Optimizing Dosing of Colistin for Infections Resistant to all Other Antibiotics

优化粘菌素治疗对所有其他抗生素耐药的感染的剂量

• 批准号: 8141270
• 负责人: Fernanda P. Silveira
• 金额: $ 77.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141270
• 关键词: Acinetobacter; Address; Affect; Anti-Bacterial Agents; Antibiotics; Area; Asia; Bacillus (bacterium); Bacteria; Bacterial Infections; Biological Assay; Carbapenems; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Colistimethate sodium; Colistin; Comorbidity; Country; Critical Illness; Daptomycin; Data; Development; Dialysis procedure; Dimensions; Disease Outbreaks; Dose; Drug Kinetics; Epithelial; Europe; Exposure to; FDA approved; Future; Genus staphylococcus; Goals; Gram-Negative Bacteria; Hemodialysis; High Pressure Liquid Chromatography; Hospitals; Human; Imipenem; Infection; Institution; Intensive Care Units; Intravenous; Iraq; Klebsiella; Klebsiella pneumonia bacterium; Lead; Linezolid; Liquid substance; Lung; Measures; Meropenem; Mesylates; Military Personnel; Monobactams; Multi-Drug Resistance; Organ failure; Organism; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase III Clinical Trials; Physicians; Plasma; Pneumonia; Polymyxin Resistance; Polymyxins; Population; Principal Investigator; Process; Pseudomonas aeruginosa; Public Health; Recommendation; Regimen; Renal Replacement Therapy; Renal function; Research; Research Personnel; Resistance; Resistance development; Serum; Site; South America; Staging; Stimulus; Techniques; Testing; Therapeutic; Time; Toxic effect; United States; Vancomycin Resistance; Vancomycin resistant enterococcus; abstracting; bacterial resistance; base; clinical efficacy; cohort; dalbavancin; doripenem; dosage; drug efficacy; economic cost; experience; mathematical model; nephrotoxicity; neurotoxicity; novel therapeutics; pathogen; pharmacokinetic characteristic; pre-clinical; primary outcome; programs; resistant strain; response; simulation; telavancin; therapy duration; tigecycline; treatment duration

DESCRIPTION (provided by applicant): Infections with Gram negative bacilli resistant to all antibiotics except colistin have become increasingly common. This is a worldwide problem, with substantial issues being noted in South America and Asia. No new antibiotic classes with activity against these resistant Gram negative organisms are likely to be commercially available in the next 5 years. Yet, the pharmacokinetics (PK) of the only remaining antibiotic option, colistin, were studied in the 1960s when many of the modern principles of antibiotic dosing were not known. The Product Information of the drug suggests dosing regimens which may not be optimal for the management of serious infections. Furthermore, many patients with multiply resistant Gram negative infections are critically ill requiring renal replacement therapy and the Product Information gives no recommendations for dosing in this scenario. Although most physicians refer to "colistin", the only form available for intravenous use is sodium colistin methanesulfonate (CMS). In the body, CMS is partially hydrolyzed to colistin. CMS and colistin differ in their antibacterial and PK characteristics. We were the first to develop HPLC assays which can separately measure both CMS and colistin. We aim to measure the levels of CMS and generated colistin in plasma in all patients and at the site of infection in patients with pneumonia (lung epithelial lining fluid) in a multicenter cohort of 238 patients. We will also measure the clearance of CMS and colistin in those patients in the cohort who are undergoing dialysis or continuous renal replacement therapy. We will determine outcome of these patients and correlate outcome with pharmacodynamic parameters such as the ratio of area under the plasma concentration-time curve:minimal inhibitory concentration (MIC) or peak concentration:MIC. The primary outcome measures will be bacteriologic and clinical response. Mathematical modeling techniques such as Monte Carlo simulation will be used to integrate the PK/PD and outcome data in order to establish optimal dosing regimens. Resistance or intolerance to CMS/colistin leaves physicians with no antibiotic options - therefore, we will secondarily explore the relationships between PK, treatment duration and patient characteristics on resistance to colistin or advent of toxicity.

