In Vitro Susceptibility Testing of Tedizolid against Nontuberculous Mycobacteria

Abstract

Tedizolid is a new oxazolidinone with improved in vitro and intracellular potency against Mycobacterium tuberculosis, including multidrug-resistant strains, and some species of nontuberculous mycobacteria (NTM) compared with that of linezolid. Using the current Clinical and Laboratory Standards Institute (CLSI)-recommended method of broth microdilution, susceptibility testing of 170 isolates of rapidly growing mycobacteria showed equivalent or lower (1-to 8-fold) MIC 50 and/or MIC 90 values for tedizolid compared with that for linezolid. The tedizolid MIC 90 values for 81 isolates of M. abscessus subsp. abscessus and 12 isolates of M. abscessus subsp. massiliense were 8 g/ml and 4 g/ml, respectively, compared with linezolid MIC 90 values of 32 g/ml for both. The MIC 90 values for 20 isolates of M. fortuitum were 2 g/ml for tedizolid and 4 g/ml for linezolid. Twenty-two isolates of M. chelonae had tedizolid and linezolid MIC 90 s of 2 g/ml and 16 g/ml, respectively. One hundred forty-two slowly growing NTM, including 7/7 M. marinum, 7/7 M. kansasii, and 7/11 of other less commonly isolated species, had tedizolid MICs of Յ1 g/ml and linezolid MICs of Յ4 g/ml. One hundred isolates of Mycobacterium avium complex and eight M. simiae isolates had tedizolid MIC 50 s of 8 g/ml and linezolid MIC 50 s 32 and 64 g/ml, respectively. Nine M. arupense isolates had MIC 50 s of 4 g/ml and 16 g/ml for tedizolid and linezolid, respectively. These findings demonstrate a greater in vitro potency of tedizolid than linezolid against NTM and suggest that an evaluation of tedizolid as a potential treatment agent for infections caused by selected NTM is warranted.KEYWORDS oxazolidinones, susceptibility testing, tedizolid N ontuberculous mycobacteria (NTM) are responsible for a multiplicity of different types of infections, including respiratory, cutaneous, and systemic infections. Many species of NTM are multidrug resistant (1), emphasizing the urgent need for new antimicrobials with efficacies against these organisms.Tedizolid phosphate is a novel oxazolidinone prodrug (TR-701) that is transformed in the serum into the active drug, tedizolid ([TZD] TR-700, formerly DA-7157) (2) with a broad range of activities against Gram-positive microorganisms, including mycobacteria. The mechanism of action of TZD is by the inhibition of protein synthesis. TZD binds to the 50S ribosome, apparently at a site near the 30S ribosome, which blocks the formation of the 70S initiation complex and, in turn, prevents protein synthesis (3). The supposition is that the major site of action of oxazolidinones is at the ribosomal peptidyltransferase center, and this unique mechanism of action eliminates the likelihood of cross-resistance with other antimicrobial classes (3).Previous reports of in vitro and in vivo (intracellular) activities against Mycobacterium tuberculosis, including multidrug-resistant strains (4), and Nocardia brasiliensis have been published (5-7). A previously published study by Vera-Cabrera et al. showed in vitro activities of TZ...

Repositioning rifamycins for Mycobacterium abscessus lung disease

“…Finally, the oxazolidinone linezolid was also reported to synergize with rifabutin [83]. Unfortunately, linezolid's toxicity profile has limited its use in the clinic, but both tedizolid and LCB01-0371 have activity against M. abscessus and improved safety profiles [90,91]. While synergies between these oxazolidinones and rifabutin have not been determined in vitro, rifabutin addition improved the potency of the imipenemtedizolid combination against M. abscessus in a macrophage infection model [92].…”

Pulmonary disease by non-tuberculous mycobacteria – clinical management, unmet needs and future perspectives

“…Addition of aminoglycosides should be considered in patients with advanced and/or fibrocavitary disease or previously treated disease, or those with macrolide resistance [27]. The roles of other potential drugs, such as, clofazimine, moxifloxacin, oxazolidinones (linezolid, tedizolid), bedaquiline, and amikacin for inhalation require further evaluation [27,[92][93][94][95][96][97][98][99][100]. Recently, a regimen of clofazimine, ethambutol, and a macrolide showed similar response rates compared with the standard regimen containing rifampin [101].…”

“…These compounds are not susceptible to erythromycin-resistance methylases, which mediate macrolide resistance [91]. Other drugs for evaluation in macrolide-resistant MAC include clofazimine, moxifloxacin, oxazolidinones (linezolid, tedizolid), and bedaquiline [27,[92][93][94][95][96]100].…”

Mycobacterium abscessus Complex Infections in Children: A Review

“…Few new antimicrobials suitable for pediatric use against nontuberculous mycobacteria are in the developmental pipeline; active research into novel agents or new uses of existing agents (such as avibactam) of a nontoxic and more easily administered nature, perhaps in combination with agents of known efficacy, would be of tremendous benefit in the face of evolving epidemiology for children at risk [71–73]. The lack of novel therapies is especially alarming in the context of contemporary evidence of mounting antimicrobial resistance by mycobacteria despite the advent of increasingly focused stewardship efforts worldwide [74].…”