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Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis
- Source :
- American Journal of Respiratory and Critical Care Medicine. 198:1208-1219
- Publication Year :
- 2018
- Publisher :
- American Thoracic Society, 2018.
-
Abstract
- Rationale: Acquired resistance is an important driver of multidrug-resistant tuberculosis (TB), even with good treatment adherence. However, exactly what initiates the resistance and how it arises remain poorly understood. Objectives: To identify the relationship between drug concentrations and drug susceptibility readouts (minimum inhibitory concentrations [MICs]) in the TB cavity. Methods: We recruited patients with medically incurable TB who were undergoing therapeutic lung resection while on treatment with a cocktail of second-line anti-TB drugs. On the day of surgery, antibiotic concentrations were measured in the blood and at seven prespecified biopsy sites within each cavity. Mycobacterium tuberculosis was grown from each biopsy site, MICs of each drug identified, and whole-genome sequencing performed. Spearman correlation coefficients between drug concentration and MIC were calculated. Measurements and Main Results: Fourteen patients treated for a median of 13 months (range, 5–31 mo) were recruited. MICs and drug resistance–associated single-nucleotide variants differed between the different geospatial locations within each cavity, and with pretreatment and serial sputum isolates, consistent with ongoing acquisition of resistance. However, pretreatment sputum MIC had an accuracy of only 49.48% in predicting cavitary MICs. There were large concentration–distance gradients for each antibiotic. The location-specific concentrations inversely correlated with MICs (P
- Subjects :
- Adult
Male
0301 basic medicine
Pulmonary and Respiratory Medicine
Tuberculosis
Adolescent
Treatment adherence
Biopsy
030106 microbiology
Antitubercular Agents
Microbial Sensitivity Tests
Drug resistance
Critical Care and Intensive Care Medicine
Drug penetration
Young Adult
03 medical and health sciences
Acquired resistance
Tuberculosis, Multidrug-Resistant
medicine
Humans
In patient
Prospective Studies
Lung
Original Research
Dose-Response Relationship, Drug
business.industry
Middle Aged
medicine.disease
Immunology
Drug Therapy, Combination
Female
Lung cavity
business
Subjects
Details
- ISSN :
- 15354970 and 1073449X
- Volume :
- 198
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory and Critical Care Medicine
- Accession number :
- edsair.doi.dedup.....4879308c26d34cc64d48f0d6532356f3