TY - JOUR
T1 - Evidence for expanding the role of streptomycin in the management of drug-resistant mycobacterium tuberculosis
AU - Cohen, Keira A.
AU - Stott, Katharine E.
AU - Munsamy, Vanisha
AU - Manson, Abigail L.
AU - Earl, Ashlee M.
AU - Pym, Alexander S.
N1 - Funding Information:
This work was supported by funding from the National Heart Lung and Blood Institute, National Institutes of Health (K08 HL139994), and a Burroughs Wellcome Fund Career Award for Medical Scientists to K.A.C. K.E.S. is a Wellcome Trust Clinical Ph.D Fellow (203919/Z/16/Z). This project has been supported in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract number HHSN272200900018C and grant number U19AI110818 to the Broad Institute.
Funding Information:
We acknowledge the support of the Africa Health Research Institute (AHRI) to conduct the research. We thank Nonkqubela Bantubani of the Medical Research Council (MRC) in Durban, in addition to Max O=Donnell and Nesri Padayatchi for contributing clinical isolates of M. tuberculosis, which were used in this study. We thank Koleka P. Mlisana and Nomonde R. Mvelase of the KwaZulu-Natal National Health Laboratory Service. This work was supported by funding from the National Heart Lung and Blood Institute, National Institutes of Health (K08 HL139994), and a Burroughs Wellcome Fund Career Award for Medical Scientists to K.A.C. K.E.S. is a Wellcome Trust Clinical Ph.D Fellow (203919/Z/16/Z). This project has been supported in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract number HHSN272200900018C and grant number U19AI110818 to the Broad Institute.
Publisher Copyright:
Copyright © 2020 Cohen et al.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - Aminoglycosides
KW - Drug resistance mechanisms
KW - Multidrug resistance
KW - Mycobacterium tuberculosis
KW - Tuberculosis
KW - Whole-genome sequencing
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U2 - 10.1128/AAC.00860-20
DO - 10.1128/AAC.00860-20
M3 - Article
C2 - 32540971
AN - SCOPUS:85089787913
SN - 0066-4804
VL - 64
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 9
M1 - e00860-20
ER -