eq. (3) Eq. (3) underestimate the AUC ss, 24 h , while estimations based on Eqs. ( 4 4 ) and ( 5 5 ) overestimate the AUC ss, 24 h . The C ss, avg can then be calculated using Eq. (6) Eq. (6) : <math display="block" id="M6"><msub><mrow><mi>C</mi></mrow><mrow><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi><mo>,</mo><mtext> </mtext><mi mathvariant="normal">a</mi><mi mathvariant="normal">v</mi><mi mathvariant="normal">g</mi></mrow></msub><mo>=</mo><mfrac><mrow><mi mathvariant="normal">A</mi><mi mathvariant="normal">U</mi><msub><mrow><mi mathvariant="normal">C</mi></mrow><mrow><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi><mo>,</mo><mtext> </mtext><mn mathvariant="normal">24</mn><mtext> </mtext><mi mathvariant="normal">h</mi></mrow></msub></mrow><mrow><mn mathvariant="normal">24</mn></mrow></mfrac></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=39691440&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=39691437&type= 27.00866890 7.45066643 , where C ss, avg is the average concentration across 24 h at steady state. (2) Population pharmacokinetics (popPK) model and Bayesian prediction method Bayesian posterior algorithms with a well-developed popPK model have been widely used for vancomycin, especially since the development of drug dosing software ( Rybak et al., 2020 Rybak et al., 2020 ). An important advantage of popPK models and Bayesian prediction is that TDM samples can be collected at any time following drug administration. PopPK models for intravenously administered polymyxin B have been developed for a variety of patient groups including critically ill adult patients, cystic fibrosis patients, and patients whose infections are caused by MDR Gram-negative bacteria. These models applied one- and two-compartmental models with first-order linear elimination ( Sandri et al., 2013 Sandri et al., 2013 ; Avedissian et al., 2018 Avedissian et al., 2018 ; Manchandani et al., 2018 Manchandani et al., 2018 ; Miglis et al., 2018 Miglis et al., 2018 ; Wang et al., 2021 Wang et al., 2021 , 2022 2022 ). The most common covariates were creatinine clearance (CrCL) and body weight. PopPK models can be used in conjunction with Bayesian feedback to predict individual pharmacokinetic parameters and calculate C ss, avg or AUC ss, 24 h ( Lunn et al., 2002 Lunn et al., 2002 ; de Velde et al., 2018 de Velde et al., 2018 ). Use of these published popPK models for TDM of polymyxin B needs to be carefully evaluated for both suitability of the patient population and accuracy of the model prediction. While studies that have summarized and evaluated previously published popPK models for polymyxin B have shown that bootstrap or visual predictive checks (VPCs) were satisfactory, external validation showed poor correlation between predicted and observed exposure ( Chen et al., 2021 Chen et al., 2021 , 2022 2022 ; Li et al., 2021 Li et al., 2021 ). The poor predictive value of these models may be due to many uncertainty factors, including the limited sample sizes during model development and external validation, cross-study discrepancy, variation in patient characteristics, and bioassay errors, as well as a lack of understanding of polymyxin B metabolic pathways in vivo. Pooled population pharmacokinetic analyses, large sample sizes, and multi-center prospective clinical studies for popPK or TDM (with central laboratory bioassay analysis) are requisite to resolve the issue. Recommendation 3: Employ the first-order elimination-based equation method to calculate AUC ss, 24 h or C ss, avg when a suitable popPK model is not available. Recommendation level as graded by external experts: strong (45.4%); medium (50.0%); weak (4.6%); not recommended (0%). Recommendation 4: Apply a popPK model and Bayesian feedback to calculate AUC ss, 24 h or C ss, avg . Recommendation level as graded by external experts: strong (54.5%); medium (45.5%); weak (0%); not recommended (0%). 5.6 Biosafety 2 Transport of TDM samples from bedside to testing laboratory must be undertaken in accordance with biosafety requirements, including the use of biosafety transport boxes to prevent samples from being damaged and/or contaminated during transportation (Bielecka, 2018). If the samples are found to be damaged upon arrival at the testing laboratory, the clinical department should be immediately contacted and the samples should be rejected and disposed of correctly. Laboratory personnel also need to be protected from biological hazards in accordance with laboratory safety management regulations during sample processing and testing. 