Use of site-specific pharmacokinetics to optimize antibiotic combinations and prevent the emergence of resistance against CRE

利用位点特异性药代动力学优化抗生素组合并防止出现 CRE 耐药性

• 批准号: 10307115
• 负责人: Ryan K Shields
• 金额: $ 19.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-24 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307115
• 关键词: Address; Antibiotics; Bacteremia; Carbapenems; Ceftazidime; Cell Membrane Permeability; Characteristics; Clinic; Clinical; Clinical Management; Clinical Research; Cloning; Combined Antibiotics; Combined Modality Therapy; Complement; Data; Development; Dose; Drug Kinetics; Effectiveness; Enterobacter cloacae; Enterobacteriaceae Infections; Enzymes; Epidemic; Epithelial; Escherichia coli; Fiber; Fosfomycin; Frequencies; Future; Gene Mutation; Genes; Imipenem; In Vitro; Infection; Klebsiella pneumoniae; Knowledge; Laboratories; Liquid substance; Measurement; Meropenem; Modeling; Molecular; Mus; Mutation; Observational Study; Patient-Focused Outcomes; Patients; Pneumonia; Positioning Attribute; Predisposition; Prevalence; Public Health; Regimen; Reporting; Resistance; Resistance development; Reverse Transcription; Safety; Sequence Analysis; Serum; Site; Testing; Therapeutic; Time; Toxic effect; Translating; Treatment Protocols; United States Food and Drug Administration; VDAC1 gene; Variant; Vertebral column; antimicrobial; beta-Lactamase; beta-Lactams; carbapenem-resistant Enterobacteriaceae; carbapenemase; clinically relevant; effective therapy; efficacy testing; improved; in vitro activity; in vivo Model; inhibitor; mutant; novel; pathogen; pneumonia model; prevent; resistance mechanism; simulation; success; treatment duration; treatment optimization; treatment strategy; whole genome

ABSTRACT Carbapenem-resistant Enterobacteriaceae (CRE) continue to be a global public health threat and priority for antimicrobial development efforts. Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) is the predominant pathogen; however, prevalence rates have decreased in endemic regions resulting in a more diverse CRE landscape that includes both KPC and non-KPC producing pathogens. Ceftazidime-avibactam (CAZ-AVI), a novel β-lactam/β-lactamase inhibitor (BL/BLI) that has become the front- line treatment of CRE infections, resulting in superior efficacy and safety compared to prior salvage regimens. Despite these encouraging findings, CAZ-AVI resistance emerged in 10% of patients following courses of 7 – 19 days. We identified mutations in blaKPC-3 encoding variant KPC-3 enzymes responsible for resistance. Variant KPC enzymes displayed reverted susceptibility to carbapenems. Two newer BL/BLI agents, meropenem- vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL) feature a carbapenem backbone that may provide stability against blaKPC mutations; however, we have showed that their activity against CRE is compromised by porin gene mutations that decrease outer membrane permeability. It is unclear how frequently resistance will emerge to each of the new BL/BLI agents. Antibiotic combination therapy is a common strategy to treat CRE infections; however, ideal BL/BLI combination regimens are not defined, nor are dosing regimens that optimize activity and reduce the selection of resistant mutants. Our primary objectives in this project are to understand mechanisms by which CRE develop resistance to CAZ-AVI, MER-VAB, and IMI-REL, and to identify strategies that effectively suppress the emergence of resistance. To accomplish these objectives we will investigate new and previously defined resistance mechanisms and suppression of resistance by partnering BL/BLI agents with other recently-approved agents that offer complimentary mechanisms or dual BL agents with each BLI. In specific aim 1, we will determine the frequency (aim 1a) and mechanisms (aim 1b) by which resistance emerges against BL/BLI agents in a dynamic hollow-fiber infection model. BL/BLI exposures will be modeled using serum and epithelial lining fluid (ELF) pharmacokinetics that are achieved during bacteremia and pneumonia, respectively. In specific aim 2, we will define BL/BLI combination regimens that suppress the emergence of resistance in hollow-fiber (aim 2a) and murine pneumonia (aim 2b) models. To do so, we will screen novel combination regimens in time-kill analyses by partnering BL/BLI agents with eravacycline, fosfomycin, and plazomicin, or CAZ-AVI plus MER or IMI and CAZ plus MER-VAB or IMI-REL. The most active combinations will be validated against representative CRE clinical isolates with diverse mechanisms. The results of this study will generate timely, clinically-relevant data that provides new information on optimized treatment regimens in the face of a rapidly changing CRE landscape. Moreover, we will define novel mechanisms of resistance, and use these data to better define the therapeutic niche of each newly-approved, CRE-active agent.

