Shiomi Yoshida1, Tomotada Iwamoto2, Kentaro Arikawa2, Tsuyoshi Sekizuka3, Makoto Kuroda3, Yoshikazu Inoue1, Satoshi Mitarai4, Taisuke Tsuji5, Kazunari Tsuyuguchi1, Katsuhiro Suzuki6. 1. Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center, Kita-ku, Sakai, Osaka, Japan. 2. Department of Infectious Diseases, Kobe Institute of Health, Kobe, Hyogo, Japan. 3. Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan. 4. Department of Mycobacterium Reference and Research, Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, Japan. 5. Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan. 6. Department of Internal Medicine, National Hospital Organization Kinki-chuo Chest Medical Center, Kita-ku, Sakai, Osaka, Japan.
Abstract
OBJECTIVES: Bacterial population kinetics of strains harbouring drug resistance-conferring mutations within a patient often show cryptic resistance in clinical practice. We report a case that showed emergence and dominance of Mycobacterium tuberculosis with uncommon rpoB and gyrA mutations, followed by an rpoC compensatory mutation, during treatment. METHODS: A pre-XDR-TB patient showed heteroresistance to rifampicin and levofloxacin during treatment as a result of intermittent self-cessation. WGS was applied to investigate intra-host strain composition using five pairs of isolates from sputum samples. RESULTS: The subclone in this study possessed rare mutations conferring resistance to rifampicin (rpoB V170F) and levofloxacin (gyrA S91P) and it rapidly outcompeted other subclones during treatment that included levofloxacin but not rifampicin (<7 days). The high-probability compensatory mutation rpoC V483A also emerged and became dominant subsequent to the rpoB V170F mutation. CONCLUSIONS: To the best of our knowledge, this is the first case showing the emergence of such a rare variant that dominated the population within a patient during treatment of TB.
OBJECTIVES: Bacterial population kinetics of strains harbouring drug resistance-conferring mutations within a patient often show cryptic resistance in clinical practice. We report a case that showed emergence and dominance of Mycobacterium tuberculosis with uncommon rpoB and gyrA mutations, followed by an rpoC compensatory mutation, during treatment. METHODS: A pre-XDR-TBpatient showed heteroresistance to rifampicin and levofloxacin during treatment as a result of intermittent self-cessation. WGS was applied to investigate intra-host strain composition using five pairs of isolates from sputum samples. RESULTS: The subclone in this study possessed rare mutations conferring resistance to rifampicin (rpoB V170F) and levofloxacin (gyrA S91P) and it rapidly outcompeted other subclones during treatment that included levofloxacin but not rifampicin (<7 days). The high-probability compensatory mutation rpoC V483A also emerged and became dominant subsequent to the rpoB V170F mutation. CONCLUSIONS: To the best of our knowledge, this is the first case showing the emergence of such a rare variant that dominated the population within a patient during treatment of TB.
Authors: Stephanie Portelli; Yoochan Myung; Nicholas Furnham; Sundeep Chaitanya Vedithi; Douglas E V Pires; David B Ascher Journal: Sci Rep Date: 2020-10-22 Impact factor: 4.379