title: Mutations in the rrs A1401G gene and phenotypic resistance to amikacin and capreomycin in Mycobacterium tuberculosis.
abstract: The aminoglycosides amikacin (AMK)/kanamycin (KAN) and the cyclic polypeptide capreomycin (CAP) are important injectable drugs in the treatment of multidrug-resistant tuberculosis. Cross-resistance among these drug classes occurs and information on the minimum inhibitory concentrations (MICs), above the normal wild-type distribution, may be useful in identifying isolates that are still accessible to drug treatment. Isolates from the Eastern Cape Province of South Africa were subjected to DNA sequencing of the rrs (1400-1500 region) and tlyA genes. Sequencing data were compared with (i) conventional susceptibility testing at standard critical concentrations (CCs) on Middlebrook 7H11 agar and (ii) MGIT 960-based MIC determinations to assess the presence of AMK- and CAP-resistant mutants. Isolates with an rrs A1401G mutation showed high-level resistance to AMK (>20 mg/L) and decreased phenotypic susceptibility to CAP (MICs 10-15 mg/L). The MICs of CAP were below the bioavailability of the drug, which suggests that it may still be effective against multi- or extensively drug resistant tuberculosis [M(X)DR-TB]. Agar-based CC testing was found to be unreliable for resistance recognition of CAP in particular.
authors: DST/NRF Centre of Excellence for Biomedical TB Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Health Science, Stellenbosch University, Cape Town, South Africa. fas@sun.ac.za
authors: Frederick A
authors: FA
authors: Sirgel
authors: Marisa
authors: M
authors: Tait
authors: Robin M
authors: RM
authors: Warren
authors: Elizabeth M
authors: EM
authors: Streicher
authors: Erik C
authors: EC
authors: Böttger
authors: Paul D
authors: PD
authors: van Helden
authors: Nicolaas C
authors: NC
authors: Gey van Pittius
authors: Gerrit
authors: G
authors: Coetzee
authors: Ebrahim Y
authors: EY
authors: Hoosain
authors: Mamisa
authors: M
authors: Chabula-Nxiweni
authors: Cindy
authors: C
authors: Hayes
authors: Thomas C
authors: TC
authors: Victor
authors: André
authors: A
authors: Trollip
mesh_terms: D000583:Amikacin / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D002207:Capreomycin / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012336:RNA, Ribosomal, 16S / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013019:South Africa; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D012336:RNA, Ribosomal, 16S; C112817:TlyA protein, Mycobacterium tuberculosis; D002207:Capreomycin; D000583:Amikacin