摘要 耐碳青霉烯类肠杆菌科细菌(CRE)继续成为全球公共卫生威胁和优先考虑的 抗菌药物的开发工作。产碳青霉烯酶(KPC)肺炎克雷伯菌 肺炎(KPC-KP)是主要病原体；然而，地方性肺炎的患病率有所下降。 这些地区造成了更多样化的CRE景观，其中既包括KPC病原体，也包括非KPC病原体。 头孢他啶-阿维巴坦(CAZ-AVI)是一种新型的β-内酰胺/β-内酰胺酶抑制剂(BLI/BLI)，已成为临床应用的前沿药物 Cre感染的直线治疗，与以前的抢救方案相比，产生了更好的疗效和安全性。 尽管有这些令人鼓舞的发现，10%的患者在7-19疗程后出现了CAZ-AVI耐药性 几天。我们鉴定了blaKPC-3编码变异的KPC-3酶的突变，该酶与耐药性有关。变体 KPC酶对碳青霉烯类具有逆转的敏感性。两个新的BL/BLI特工，美罗培南- 瓦博巴坦(Mer-VAB)和亚胺培南-释放巴坦(IMI-Rel)的特点是碳青霉烯类主干可以 提供对blaKPC突变的稳定性；然而，我们已经表明它们对Cre的活性是 受到降低外膜通透性的孔蛋白基因突变的影响。目前还不清楚多久一次 对每一种新的BL/BLI特工都会产生抗药性。抗生素联合治疗是一种常见的策略 治疗Cre感染；然而，理想的BL/BLI联合方案没有定义，剂量方案也没有定义 这优化了活性，减少了抗性突变体的选择。我们在这个项目中的主要目标是 了解Cre对Caz-AVI、mer-VAB和IMI-Rel产生抗性的机制，并识别 有效抑制抵抗出现的策略。为了实现这些目标，我们将 研究新的和以前定义的抗性机制和通过伙伴关系抑制抗性 BL/BLI代理与其他最近批准的提供免费机制的代理或具有 每个BLI。在具体目标1中，我们将确定频率(目标1a)和机制(目标1b) 在一个动态的中空纤维感染模型中，出现了对BL/BLI病毒的耐药性。BL/BLI曝光将是 使用血清和上皮衬里液体(ELF)药代动力学建模，这些药代动力学是在菌血症和 分别为肺炎。在具体目标2中，我们将定义BL/BLI联合方案，以抑制 在中空纤维(Aim 2a)和小鼠肺炎(Aim 2b)模型中出现耐药性。要做到这一点，我们将 通过将BL/BLI制剂与伊拉瓦环素配对，在时间杀灭分析中筛选新的组合方案， 磷霉素、平阳霉素或CAZ-AVI+Mer或IMI+CAZ+Mer-VAB或IMI-Rel。最活跃的 组合将针对具有不同机制的代表性CRE临床分离株进行验证。结果是 这项研究将产生及时的临床相关数据，为优化治疗提供新的信息 在面对快速变化的CRE景观时的养生。此外，我们还将定义新的机制 耐药性，并使用这些数据更好地定义每一种新批准的CRE活性药物的治疗利基。

项目成果

Cefiderocol for the Treatment of Infections Due to Metallo-B-lactamase-Producing Pathogens in the CREDIBLE-CR and APEKS-NP Phase 3 Randomized Studies.

• DOI: 10.1093/cid/ciac078
• 发表时间: 2022-09-29
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials.

• DOI: 10.1089/mdr.2021.0180
• 发表时间: 2022-04
• 期刊: MICROBIAL DRUG RESISTANCE
• 影响因子: 2.6
• 作者: Nordmann, Patrice;Shields, Ryan K.;Doi, Yohei;Takemura, Miki;Echols, Roger;Matsunaga, Yuko;Yamano, Yoshinori
• 通讯作者: Yamano, Yoshinori

Ceftolozane/tazobactam for refractory P. aeruginosa endocarditis: A case report and pharmacokinetic analysis.

头孢特洛嗪/他唑巴坦治疗难治性铜绿假单胞菌心内膜炎：病例报告和药代动力学分析。

• DOI: 10.1016/j.jiac.2021.08.013
• 发表时间: 2022
• 期刊: Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy
• 作者: Shah,Sunish;Bremmer,DerekN;Kline,EllenG;Nicolau,DavidP;Shields,RyanK
• 通讯作者: Shields,RyanK

Oxacillin plus ertapenem combination therapy leads to rapid blood culture clearance and positive outcomes among patients with persistent MSSA bacteraemia: a case series.

• DOI: 10.1093/jacamr/dlab148
• 发表时间: 2021-09
• 期刊: JAC-antimicrobial resistance
• 影响因子: 3.4
• 作者: El-Dalati S;Sridaran S;Uricchio M;Kline EG;Shields R
• 通讯作者: Shields R

Contemporary Perspective on the Treatment of Acinetobacter baumannii Infections: Insights from the Society of Infectious Diseases Pharmacists.

• DOI: 10.1007/s40121-021-00541-4
• 发表时间: 2021-12
• 期刊: Infectious diseases and therapy
• 影响因子: 5.4
• 作者: Abdul-Mutakabbir JC;Griffith NC;Shields RK;Tverdek FP;Escobar ZK
• 通讯作者: Escobar ZK