De facto monotherapy during multidrug TB treatment and emergence of resistance

多药结核病治疗期间事实上的单一疗法和耐药性的出现

• 批准号: 8708403
• 负责人: David Alland
• 金额: $ 80.27万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708403
• 关键词: Bacillus (bacterium); Bacterial Genes; Characteristics; Chronic; Clinical; Combined Modality Therapy; Computer Simulation; DNA Damage; Development; Disease Resistance; Dose; Drug Combinations; Drug Design; Drug Exposure; Drug Kinetics; Drug Resistant Tuberculosis; Drug effect disorder; Drug resistance; Drug-sensitive; Ensure; Ethambutol; Evolution; Extreme drug resistant tuberculosis; Fluoroquinolones; Frequencies; Future; Genetic; Genetic Polymorphism; Germ; Granuloma; Human; Image; In Vitro; Individual; Individual Differences; Integration Host Factors; Kinetics; Lesion; Link; Mass Spectrum Analysis; Measures; Mediating; Microbiology; Modeling; Moxifloxacin; Mutagenesis; Mutation; Mycobacterium tuberculosis; Necrosis; Nitroimidazoles; Oryctolagus cuniculus; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Predisposition; Pyrazinamide; Reading; Regimen; Relative (related person); Research; Resistance; Resistance development; Rifampin; Risk; Route; Schedule; Severity of illness; Solid; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Streptomycin; Testing; Translating; Tuberculosis; Vertebral column; Wit; Work; active method; base; clinically relevant; design; drug distribution; fitness; in vivo; isoniazid; microbial host; pathogen; pharmacodynamic model; pharmacokinetic model; pill; prevent; programs; public health relevance; research study; tuberculosis treatment

DESCRIPTION (provided by applicant): Uncomplicated drug-sensitive tuberculosis (TB) must be treated with up to four drugs to prevent emergence of drug resistance. Yet, resistance is on the rise, with multi-drug and extensively-drug resistant cases increasing globally. Poor compliance due to a large pill burden and lengthy therapy has been largely blamed for the escalation of drug-resistant TB. While this is probably a contributing factor, it is likely that fators intrinsic to the host and pathogen also drive the emergence of drug resistance. Our proposed research will investigate the contribution of the following four factors to the development of drug resistance at the level of the TB lesion: (i) clinical Mycobacterium tuberculosis (Mtb) strains wit mutations that produce small increases in MIC which are well below MIC cutoffs that usually identify drug resistance; (ii) inter-patient variability in drug exposure; (iii) heterogeneous drug distribution within lesion compartments; and (iv) drug induced mutagenesis. We propose to determine how these factors interact to create de facto monotherapy in selected niches in vitro and in the rabbit model of active cavitary TB. In vitro, we will establish the routes by which Mtb strains evolve from fully susceptible to fully resistant following a stepwise decline of susceptibility, with Mtb strains that have defined mutations likely to emulate several different clinical scenarios of drug-resistance risk. Surprisingly, the potential of fluoroquinolone-mediated DNA damage to increase the frequency of resistance-conferring mutations has not been explored for Mtb, while it is well-characterize for other bacterial species. Since fluoroquinolones are being considered as the new backbone for TB therapy, both for drug susceptible and drug resistant disease, we will fill this gap and translate our in vitro findings in the rabbit model, uing single drug treatment and combination therapy. We will use an optimized rabbit model of chronic active TB which recapitulates the major pathological features of human TB: solid cellular granulomas, necrotic fibrotic lesions and cavities. The model is ideally suited to query lesion-centric read-outs of microbiology, genetic resistance, drug penetration, and strain-specific polymorphisms. We will focus our studies on the three-drug combination currently viewed as among the most promising in clinical development for drug-sensitive and drug-resistant TB. This regime combines the fluoroquinolone moxifloxacin, pyrazinamide and the nitroimidazole PA-824. Using pharmacometrics approaches, we will build a pharmacokinetic-pharmacodynamic model that integrates small MIC increases, plasma and lesion PK variability, drug-induced mutagenesis and spatial drug distribution in relation to emergence of resistance. By predicting the risk of de facto monotherapy, the model will inform in silico predictions of safe individualize human combinations that prevent acquisition of drug resistance during treatment of active TB. It is our intent that future use of this approach will shift the paradigm from empirical to rational design of drug/dosing regimens with decreased risk for the development of drug resistance.

描述（由申请人提供）：简单的药物敏感结核病（TB）必须用最多四种药物治疗，以防止出现耐药性。然而，耐药性正在上升，全球多药和广泛耐药病例不断增加。由于服药负担大和治疗时间长，依从性差在很大程度上被归咎于耐药结核病的升级。虽然这可能是一个促成因素，但宿主和病原体的内在因素也可能推动耐药性的出现。我们提出的研究将探讨以下四个因素对药物开发的贡献