6 ‍‍ Explanation of TDM results and dose adjustment 1 6.1 Dose adjustment based on TDM target 2 TDM reports must include a variety of information including basic patient demographics, the name of the clinical department or unit that requested TDM, the type of tubes (anticoagulant or coagulant) in which the samples were collected, sample-collection time and the time received by the testing laboratory, the serial number or barcode of the samples, the drugs for which TDM was undertaken, testing equipment and methods, test results, and target ranges or reference values. The lower limit of quantification (LLOQ) will be dependent on the self-developed LC-MS/MS method and will differ between laboratories. Concentrations lower than the LLOQ should be reported as “ < lower limit of quantification” ( Duggan, 2019 Duggan, 2019 ); concentrations higher than the upper limit of quantification should be reported either as “ > upper limit of quantification” or alternatively remeasured following appropriate dilution. It is necessary to double-check the consistency between the raw data and the reported tested results with the information listed on the TDM report. It may be necessary to explain abnormal situations. It is recommended that qualified clinical pharmacists make individualized dosing recommendations based on TDM reports and the specific physiological and disease conditions of patients. Recommendation 5: For patients with C ss, avg < 2 mg/L or AUC ss, 24 h < 50 mg·h/L, dose adjustments should be based on clinical and microbiological efficacy. A dosage increase is recommended when the clinical condition of the patient is not improved. Recommendation level as graded by external experts: strong (59.1%); medium (40.9%); weak (0%); not recommended (0%). Recommendation 6: For patients with C ss, avg > 4 mg/L or AUC ss, 24 h > 100 mg·h/L, the dose should be reduced based on TDM results in order to reduce the likelihood of nephrotoxicity. Recommendation level as graded by external experts: strong (68.2%); medium (22.7%); weak (9.1%); not recommended (0%). Due to the potential of nephrotoxicity, dose increases should be considered with much more caution in clinical settings. If good clinical and microbiology efficacy is achieved, then increasing the dose is not necessary even when TDM results were shown lower than the target. However, if the TDM showed results higher than the target, the dose needs to be reduced, even when clinical efficacy is not improved. Other strategies such as synergistic combinations could be considered to improve efficacy. The PK/PD index of polymyxin B is f AUC/MIC, so changing the single dose is more commonly recommended than changing the frequency of administration. Dose adjustment can be undertaken in either of the following two ways. (1) Adjustments can be made using an equation-based method, for example by use of Eq. (7) Eq. (7) ( Begg et al., 1995 Begg et al., 1995 ): <math display="block" id="M7"><mi mathvariant="normal">D</mi><mi mathvariant="normal">o</mi><mi mathvariant="normal">s</mi><msub><mrow><mi mathvariant="normal">e</mi></mrow><mrow><mn mathvariant="normal">2</mn></mrow></msub><mo>=</mo><mfrac><mrow><mi mathvariant="normal">A</mi><mi mathvariant="normal">U</mi><msub><mrow><mi mathvariant="normal">C</mi></mrow><mrow><mi mathvariant="normal">t</mi><mi mathvariant="normal">a</mi><mi mathvariant="normal">r</mi><mi mathvariant="normal">g</mi><mi mathvariant="normal">e</mi><mi mathvariant="normal">t</mi><mi mathvariant="normal">e</mi><mi mathvariant="normal">d</mi></mrow></msub></mrow><mrow><mi mathvariant="normal">A</mi><mi mathvariant="normal">U</mi><msub><mrow><mi mathvariant="normal">C</mi></mrow><mrow><mi mathvariant="normal">o</mi><mi mathvariant="normal">b</mi><mi mathvariant="normal">s</mi><mi mathvariant="normal">e</mi><mi mathvariant="normal">r</mi><mi mathvariant="normal">v</mi><mi mathvariant="normal">e</mi><mi mathvariant="normal">d</mi></mrow></msub></mrow></mfrac><mo>×</mo><mi mathvariant="normal">D</mi><mi mathvariant="normal">o</mi><mi mathvariant="normal">s</mi><msub><mrow><mi mathvariant="normal">e</mi></mrow><mrow><mn mathvariant="normal">1</mn></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=39691448&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=39691445&type= 42.50266647 8.21266651 , where Dose 2 is the target adjustment dose; AUC targeted is the targeted area under the plasma concentration-time curve; AUC observed is the calculated area under the plasma concentration-time curve based on TDM; and Dose 1 is the initial maintenance dose. (2) Alternatively, adjustments can be made based on a popPK model and dosing predictions with Bayesian predictions ( Roberts et al., 2011 Roberts et al., 2011 ). 