View Abstract

A1152 - Untapped Potential for Streptomycin: Using Genomics to Optimize Aminoglycoside Selection in Drug-Resistant Mycobacterium Tuberculosis
Author Block: K. A. Cohen1, K. E. Stott2, A. L. Manson3, V. Munsamy4, A. M. Earl3, A. S. Pym5; 1Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom, 3Broad Institute of MIT and Harvard, Cambridge, MA, United States, 4Africa Health Research Institute, Durban, South Africa, 5Pulmonary and Critical Care Medicine, Africa Health Research Institute, Durban, South Africa.
RATIONALE Streptomycin, the first antitubercular drug to be discovered, formed part of the original multi-drug regimen for tuberculosis (TB) chemotherapy in the 1950s. Its initial widespread use led to the early emergence of streptomycin resistance, which subsequently limited its clinical utility. With the advent of second-line injectable agents with more favorable antitubercular activity (including amikacin, kanamycin and capreomycin), current guidelines recommend streptomycin use only in limited circumstances. While the majority of the molecular determinants of aminoglycoside resistance are known, there are no commercial diagnostic tests that assay for genotypic streptomycin resistance. Guidelines for clinical management of drug-resistant TB do not take into account the relative level of phenotypic resistance to aminoglycosides. Given limited treatment options, patients with multidrug resistant (MDR) and extensively drug-resistant (XDR) TB are frequently treated with kanamycin or amikacin, despite high-levels of resistance to these drugs. The ongoing global epidemic of drug-resistant TB has prompted a reanalysis of the current arsenal of antitubercular drugs in search of untapped potential, and streptomycin may be one such underutilized drug. METHODS Standard drug susceptibility testing by critical concentration and MIC determination to aminoglycosides were performed on 211 clinical isolates of M. tuberculosis from South Africa. Whole-genome sequencing identified known genotypic resistance elements to these respective drugs. Levels of phenotypic resistance between strains with different streptomycin and kanamycin resistance genotypes were compared. RESULTS Substantial inter-strain variability in aminoglycoside resistance was observed, corresponding to different resistance genotypes. Low-level streptomycin resistance was conferred by gidB mutations (median MIC 4 μg/mL, IQR 2-4), whereas high-level resistance was conferred by rrs and rpsL mutations. Of note, a large number of strains with concomitant high-level kanamycin resistance and low-level streptomycin resistance were identified. CONCLUSIONS These results indicate that the level of phenotypic streptomycin resistance is mediated by resistance genotype, and that a significant proportion of strains display discordant levels of resistance to streptomycin (low-level) and kanamycin (high-level). These discordant strains—which could likely be successfully killed by therapeutic doses of streptomycin—go unidentified by current methods of critical concentration testing that do not differentiate between low and high-level streptomycin resistance. Current guidelines that recommend only limited use of streptomycin may unwittingly withhold a potentially lifesaving, inexpensive and available drug from patients with drug-resistant TB. Our results highlight the need to revise current critical concentration methods as well as treatment guidelines where aminoglycoside therapy is indicated for drug-resistant TB.