Asunto(s)
Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Medicina de Precisión/métodos , Tuberculosis Pulmonar/tratamiento farmacológico , Farmacorresistencia Microbiana , Quimioterapia Combinada , Etambutol/uso terapéutico , Humanos , Isoniazida/uso terapéutico , Pruebas de Sensibilidad Microbiana , Pirazinamida/uso terapéutico , Rifampin/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Treatment of drug-sensitive tuberculosis (TB) is effective, whereas that of multidrug-resistant and extensively drug-resistant TB as well as nontuberculous mycobacterial (NTM) disease are less so. Therapy in general requires good adherence to potentially toxic drug regimens over prolonged periods. Poor adherence is associated with resistance development and poor outcome. This review will present promising new treatments, both new drugs and regimens, for difficult mycobacterial pulmonary infections. RECENT FINDINGS: A number of new and repurposed drugs including bedaquiline, delamanid, pretomanid, linezolid and clofazimine, and drug regimens, such as the The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) trial regimens, are currently progressing from basic research through clinical trials.
Asunto(s)
Antibacterianos/uso terapéutico , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Enfermedades Pulmonares/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Amicacina/administración & dosificación , Antibacterianos/administración & dosificación , Clofazimina/uso terapéutico , Diarilquinolinas/uso terapéutico , Humanos , Linezolid/uso terapéutico , Liposomas , Enfermedades Pulmonares/microbiología , Pruebas de Sensibilidad Microbiana , Nitroimidazoles/uso terapéutico , Oxazoles/uso terapéuticoRESUMEN
BACKGROUND: The largest outbreak of isoniazid-resistant (INH-R) Mycobacterium tuberculosis in Western Europe is centred in North London, with over 400 cases diagnosed since 1995. In the current study, we evaluated the genetic variation in a subset of clinical samples from the outbreak with the hypothesis that these isolates have unique biological characteristics that have served to prolong the outbreak. METHODS: Fitness assays, mutation rate estimation, and whole-genome sequencing were performed to test for selective advantage and compensatory mutations. RESULTS: This detailed analysis of the genetic variation of these INH-R samples suggests that this outbreak consists of successful, closely related, circulating strains with heterogeneous resistance profiles and little or no associated fitness cost or impact on their mutation rate. CONCLUSIONS: Specific deletions and SNPs could be a peculiar feature of these INH-R M. tuberculosis isolates, and could potentially explain their persistence over the years.
Asunto(s)
Brotes de Enfermedades , Variación Genética/genética , Isoniazida/uso terapéutico , Mycobacterium tuberculosis/genética , Tuberculosis/epidemiología , Tuberculosis/genética , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Europa (Continente)/epidemiología , Humanos , Isoniazida/farmacología , Londres/epidemiología , Pruebas de Sensibilidad Microbiana/métodos , Mutación/genética , Mycobacterium tuberculosis/aislamiento & purificación , Polimorfismo de Nucleótido Simple/genética , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples MedicamentosRESUMEN
Multidrug resistant tuberculosis is an increasing problem globally. The current gold standard in drug sensitivity testing is slow and cumbersome. To tackle drug resistance effectively, a more rapid method of testing is required. Current molecular tests are fast, but only offer information on a limited number of genetic loci. Whole genome sequencing presents an attractive alternative that can provide comprehensive, clinically relevant information on all described loci. Although the standard approach to whole genome sequencing of Mycobacterium tuberculosis is slow due to the requirement of culture, this article will describe recent advances that mean it has the potential to provide results within days.