Evidence for expanding the role of streptomycin in the management of drug-resistant mycobacterium tuberculosis

Keira A. Cohen, Katharine E. Stott, Vanisha Munsamy, Abigail L. Manson, Ashlee M. Earl, Alexander S. Pym

Research output: Contribution to journalArticlepeer-review

Abstract

In 2019, the WHO tuberculosis (TB) treatment guidelines were updated to recommend only limited use of streptomycin, in favor of newer agents or amikacin as the preferred aminoglycoside for drug-resistant Mycobacterium tuberculosis. However, the emergence of resistance to newer drugs, such as bedaquiline, has prompted a reanalysis of antitubercular drugs in search of untapped potential. Using 211 clinical isolates of M. tuberculosis from South Africa, we performed phenotypic drug susceptibility testing (DST) to aminoglycosides by both critical concentration and MIC determination in parallel with whole-genome sequencing to identify known genotypic resistance elements. Isolates with low-level streptomycin resistance mediated by gidB were frequently misclassified with respect to streptomycin resistance when using the WHO-recommended critical concentration of 2 μg/ml. We identified 29 M. tuberculosis isolates from South Africa with low-level streptomycin resistance concomitant with high-level amikacin resistance, conferred by gidB and rrs 1400, respectively. Using a large global data set of M. tuberculosis genomes, we observed 95 examples of this corresponding resistance genotype (gidB-rrs 1400), including identification in 81/257 (31.5%) of extensively drug resistant (XDR) isolates. In a phylogenetic analysis, we observed repeated evolution of low-level streptomycin and highlevel amikacin resistance in multiple countries. Our findings suggest that current critical concentration methods and the design of molecular diagnostics need to be revisited to provide more accurate assessments of streptomycin resistance for gidBcontaining isolates. For patients harboring isolates of M. tuberculosis with high-level amikacin resistance conferred by rrs 1400, and for whom newer agents are not available, treatment with streptomycin may still prove useful, even in the face of lowlevel resistance conferred by gidB.

Original languageEnglish (US)
Article numbere00860-20
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number9
DOIs
StatePublished - Sep 2020

Keywords

  • Aminoglycosides
  • Drug resistance mechanisms
  • Multidrug resistance
  • Mycobacterium tuberculosis
  • Tuberculosis
  • Whole-genome sequencing

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Evidence for expanding the role of streptomycin in the management of drug-resistant mycobacterium tuberculosis'. Together they form a unique fingerprint.

Cite this