Lesion Heterogeneity and Long-Term Heteroresistance in Multidrug-Resistant Tuberculosis

Abstract Tuberculosis heteroresistance, in which only a fraction of the bacteria in a patient with tuberculosis contains drug-resistant mutations, has been a rising concern. However, its origins and prevalence remain elusive. Here, whole-genome sequencing was performed on 83 serial isolates from 31 patients with multidrug-resistant tuberculosis, and heteroresistance was detected in isolates from 21 patients (67.74%). Heteroresistance persisted in the host for long periods, spanning months to years, and was associated with having multiple tubercular lesions. Our findings indicate that heteroresistance is common and persistent in patients with multidrug-resistant tuberculosis and may affect the success of their treatment regimens. Comparing whole-genome sequencing of Mycobacterium tuberculosis isolates with computed tomography, we found that heteroresistance was associated with more cavities. The prevalence and duration of heteroresistance may be underestimated owing to underrepresentation of the within-host bacilli population in single sputum samples.