title: 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.
authors.affiliation: IML, Institute of Microbiology & Laboratory Medicine, Supranational Reference Laboratory (SNRL), Asklepios Fachkliniken, Robert-Koch-Allee 2, D-82131 Gauting, Germany. Harald.Hoffmann@asklepios.com
authors.forename: S
authors.initials: S
authors.lastname: Hofmann-Thiel
authors.forename: J
authors.initials: J
authors.lastname: van Ingen
authors.forename: K
authors.initials: K
authors.lastname: Feldmann
authors.forename: L
authors.initials: L
authors.lastname: Turaev
authors.forename: G T
authors.initials: GT
authors.lastname: Uzakova
authors.forename: G
authors.initials: G
authors.lastname: Murmusaeva
authors.forename: D
authors.initials: D
authors.lastname: van Soolingen
authors.forename: H
authors.initials: H
authors.lastname: Hoffmann
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology; D015373:Bacterial Typing Techniques; D003062:Codon; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics*; D010641:Phenotype; D012293:Rifampin / Q000494:pharmacology*; D014376:Tuberculosis / Q000235:genetics* / Q000382:microbiology / Q000628:therapy; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis / Q000453:epidemiology*; D014610:Uzbekistan
chemical_list: D000995:Antitubercular Agents; D003062:Codon; D007538:Isoniazid; D012293:Rifampin