6.2 Dose adjustment based on PK/PD 2 When individualized medication recommendations are made based on PK/PD calculations, it is important to consider the MIC of the infecting pathogen(s). Dose adjustment is based on a probability of target attainment (PTA) of ≥90%. PTAs are calculated through Monte Carlo simulations of the PK/PD index ( f AUC/MIC) that are equal to or greater than the PK/PD targets for different pathogens, such as A. baumannii , P. aeruginosa , or K. pneumoniae . Notably, the MIC measurements are influential elements for PTA calculations and the accuracy of MIC results is important for dose adjustment. The recommended method for determining susceptibility to polymyxin B (i.e., MIC determination) is broth microdilution rather than agar dilution ( Pogue et al., 2020 Pogue et al., 2020 ). If a different susceptibility-testing method is used, the results generated need to be compared with those from broth microdilution and validated accordingly. Only MIC results from suitably validated methods should be accepted. In addition, it should be noted that even if broth microdilution is used for MIC determination, this method has a margin of error of ±1 dilution. Hence, when calculating PK/PD targets, errors in MIC determination should be considered and clinical responses should be monitored when making dose adjustments ( Fratoni et al., 2021 Fratoni et al., 2021 ). 7 Quality control and assurance 1 Quality control and assurance measures for TDM of polymyxin B need to take into consideration the TDM management system, analysis methods, and clinical intervention related to TDM. The management system requires procedures for the implementation of TDM including personnel management, relevant technical documents, standard operating practices, and clinical intervention guidelines to ensure the progress of TDM. The cooperation of clinicians, nurses, laboratory analysts, and clinical pharmacists is required to ensure that all TDM processes such as dosing records, sampling, inspection, testing, and reporting are correctly followed and double-checked, and can be traced back for further investigation and clarification when necessary. For testing laboratories, it is necessary to regularly calibrate the relevant testing equipment and offer appropriate training and assessment to the analysts. Daily intra- and inter-laboratory quality controls are needed to avoid random or systematic errors during analysis. When assessing the intra-laboratory quality control of polymyxin B, it is important to follow the requirements laid out in quality-control charts or in the 9012 Guidelines for Validation of Quantitative Analysis Methods for Biological Samples ( Chinese Pharmacopoeia Commission, 2020 Chinese Pharmacopoeia Commission, 2020 ). At least two quality-control samples at each of three concentrations (low, medium, and high) should be incorporated into daily analysis. In exceptional circumstances such as instrument failure or quality-control deviation, it is important to analyze the potential causes and take appropriate measures such as re-injection, re-assignment of quality control, or re-calibration. Inter-laboratory comparison of polymyxin B should be carried out to avoid systematic errors affecting clinical practice. For other quality-assurance concerns, the Expert Consensus on the Standards of Therapeutic Drug Monitoring (2019 Edition) (Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society, 2019), the Expert Consensus on the Interpretation of Therapeutic Drug Monitoring (Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society et al., 2020), and the Expert Consensus on Quality Assurance of Chromatographic Technology for Therapeutic Drug Monitoring (2021 Edition) (Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society et al., 2021) should be consulted. Terminology AUC ss, 24 h : an area under the total plasma concentration-time curve across 24 h at steady state, which reflects in vivo drug exposure after administration of multiple doses of a certain drug. Concentration-dependent killing: antibacterial activity correlated with peak concentrations or exposure to a drug. Monte Carlo simulations: a mathematical method for estimating the possibility of likely outcomes of an event based on a range of input values, which is applied to pharmacokinetic/pharmacodynamic (PK/PD) simulations to calculate the probability of PK/PD target attainment and to assess antibacterial dosing regimens. MIC (minimum inhibitory concentration): the lowest concentration of antibacterial agents able to inhibit the visible growth of bacteria in vitro. popPK (population pharmacokinetics): an approach to studying the variabilities in drug concentrations within a patient population receiving a certain drug in clinics. TDM (therapeutic drug monitoring): an important approach to individualized or precision dosing through maintaining plasma or blood drug concentration within the therapeutic window of a certain drug, which has become a multidisciplinary collaborative project among testing laboratorians, clinical pharmacists, and physicians, with the aim of optimal dosing. 