Mechanisms of Heteroresistance to Isoniazid and Rifampin of M. tuberculosis in Tashkent, Uzbekistan

¹ IML, Institute of Microbiology & Laboratory Medicine, Supranational Reference Laboratory of Tuberculosis, Gauting, Germany
² National Mycobacteria Reference Laboratory, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
³ National Reference Laboratory of Tuberculosis, TB-Institute, Tashkent, Uzbekistan
⁴ DOTS Center, GFATM, Tashkent, Uzbekistan

^* To whom correspondence should be addressed. E-mail: Harald.Hoffmann{at}asklepios.com.

	Abstract

Heteroresistance of Mycobacterium tuberculosis (MTB) is defined as the co-existence of susceptible and resistant organisms to anti-tuberculosis (TB) drugs in the same patient. Heteroresistance of MTB is considered a pre-stage to full resistance. So far, no mechanism causing heteroresistance of MTB has been proven.

Clinical specimens and cultures from 35 TB patients from Tashkent, Uzbekistan, were analyzed using the Genotype MTBDR assay, which is designed to detect genetic mutations associated with resistance to rifampin and isoniazid. Cases of heteroresistance were further subjected to genotyping using MIRU-VNTR typing, spoligotyping and IS6110 fingerprinting.

Heteroresistance to rifampin and/or isoniazid was found in seven cases (20%). In five of them, heteroresistance was caused by two different strains, in two by a single strain of the Beijing genotype. The latter cases had a history of relapse of their TB.

For the first time, two different mechanisms of heteroresistance in TB have been proven using a stepwise molecular-biological approach: super-infection with two different strains which is of interest for clinical infection control practitioners and splitting of one single strain in susceptible and resistant organisms. The latter one is most likely related to poor treatment quality and could serve as quality marker for TB therapy programs in future.