Mechanisms of heteroresistance to isoniazid and rifampin of Mycobacterium tuberculosis in Tashkent, Uzbekistan

Abstract

Heteroresistance of Mycobacterium tuberculosis (MTB) is defined as the coexistence of susceptible and resistant organisms to anti-tuberculosis (TB) drugs in the same patient. Heteroresistance of MTB is considered a preliminary stage to full resistance. To date, no mechanism causing heteroresistance of MTB has been proven.Clinical specimens and cultures from 35 TB patients from Tashkent, Uzbekistan, were analysed using the Genotype MTBDR assay (Hain Lifescience, Nehren, Germany), which is designed to detect genetic mutations associated with resistance to rifampin and isoniazid. Cases of heteroresistance were further subjected to genotyping using mycobacterial interspersed repetitive unit-variable-number tandem repeat 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 and 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 tuberculosis have been proven using a stepwise molecular-biological approach: 1) superinfection with two different strains, which is of interest for clinical infection control practitioners; and 2) splitting of a single strain into susceptible and resistant organisms. The latter mechanism is most likely to be related to poor treatment quality and could serve as a quality marker for tuberculosis therapy programmes in the future.

Predictive Value of Molecular Drug Resistance Testing of Mycobacterium tuberculosis Isolates in Valle del Cauca, Colombia

“…This study revealed the presence of heteroresistance, which is defined as the coexistence of susceptible and resistant microorganisms to antituberculosis drugs in the same patient (27). Alternatively, other less-studied molecular mechanisms, such as gene duplications, may play a role.…”

Evaluation of Two Molecular Assays for Rapid Detection of Mycobacterium tuberculosis Resistance to Fluoroquinolones in High-Tuberculosis and -Multidrug-Resistance Settings

“…Therefore, mixed allelic variants could be explained by heteroresistance (the presence of FQ-susceptible and -resistant populations of bacteria as a result of ongoing resistance development) (39). Heteroresistance and mixed allelic variants in gyrA codons have been previously reported in areas with high rates of drug resistance (9,18,31). Such cases should be interpreted clinically with caution.…”

Mycobacterium tuberculosis Population Structure Determines the Outcome of Genetics-Based Second-Line Drug Resistance Testing

“…The clinical importance of heterogeneous M. tuberculosis populations is particularly relevant for patients where both drug- susceptible and drug-resistant strains are present in the same sputum (2, 36). Thus, heteroresistance poses a significant challenge to genetics-based drug resistance diagnostics, as the sensitivity of detecting genomic mutations conferring drug resistance will be dependent on the complexity of the bacterial population structure within the specimen being analyzed, including the number of different mutations conferring resistance to a single anti-TB drug as well as the ratio between resistant and susceptible clones (9,16). In most instances, primary resistance would be associated with a homogeneous population of bacilli harboring the same single mutation.…”