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

Abstract

Microbial Drug ResistanceVol. 29, No. 3 DiseaseFree AccessLetter to the Editor: In Vitro Activity of Oxazolidinone Against Nontuberculous Mycobacteria in ChinaHuiwen Zheng, Yiting Wang, Wencong He, Feina Li, Hui Xia, Jing Xiao, Xichao Ou, Shengfen Wang, Chen Shen, and Yanlin ZhaoHuiwen ZhengLaboratory of Respiratory Diseases, Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing, China.*These are co-first authors who contributed equally to this study.Search for more papers by this author, Yiting WangNational Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing, China.Institute for Immunization and Prevention, Beijing Center for Disease Control and Prevention, Beijing Academy for Preventive Medicine, Beijing Institute of Tuberculosis Control, Beijing, China.*These are co-first authors who contributed equally to this study.Search for more papers by this author, Wencong HeNational Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing, China.Search for more papers by this author, Feina LiLaboratory of Respiratory Diseases, Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing, China.Search for more papers by this author, Hui XiaNational Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing, China.Search for more papers by this author, Jing XiaoLaboratory of Respiratory Diseases, Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing, China.Search for more papers by this author, Xichao OuNational Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing, China.Search for more papers by this author, Shengfen WangNational Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing, China.Search for more papers by this author, Chen ShenAddress correspondence to: Chen Shen, PhD, Laboratory of Respiratory Diseases, Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing 100045, China E-mail Address: shenchen1110@126.comLaboratory of Respiratory Diseases, Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing, China.Search for more papers by this author, and Yanlin ZhaoAddress correspondence to: Yanlin Zhao, PhD, National Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing 102200, China E-mail Address: zhaoyl@chinacdc.cnNational Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing, China.Search for more papers by this authorPublished Online:16 Mar 2023https://doi.org/10.1089/mdr.2022.0216AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Dear Editor:The prevalence of nontuberculous mycobacterial pulmonary disease is increasing worldwide.1,2 However, the acquired resistance renders treatment highly challenging.3The 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).7The 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.Table 1. Minimal Inhibitory Concentration Values for Delpazolid, Sutezolid, and Linezolid in Clinical Nontuberculous Mycobacteria IsolatesNTM species (n)AntibioticNo. of isolates with indicated MIC (μg/mL)MIC50 (μg/mL)MIC90 (μg/mL)0.031250.06250.1250.250.512481632>32Mycobacterium avium (13)Delpazolid———31—112—148>32Sutezolid——11132——23—232Linezolid—————1——142532>32Mycobacterium intracellulare (16)Delpazolid————1—21651—816Sutezolid1———284———1—12Linezolid—————11———410>32>32Mycobacterium kansasii (28)Delpazolid—1—271331—1——12Sutezolid61551—1——————0.06250.125Linezolid—————381133——416Mycobacterium abscessus (45)Delpazolid—————113274———44Sutezolid——————22815———48Linezolid——————16317——816Mycobacterium massiliense (29)Delpazolid————138116———48Sutezolid—————28172———44Linezolid——————24284916>32MIC, minimal inhibitory concentration; NTM, nontuberculous mycobacteria.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.5According 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.Authors' ContributionsConceptualization, methodology, formal analysis, and writing—original draft by H.Z. Conceptualization, methodology, and writing—original draft by Y.W. Resources and supervision by W.H. Supervision and validation by F.L. Resources and validation by H.X. and X.O. Software and validation by J.X. Project administration by S.W. Conceptualization, writing—review and editing, and funding acquisition by C.S. Conceptualization, resources, funding acquisition, writing—review and editing, and funding acquisition by Y.Z.Disclosure StatementNo competing financial interests exist.Funding InformationThis study was supported by National Key R&D Program of China (2022YFC2305200), Beijing Natural Science Foundation (7224328) and Beijing Natural Science Foundation (7202043).