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Total-deletion mutation of pncA as a new mechanism of pyrazinamide resistance in Mycobacterium tuberculosis †-The first report from Japan-

Session: Poster Abstract Session: Mycobacterial Infections: DrugóResistance
Saturday, October 11, 2014
Room: The Pennsylvania Convention Center: IDExpo Hall BC
Background: Pyrazinamide (PZA) is an indispensable first-line anti-tuberculosis drug that is part of the currently used short-course, combination chemotherapy against tuberculosis (TB). PZA is a prodrug that has to be converted to the active form, pyrazinoic acid, by pyrazinamidase (PZase) activity, encoded by the pncA gene of Mycobacterium tuberculosis, and loss of PZase activity is associated with PZA resistance. Thus most of PZA-resistant strains are due to mutations of the pncA gene. Though many pncA mutations are known, total-deletion of the gene has never been reported in clinical case yet. We report the first case of PZA-monoresistant TB by total-deletion of the pncA gene.

Methods: A 73-year-old man had no history of TB treatment. His chest CT demonstrated multiple discrete nodules in the bilateral upper lung fields and cavitary lesions in right upper lobe.

Results: Sputum examination showed positivity of smear-microscopy, culture and TB-PCR. Together with chronic occupational exposure to silica dust, he was diagnosed of silicotuberculosis. In vitro anti-tuberculosis drug susceptibility testing by standardized proportion method revealed that the isolate was susceptible to isoniazid (INH), rifampin (RIF), rifabutin (RBT), ethambutol (EMB), streptomycin (STR) and levofloxacin (LVFX), whereas it was resistant to PZA. PZA susceptibility testing was carried out in liquid media (Kyokuto Pharmaceutical Industrial Co.,Ltd.). Further investigation by the Research Institute of Tuberculosis revealed that the species was identified as Mycobacterium tuberculosis sensu stricto and kept no pyrazinamidase activity. Further sequencing analysis revealed the large deletion (22,934bp) including the total pncA gene.

Conclusion: Yee DP et al. reported that patients with PZA-monoresistant TB had significantly worse clinical outcomes than patients with fully susceptible strains. PZA resistances were almost due to point mutations in pncA. The total-deletion mutation of pncA shown in the present case was also highly resistant to PZA. To the best of our knowledge, this is the first reported case of total pncA deletion with PZA resistance. Not only pncA mutation but also pncA deletion will cause PZA resistance.

Masahiro Kobayashi1, Sadao Aoki1, Takefumi Saito, MD, PhD2, Akio Aono3 and Satoshi Mitarai, MD, PhD3, (1)Department of Clinical Laboratory, National Hospital Organization Ibarakihigashi Hospital, Ibaraki, Japan, (2)Departmen of Internal Medicine, National Hospital Organization Ibarakihigashi Hospital, Ibaraki, Japan, (3)Department of Mycobacterium Reference and Research, Research Institute of Tuberculosis,Japan Anti-Tuberculosis Association, Tokyo, Japan


M. Kobayashi, None

S. Aoki, None

T. Saito, None

A. Aono, None

S. Mitarai, None

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