Clinical application of whole-genome sequencing in the management of extensively drug-resistant tuberculosis: a case report

Abstract

Background: Whole-genome sequencing (WGS)-based prediction of drug resistance in Mycobacterium tuberculosis has the potential to guide clinical decisions in the design of optimal treatment regimens.

Methods: We utilized WGS to investigate drug resistance mutations in a 32-year-old Tanzanian male admitted to Kibong'oto Infectious Diseases Hospital with a history of interrupted multidrug-resistant tuberculosis treatment for more than three years. Before admission, he received various all-oral bedaquiline-based multidrug-resistant tuberculosis treatment regimens with unfavourable outcomes.

Results: Drug susceptibility testing of serial M. tuberculosis isolates using Mycobacterium Growth Incubator Tubes culture and WGS revealed resistance to first-line anti-TB drugs, bedaquiline, and fluoroquinolones but susceptibility to linezolid, clofazimine, and delamanid. WGS of serial cultured isolates revealed that the Beijing (Lineage 2.2.2) strain was resistant to bedaquiline, with mutations in the mmpR5 gene (Rv0678. This study also revealed the emergence of two distinct subpopulations of bedaquiline-resistant tuberculosis strains with Asp47f and Glu49fs frameshift mutations in the mmpR5 gene, which might be the underlying cause of prolonged resistance. An individualized regimen comprising bedaquiline, delamanid, pyrazinamide, ethionamide, and para-aminosalicylic acid was designed. The patient was discharged home at month 8 and is currently in the ninth month of treatment. He reported no cough, chest pain, fever, or chest tightness but still experienced numbness in his lower limbs.

Conclusion: We propose the incorporation of WGS in the diagnostic framework for the optimal management of patients with drug-resistant and extensively drug-resistant tuberculosis.

Keywords: Case Report; Clinical application; Genomic Diagnostics; Whole-genome sequencing; XDR-TB.

Fig. 1

Chest radiography of the extensively drug resistance tuberculosis patient

Fig. 2

Phylogenetic relationship between the eight serial M. tuberculosis isolates collected over two years from the presented case and genotypic drug resistance pattern: black circle: drug resistant variants were detected, white circles: susceptible

Fig. 3

The evolution Bedaquiline resistance in the presented case through the emergence of two distinct subpopulations; the first developed Asp47fs mutation through insertion of 2 bases “GA” at genomic position 779,127 and the second with Glu49fs through insertion of 1 base “C” at genomic position 779,130. Across the subsequent M. tuberculosis isolates the first subpopulation was diminishing while the second was rising; the percentages of both variants are displayed on each sequence pane next to the corresponding mutation position