title: Polymorphisms associated with resistance and cross-resistance to aminoglycosides and capreomycin in Mycobacterium tuberculosis isolates from South Korean Patients with drug-resistant tuberculosis.
abstract: The aminoglycosides streptomycin, amikacin, and kanamycin and the cyclic polypeptide capreomycin are all widely used in second-line therapy for patients who develop multidrug-resistant tuberculosis. We have characterized a set of 106 clinical isolates of Mycobacterium tuberculosis using phenotypic drug susceptibility testing (DST) to determine the extent of resistance to each agent and cross-resistance between agents. These results were compared with polymorphisms in the DNA sequences of ribosome-associated genes previously implicated in resistance and with the clinical outcomes of subjects from whom these isolates were obtained. Thirty-six (34%) of these isolates displayed resistance to one or more of these agents, and the majority of these (20 of 36) showed cross-resistance to one or more agents. Most (33 of 36) of the resistant isolates showed polymorphisms in the 16S ribosome components RpsL and rrs. Three resistant strains (3 of 36) were identified that had no known polymorphisms in ribosomal constituents. For kanamycin and streptomycin, molecular DST significantly outperformed phenotypic DST using the absolute concentration method for predicting 4-month sputum conversion (likelihood ratios of 4.0 and 2.0, respectively) and was equivalent to phenotypic DST using the National Committee for Clinical Laboratory Standards (NCCLS)-approved agar proportion method for estimating MIC (likelihood ratio, 4.0). These results offer insight into mechanisms of resistance and cross-resistance among these agents and suggest that the development of rapid molecular tests to distinguish polymorphisms would significantly enhance clinical utility of this important class of second-line antituberculosis drugs.
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.forename: Soohee
authors.initials: S
authors.lastname: Hwang
authors.forename: Hyeeun
authors.initials: H
authors.lastname: Bang
authors.forename: Seung Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Hyung Seok
authors.initials: HS
authors.lastname: Kang
authors.forename: Doosoo
authors.initials: D
authors.lastname: Jeon
authors.forename: Seon Yeong
authors.initials: SY
authors.lastname: Min
authors.forename: Taegwon
authors.initials: T
authors.lastname: Oh
authors.forename: Yeun
authors.initials: Y
authors.lastname: Kim
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Vignesh
authors.initials: V
authors.lastname: Rajan
authors.forename: Sharon Y
authors.initials: SY
authors.lastname: Wong
authors.forename: Isdore Chola
authors.initials: IC
authors.lastname: Shamputa
authors.forename: Matthew
authors.initials: M
authors.lastname: Carroll
authors.forename: Lisa
authors.initials: L
authors.lastname: Goldfeder
authors.forename: Song A
authors.initials: SA
authors.lastname: Lee
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Seokyong
authors.initials: S
authors.lastname: Eum
authors.forename: Hyeyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics; D002207:Capreomycin / Q000494:pharmacology* / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D024881:Drug Resistance, Bacterial; D005798:Genes, Bacterial; D020459:Genes, rRNA; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D011110:Polymorphism, Genetic; D056910:Republic of Korea; D012269:Ribosomal Proteins / Q000235:genetics; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology*
chemical_list: D000617:Aminoglycosides; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D012269:Ribosomal Proteins; D002207:Capreomycin