Letter to the Editor: In Vitro Activity of Oxazolidinone Against Nontuberculous Mycobacteria in China

Dear Editor:

The prevalence of nontuberculous mycobacterial pulmonary disease is increasing worldwide.^1,2 However, the acquired resistance renders treatment highly challenging. ³

The oxazolidinones exhibit good activity against Gram-positive bacteria. ⁴ Linezolid (LZD), the first licensed oxazolidinone, exhibits excellent antibacterial activities against nontuberculous mycobacteria (NTM) infections. ⁴ Sutezolid (SZD) exhibited superior efficacy against Mycobacterium tuberculosis.^2,4,6 Delpazolid (DZD) improved antibacterial activity and safety against Gram-positive pathogen.^4–6 However, comparison of the oxazolidinone derivatives for NTM isolates are limited. In this study, we measured the activities of these antimicrobial against various NTM species in China.

A total of 131 clinical isolates of five major pathogenic NTM were collected from a national drug resistance surveillance program between 2019 and 2021. Broth-microdilution was performed, as per clinical and laboratory standards institute (CLSI) standards, ⁷ to test the in vitro activity of LZD, SZD, and DZD against clinical isolates of Mycobacterium abscessus (n = 45), Mycobacterium massiliense (n = 29), Mycobacterium kansasii (n = 28), Mycobacterium avium (n = 13), and Mycobacterium intracellulare (n = 16) characterized by matrix-assisted laser desorption-ionization time-of-flight.

The minimal inhibitory concentration (MIC) of the antimicrobial agents was determined by broth microdilution method according to the guidelines of the CLSI. The bacterial suspensions prepared from subcultures collected from Löwenstein–Jensen medium were diluted to the density of a 0.5-McFarland standard using saline. The CAMHB medium (pH 7.3–7.4) was used to prepare the final inoculum density of ∼5 × 10⁵ CFU/mL, and then 100 μL bacterial suspension was added to the 96-well microtiter plates containing successive twofold dilutions of the antimicrobial agents.

MICs for the rapidly growing mycobacterium were determined after incubating for 3–5 days until sufficient growth was evident in the control sample, whereas the slowly growing NTM were assessed after incubating for 7–14 days. The breakpoint of LZD was adopted from the CLSI document M24-A2 (susceptible: ≤8 mg/L; intermediate susceptible: 16 mg/L; resistant: ≥32 mg/L). ⁷

The MIC of the clinical isolates are presented in Table 1. For LZD, except for M. kansasii and M. abscessus, with lower MIC₅₀ (4 and 8 μg/mL) and MIC₉₀ (16 μg/mL) values, M. avium, M. intracellulare, and M. massiliense had high MIC₅₀ (>16 μg/mL) and MIC₉₀ (>32 μg/mL) values. According to the CLSI for LZD, the resistant rates of the recruited isolates of M. avium, M. intracellulare, and M. massiliense in this study were 53.8%, 87.5%, and 44.8%, respectively.

SZD showed the strongest activity against M. kansasii with MIC₅₀ (0.0625 μg/mL) and MIC₉₀ (0.125 μg/mL) values. Although M. avium and M. intracellulare had lower MIC₅₀ (2 and 1 μg/mL, respectively) values than those for M. abscessus and M. massiliense (4 μg/mL), compared with these NTM, M. avium and M. abscessus had higher MIC90 (32 and 1 μg/mL, respectively) values.

For DZD, M. avium, M. intracellulare, M. abscessus, and M. massiliense had high MIC₅₀ (4–8 μg/mL) and MIC₉₀ (4–>32 μg/mL) values. Compared with these NTM, M. kansasii had lower MIC₅₀ (1 μg/mL) and MIC₉₀ (2 μg/mL) values.

The outcomes for the treatment of NTM are unsatisfactory, highlighting the need for new and effective drugs. In this study, we compared the activity of oxazolidinone derivatives for important NTM isolates. SZD showed the strongest antimicrobial activity against the slowly growing mycobacterium, followed by DZD, whereas SZD and DZD showed similar values against the rapidly growing mycobacterium. Given that there have been little data comparing the in vitro activity of oxazolidinone derivatives against various types of clinical NTM strains in China, our study provides important implications.

Although the MIC₉₀ value of oxazolidinones for the M. avium complex was different from other studies, the results also indicated that the MIC₉₀ value for the M. avium complex was relatively high. ⁵ And consistent with previous studies, SZD showed low MIC₉₀ value in slowly growing mycobacterium, implying the structural characteristic of SZD may specifically treat SGMs. ⁵

According to the CLSI resistance criteria for LZD, all M. abscessus isolates were sensitive to LZD, SZD, and DZD, and the susceptibility rate of M. massiliense to LZD, SZD, and DZD was 100% (29/29), 100% (29/29), and 55.2% (16/29), respectively, higher than the previous reported. ⁶ This discrepancy may be attributed to the different critical concentrations adopted for LZD, which we used 32 mg/L and previous study used 16 mg/L. The MIC values of oxazolidinone derivatives vary among different NTM species, which will provide a basis for pharmacokinetic studies.

In conclusion, our results demonstrated that oxazolidinones had good in vitro activity against NTMs, and were variable against different species.^1,3,4 Compared with LZD with side effects, SZD and DZD showed better efficacy against NTMs, suggesting that these drugs may substitute LZD. Further studies are needed to identify the contribution of SZD and DZD in NTM.