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Nephrotoxicity of polymyxins: is there any difference between colistimethate and polymyxin B? Antimicrob Agents Chemother , 61 ( 3 ): e02319-16 . https://doi.org/10.1128/aac.02319-16 https://doi.org/10.1128/aac.02319-16 Nephrotoxicity of polymyxins: is there any difference between colistimethate and polymyxin B? Zavascki AP , Goldani LZ , Cao GY , et al. , 2008 . Pharmacokinetics of intravenous polymyxin B in critically ill patients . Clin Infect Dis , 47 ( 10 ): 1298 - 1304 . https://doi.org/10.1086/592577 https://doi.org/10.1086/592577 Pharmacokinetics of intravenous polymyxin B in critically ill patients Zhang XJ , Qi SY , Duan XG , et al. , 2021 . Clinical outcomes and safety of polymyxin B in the treatment of carbapenem-resistant Gram-negative bacterial infections: a real-world multicenter study . J Transl Med , 19 ( 1 ): 431 . https://doi.org/10.1186/s12967-021-03111-x https://doi.org/10.1186/s12967-021-03111-x Clinical outcomes and safety of polymyxin B in the treatment of carbapenem-resistant Gram-negative bacterial infections: a real-world multicenter study Xiaofen LIU, Chenrong HUANG, and Phillip J. BERGEN wrote and edited the manuscript. Liyan MIAO and Jing ZHANG initiated the consensus. Jian LI, Jingjing ZHANG, Yijian CHEN, Yongchuan CHEN, Beining GUO, Fupin HU, Jinfang HU, Linlin HU, Xin LI, Hongqiang QIU, Hua SHAO, Tongwen SUN, Yu WANG, Ping XU, Jing YANG, Yong YANG, Zhenwei YU, Bikui ZHANG, Huaijun ZHU, Xiaocong ZUO, Yi ZHANG, Liyan MIAO, and Jing ZHANG were consensus panel. All authors have read and approved the final manuscript. This work was supported by the Shanghai Leading Talents Award, Shanghai Municipal Health Commission (No. LJ2016-01) and the Clinical Research Plan of Shanghai Hospital Development Center (No. SHDC2022CRW004). We thank Yalin DONG (the First Affiliated Hospital of Xi’an Jiaotong University), Zhanjun DONG (Hebei General Hospital), Dong LIU (Tongji Medical College of Huazhong University of Science and Technology), Maobai LIU (Fujian Medical University Union Hospital), Xuemei LUO (Nanjing Drum Tower Hospital), Xueyan LIU (Shenzhen People’s Hospital), Suiqin NI (Guangzhou First People’s Hospital), Qi PEI (the Third Xiangya Hospital of Central South University), Yi QIN (the First Affiliated Hospital of Soochow University), Jingwen WANG (Xijing Hospital), Li WEI (the First Affiliated Hospital of Guangzhou Medical University), Yanzhe XIA (the First Affiliated Hospital, Sun Yat-sen University), Hengjie YUAN (Tianjin Medical University General Hospital), Mingjie YU (the Southwest Hospital of Army Medical University), Qiwen YANG (Peking Union Medical College Hospital), Xiuling YANG (the Second Hospital of Hebei Medical University), Yuetian YU (Renji Hospital, School of Medicine, Shanghai Jiao Tong University), Chunhong ZHANG (the First Affiliated Hospital of Wenzhou Medical University), Kanghuai ZHANG (the Second Affiliated Hospital of Xi’an Jiaotong University), Pengcheng ZHENG (the First People’s Hospital of Yunnan Province), Suodi ZHAI (Peking University Third Hospital), Xianglin ZHANG (China-Japan Friendship Hospital), and Xiaojian ZHANG (the First Affiliated Hospital of Zhengzhou University) for providing expert reviews and suggestions. 10.1631/jzus.B2200466 1673-1581（2023）02-0130-13 刘笑芬,黄晨蓉,Phillip J. BERGEN等.多黏菌素B治疗药物监测专家共识：中国药理学会治疗药物监测研究专业委员会及上海市医学会感染与化疗专科分会发起制定[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(02):130-142. 刘笑芬,黄晨蓉,Phillip J. BERGEN等.多黏菌素B治疗药物监测专家共识：中国药理学会治疗药物监测研究专业委员会及上海市医学会感染与化疗专科分会发起制定[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(02):130-142. This work was supported by the Shanghai Leading Talents Award, Shanghai Municipal Health Commission (No. LJ2016-01) and the Clinical Research Plan of Shanghai Hospital Development Center (No. SHDC2022CRW004). 2022-09-20 2022-12-04 2023-02-15 2023-02-09 2022-12-21 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2023 浙江大学出版社 Jian LI licensed his new peptide antibiotics to Qpex Biopharma and has received research grants, speaking honoraria and consulting fees from Northern Antibiotics, Avexa, Genentech, Healcare, CTTQ, MedCom, Jiayou Medicine, Aosaikang, DanDi BioScience, and Qpex Biopharma. Xiaofen LIU, Chenrong HUANG, Phillip J. BERGEN, Jingjing ZHANG, Yijian CHEN, Yongchuan CHEN, Beining GUO, Fupin HU, Jinfang HU, Linlin HU, Xin LI, Hongqiang QIU, Hua SHAO, Tongwen SUN, Yu WANG, Ping XU, Jing YANG, Yong YANG, Zhenwei YU, Bikui ZHANG, Huaijun ZHU, Xiaocong ZUO, Yi ZHANG, Liyan MIAO, and Jing ZHANG declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 2 24