A Novel Combination Therapy to Treat Biofilm-based Pneumonia Infections
治疗生物膜肺炎感染的新型联合疗法
基本信息
- 批准号:9888308
- 负责人:
- 金额:$ 27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-06 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAgeAnimal ModelAnti-Bacterial AgentsAntibiotic ResistanceAntibiotic TherapyAntibioticsBacteriaBacterial InfectionsBacteriologyBronchiBronchiectasisCessation of lifeChronicChronic Obstructive Airway DiseaseClinicClinicalCombined AntibioticsCombined Modality TherapyCommunicable DiseasesCoughingCoupledCystic FibrosisDataDiagnosisDiseaseDoseDrug CombinationsDrug KineticsEconomic BurdenEnsureEvaluationExhibitsFormulationFoundationsHealthcare SystemsHospitalizationInfectionInflammationInflammatory ResponseInhalationInheritedLaboratoriesLeadLength of StayLicensingLungLung diseasesLung infectionsMichiganMicrobeMicrobial BiofilmsMicrobiologyMorbidity - disease rateMusNebulizerNewly DiagnosedOutcomePatientsPersonsPharmaceutical PreparationsPharmacodynamicsPhasePneumoniaPowder dose formPremature MortalityPrevalenceProductionProton-Motive ForcePseudomonas aeruginosaPulmonary PathologyQuality of lifeRecurrenceResearchResistanceRespiratory Tract InfectionsSafetySmall Business Innovation Research GrantSputumTechnologyTherapeuticTissuesTobramycinToxic effectToxicologyTreatment EfficacyTreatment outcomeTriclosanUnited StatesUniversitiesWaterantibiotic toleranceantimicrobialantimicrobial drugbasechronic infectionclinical developmentcostcystic fibrosis infectioncystic fibrosis patientsdesigneffective therapyefflux pumpexperienceexperimental studyhigh throughput screeninghospitalization ratesimprovedin vitro activityin vivolung basal segmentmedication safetymeetingsmortalitynovelnovel therapeutic interventionpatient registrypharmacokinetics and pharmacodynamicspre-clinicalpreclinical efficacypreclinical studypreventproduct developmentpulmonary functionresponsesafety studysmall moleculesurvival prediction
项目摘要
Abstract
Bronchiectasis is a lung pathology characterized by a permanent dilation of the bronchi and is associated with a
chronic cough, sputum production and recurrent respiratory infections. Cystic fibrosis (CF) is one of the best
understood inherited conditions that leads to progressive bronchiectasis, chronic bacterial infection and
premature mortality. Both non-CF bronchiectasis (NCFB) and CF have increased in prevalence and present a
significant burden on healthcare systems worldwide, with an estimated prevalence of NCFB of about 213 cases
per 100,000 persons. These data suggest that between 340,000 and 522,000 adults were receiving treatment
for NCFB in 2013 and that 70,000 adults were newly diagnosed that year. CF, affects 70,000 people worldwide.
Both CF and NCFB are associated with bacterial biofilms, which are difficult to clear with standard antibiotics as
bacteria residing in a biofilm have increased basal resistance or tolerance to antibiotics, often at 1000X the level
of their planktonic counterparts. Therefore, many biofilm-based infections, such as CF and NCFB, are never
cleared by antibiotic therapy, and chronic infections are now recognized as a biofilm-based disease. Developing
new therapeutic interventions that potentiate the ability of antibiotics to sterilize biofilms would be highly
significant in the clinic to prevent and resolve these infections.
This Phase I SBIR proposes experiments to further develop a novel antimicrobial combination therapeutic for
the treatment of CF and NCFB by pulmonary delivery. We previously designed and carried out a high-throughput
screen to identify small molecules that enhances tobramycin killing of P. aeruginosa biofilms. This screen led us
to discover that the commonly used antimicrobial agent triclosan, when combined with tobramycin, increases
biofilm eradication by over 100-fold compared to either treatment alone. This combination also shows activity
against Gram-positive biofilm formers. Based on the extensive safety studies of triclosan and an acceptable
safety profile, this combination, delivered directly to the lung, has significant clinical potential. Our team of the
Waters laboratory at Michigan State University and the TSRL Preclinical Accelerator brings together diverse
expertise in biofilm formation, animal models of efficacy, PK/PD studies, and product development to perform
the pre-clinical studies necessary to initiate a pre-IND meeting with the FDA.
抽象的
支气管扩张是一种肺病理学,其特征是对支气管的永久解释,与A有关
慢性咳嗽,痰液产生和复发性呼吸道感染。囊性纤维化(CF)是最好的之一
了解导致进行性支气管扩张,慢性细菌感染和的遗传条件
过早死亡。非CF支气管平(NCFB)和CF的患病率都增加并呈现
全球医疗保健系统的大量燃烧,估计NCFB的患病率约为213例
每10万人。这些数据表明,有340,000至522,000名成年人接受治疗
对于NCFB而言,2013年和当年有70,000名成年人被新诊断出来。 CF,全世界有70,000人。
CF和NCFB都与细菌生物膜有关,标准抗生素很难清除
居住在生物膜中的细菌具有碱性或对抗生素的耐受性的提高,通常在1000倍的水平下
他们的浮游物。因此,许多基于生物膜的感染,例如CF和NCFB,从来都不是
通过抗生素疗法清除,慢性感染现在被认为是一种基于生物膜的疾病。发展
新的理论干预措施潜在抗生素刻板印象生物膜的能力将是高度的
在诊所中有意义,以预防和解决这些感染。
这一阶段I SBIR提案实验,以进一步开发一种新型的抗菌组合疗法
通过肺部递送对CF和NCFB的处理。我们以前设计并进行了高通量
屏幕以鉴定小分子,从而增强铜绿假单胞菌生物膜杀死毒素。这个屏幕引导我们
为了发现常用使用的抗菌剂三氯生成与毒素相结合时,会增加
与单独的任何一种治疗相比,生物膜根除超过100倍。这种组合还显示了活动
针对革兰氏阳性生物膜形成。基于对三氯生的广泛安全研究和可接受的
这种组合直接传递到肺部具有巨大的临床潜力。我们的团队
密歇根州立大学和TSRL临床前加速器的沃特斯实验室汇集了潜水员
生物膜形成,效率动物模型,PK/PD研究和产品开发的专业知识以执行
启动与FDA预先开会的临床前研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Elke Lipka其他文献
Elke Lipka的其他文献
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