描述（由申请人提供）：对除粘菌素之外的所有抗生素具有耐药性的革兰氏阴性杆菌感染已变得越来越普遍。这是一个世界性问题，南美和亚洲也注意到了重大问题。未来 5 年内，可能不会有针对这些耐药革兰氏阴性微生物的新抗生素类别上市。然而，仅存的抗生素选择粘菌素的药代动力学 (PK) 是在 20 世纪 60 年代进行的研究，当时许多现代抗生素给药原则尚不清楚。该药物的产品信息建议的给药方案可能不是治疗严重感染的最佳方案。此外，许多患有多重耐药革兰氏阴性菌感染的患者病情危重，需要肾脏替代治疗，并且产品信息没有给出这种情况下的剂量建议。尽管大多数医生提到“粘菌素”，但唯一可用于静脉注射的形式是粘菌素甲磺酸钠 (CMS)。在体内，CMS 部分水解为粘菌素。 CMS 和粘菌素的抗菌和 PK 特性不同。我们率先开发了 HPLC 检测方法，可以分别测量 CMS 和粘菌素。我们的目标是在一个由 238 名患者组成的多中心队列中测量所有患者血浆中以及肺炎患者（肺上皮内层液）感染部位的 CMS 和生成的粘菌素水平。我们还将测量队列中正在接受透析或连续肾脏替代治疗的患者中 CMS 和粘菌素的清除率。我们将确定这些患者的结果，并将结果与​​药效学参数相关联，例如血浆浓度-时间曲线下面积比：最低抑菌浓度（MIC）或峰浓度：MIC。主要结果指标是细菌学和临床反应。蒙特卡罗模拟等数学建模技术将用于整合 PK/PD 和结果数据，以建立最佳给药方案。对 CMS/粘菌素的耐药性或不耐受使医生没有抗生素选择 - 因此，我们将其次探讨 PK、治疗持续时间和患者特征对粘菌素耐药或出现毒性之间的关系。

项目成果

Reply to Corona and Cattaneo.

回复科罗娜和卡塔内奥。

• DOI: 10.1093/cid/cix390
• 发表时间: 2017
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Nation,RogerL;Garonzik,SamiraM;Thamlikitkul,Visanu;Giamarellos-Bourboulis,EvangelosJ;Forrest,Alan;Paterson,DavidL;Li,Jian;Silveira,FernandaP
• 通讯作者: Silveira,FernandaP

Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform?

• DOI: 10.1093/cid/civ964
• 发表时间: 2016-03-01
• 期刊: CLINICAL INFECTIOUS DISEASES
• 影响因子: 11.8
• 作者: Nation, Roger L.;Garonzik, Samira M.;Silveira, Fernanda P.
• 通讯作者: Silveira, Fernanda P.

Drug release from nanomedicines: Selection of appropriate encapsulation and release methodology.

• DOI: 10.1007/s13346-012-0064-4
• 发表时间: 2012-08
• 期刊: DRUG DELIVERY AND TRANSLATIONAL RESEARCH
• 影响因子: 5.4
• 作者: Wallace, Stephanie J.;Li, Jian;Nation, Roger L.;Boyd, Ben J.
• 通讯作者: Boyd, Ben J.

Design, synthesis, and evaluation of a new fluorescent probe for measuring polymyxin-lipopolysaccharide binding interactions.

• DOI: 10.1016/j.ab.2010.10.033
• 发表时间: 2011-02-15
• 期刊: Analytical biochemistry
• 影响因子: 2.9
• 作者: Soon RL;Velkov T;Chiu F;Thompson PE;Kancharla R;Roberts K;Larson I;Nation RL;Li J
• 通讯作者: Li J

Molecular basis for the increased polymyxin susceptibility of Klebsiella pneumoniae strains with under-acylated lipid A.

• DOI: 10.1177/1753425912459092
• 发表时间: 2013-06
• 期刊: Innate immunity
• 影响因子: 3.2
• 作者: Velkov T;Soon RL;Chong PL;Huang JX;Cooper MA;Azad MA;Baker MA;Thompson PE;Roberts K;Nation RL;Clements A;Strugnell RA;Li J
• 通讯作者: Li J