Association between 16S rRNA gene mutations and susceptibility to amikacin in Mycobacterium avium Complex and Mycobacterium abscessus clinical isolates

Su-Young Kim,Hee Jae Huh,Seong Mi Moon,Sung Jae Shin,Dae Hun Kim,Nam Yong Lee,Won-Jung Koh,Byung Woo Jhun,Ju Yeun Song

doi:10.1038/s41598-021-85721-5

Abstract

We evaluated the association between 16S rRNA gene (rrs) mutations and susceptibility in clinical isolates of amikacin-resistant nontuberculous mycobacteria (NTM) in NTM-pulmonary disease (PD) patients. Susceptibility was retested for 134 amikacin-resistant isolates (minimum inhibitory concentration [MIC] ≥ 64 µg/ml) from 86 patients. Amikacin resistance was reconfirmed in 102 NTM isolates from 62 patients with either Mycobacterium avium complex-PD (MAC-PD) (n = 54) or M. abscessus-PD (n = 8). MICs and rrs mutations were evaluated for 318 single colonies from these isolates. For the 54 MAC-PD patients, rrs mutations were present in 34 isolates (63%), comprising all 31 isolates with amikacin MICs ≥ 128 µg/ml, but only three of 23 isolates with an MIC = 64 µg/ml. For the eight M. abscessus-PD patients, all amikacin-resistant (MIC ≥ 64 µg/ml) isolates had rrs mutations. In amikacin-resistant isolates, the A1408G mutation (n = 29) was most common. Two novel mutations, C1496T and T1498A, were also identified. The culture conversion rate did not differ by amikacin MIC. Overall, all high-level and 13% (3/23) of low-level amikacin-resistant MAC isolates had rrs mutations whereas mutations were present in all amikacin-resistant M. abscessus isolates. These findings are valuable for managing MAC- and M. abscessus-PD and suggest the importance of phenotypic and genotypic susceptibility testing.

Highlights

Nontuberculous mycobacteria (NTM) are ubiquitous organisms that cause chronic disease, and the burdens of nontuberculous mycobacteria (NTM)-pulmonary disease (PD) are increasing globally, including in South K orea[1,2]
Given that approximately 90% of Mycobacterium avium complex (MAC) or M. abscessus clinical isolates have been reported to be amikacin susceptible[16,17], amikacin is one of the few drugs that can be used as salvage therapy in refractory disease, and it plays an important role in long-term NTM-PD treatment
The purposes of this study were to elucidate the association between rrs mutations and amikacin resistance in amikacin-resistant MAC and M. abscessus clinical isolates and to evaluate the clinical outcomes of patients with amikacin-resistant NTM-PD according to the MIC of amikacin

Summary

Introduction

Nontuberculous mycobacteria (NTM) are ubiquitous organisms that cause chronic disease, and the burdens of NTM-pulmonary disease (PD) are increasing globally, including in South K orea[1,2]. For MAC-PD, amikacin is recommended for patients with advanced disease or those whose isolates acquired macrolide resistance[7,8]. Given that approximately 90% of MAC or M. abscessus clinical isolates have been reported to be amikacin susceptible[16,17], amikacin is one of the few drugs that can be used as salvage therapy in refractory disease, and it plays an important role in long-term NTM-PD treatment. There are limited data from NTM clinical isolates on the association between these mutations and amikacin susceptibility, or on the clinical outcomes of patients with amikacin-resistant NTM-PD. The purposes of this study were to elucidate the association between rrs mutations and amikacin resistance in amikacin-resistant MAC and M. abscessus clinical isolates and to evaluate the clinical outcomes of patients with amikacin-resistant NTM-PD according to the MIC of amikacin

Methods

Results

Conclusion