Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis

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. ...