Tedizolid

Tedizolid is an oxazolidinone antimicrobial agent with MIC50 value of 0.5 μg/ml for MSSA, MRSA, VR E. faecium and VR E. faecalis and 0.25 μg/ml for MSSE, MRSE, PSSP and PRSP [1].

The resistant Gram-positive infection is a serious global health problem. For instant, the methicillin-resistant S. aureus (MRSA) has spread all over the world with rates ranging from 18 to 26 cases among 100,000 people. Besides that, there come out a serious of resistant strains such as the linezolid-resistant S. aureus (LRSA) and the vancomycin-resistant S. aureus (VRSA). Due to the unfavorable outcomes of the existed antibiotics, alternative treatments have been developed. Tedizolid is a synthetic antibiotic that works based on the inhibition of protein synthesis. It binds to the 50S ribosome and inhibits the formation of the 70S complex [1].

Tedizolid showed potent bacteriostatic activity against many resistant Gram-positive pathogens such as MSSA, MRSA, S. pyogenes and S. pneumoniae. For the enterococcal and staphylococcal isolates, tedizolid displayed more than 4-fold higher potency than that of linezolid. It also showed inhibitory effects on a panel of 169 linezolid-resistant staphylococcal isolates with 79.2% inhibition at concentration of ≤ 4μg/ml. The MIC values of tedizolid against linezolid-resistant staphylococci were in a range from 0.06 to 16 mg/L. Besides that, tedizolid was found to be the inhibitors of human monoamine oxidase with IC50 values of 8.7 and 5.7 μM for MAO-A and MAO-B, respectively [1, 2 and 3].

When treated in vivo, tedizolid was the active moiety converted from the pro-drug tedizolid phosphate. It was found that granulocytes could affect the antistaphylococcal effect of tedizolid. In neutropenic mice, the administration of tedizolid for 24 hours or 48 hours caused ED50 values of 25.2 and 35.7 mg/kg/day, respectively [1 and 4].

References:
[1] Kanafani Z A, Corey G R.  Tedizolid (TR-701): a new oxazolidinone with enhanced potency. Expert opinion on investigational drugs, 2012, 21(4): 515-522.
[2] Rodríguez-Avial I, Culebras E, Betriu C, et al.  In vitro activity of tedizolid (TR-700) against linezolid-resistant staphylococci. Journal of antimicrobial chemotherapy, 2012, 67(1): 167-169.
[3] Flanagan S, Bartizal K, Minassian S L, et al.  In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrobial agents and chemotherapy, 2013, 57(7): 3060-3066.
[4] Louie A, Liu W, Kulawy R, et al.  In vivo pharmacodynamics of torezolid phosphate (TR-701), a new oxazolidinone antibiotic, against methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains in a mouse thigh infection model. Antimicrobial agents and chemotherapy, 2011, 55(7): 3453-3460.

In vitro activity of tedizolid and linezolid against Staphylococcus epidermidis isolated from prosthetic joint infections.[Pubmed:28326447]

Eur J Clin Microbiol Infect Dis. 2017 Sep;36(9):1549-1552.

Prosthetic joint infections (PJIs) are rare but long-lasting and are serious complications without any spontaneous resolution, requiring additional surgery and long-term treatment with antibiotics. Staphylococci are the most important aetiological agents of PJIs, and among the coagulase-negative staphylococci Staphylococcus epidermidis is the most common. However, S. epidermidis often displays multidrug resistance (MDR), demanding additional treatment options. The objective was to examine the effectiveness of Tedizolid and linezolid against S. epidermidis isolated from PJIs. The standard antibiotic susceptibility pattern of S. epidermidis (n = 183) obtained from PJIs was determined by disc diffusion test, and MIC was determined by Etest for Tedizolid, linezolid, and vancomycin. Tedizolid displayed MIC values ranging from 0.094 to 0.5 mg/L (MIC50: 0.19 mg/L, MIC90: 0.38 mg/L), linezolid MIC values ranging from 0.25 to 2 mg/L (MIC50: 0.75 mg/L, MIC90: 1 mg/L), and vancomycin MIC values ranging from 0.5 to 3 mg/L (MIC50 and MIC90 both 2 mg/L). According to the disc diffusion test, 153/183 (84%) isolates were resistant to >/=3 antibiotic groups, indicating MDR. In conclusion, S. epidermidis isolates from PJIs were fully susceptible, and the MIC50 and MIC90 values for Tedizolid were two- to four-fold dilution steps lower compared with linezolid. Tedizolid is not approved, and there are no reports of long-term treatment, but it may display better tolerability and fewer adverse effects than linezolid; it thus could be a possible treatment option for PJIs, alone or in combination with rifampicin.

In Vitro Susceptibility Testing of Tedizolid against Nontuberculous Mycobacteria.[Pubmed:28330892]

J Clin Microbiol. 2017 Jun;55(6):1747-1754.

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) MIC50 and/or MIC90 values for Tedizolid compared with that for linezolid. The Tedizolid MIC90 values for 81 isolates of M. abscessus subsp. abscessus and 12 isolates of M. abscessus subsp. massiliense were 8 mug/ml and 4 mug/ml, respectively, compared with linezolid MIC90 values of 32 mug/ml for both. The MIC90 values for 20 isolates of M. fortuitum were 2 mug/ml for Tedizolid and 4 mug/ml for linezolid. Twenty-two isolates of M. chelonae had Tedizolid and linezolid MIC90s of 2 mug/ml and 16 mug/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 Tedizolid MIC50s of 8 mug/ml and linezolid MIC50s 32 and 64 mug/ml, respectively. Nine M. arupense isolates had MIC50s of 4 mug/ml and 16 mug/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.

Efficacy of tedizolid against methicillin-resistant Staphylococcus aureus and Peptostreptococcus anaerobius in thigh mixed-infection mouse model.[Pubmed:28343752]

J Infect Chemother. 2017 Jun;23(6):368-373.

OBJECTIVE: The purpose of this study is to compare the antimicrobial activity of human simulated exposures of Tedizolid 200 mg daily, and linezolid 600 mg every 12 h for the treatment of complicated skin and skin structure infection (cSSSI) caused by MRSA and Peptostreptococcus anaerobius in both the neutropenic mice thigh mixed-infection models. MATERIAL AND METHOD: Tedizolid phosphate and linezolid were used for all in vivo testing. A total of one MRSA and two P. anaerobius isolates were utilized. Antimicrobial efficacy was calculated for each isolate as the change in bacterial numbers (Deltalog10 CFU/ml) obtained in the treated mice after 24 h compared with the numbers in the starting control animals (0 h). RESULTS: The Tedizolid and linezolid MICs for MRSA was 0.25 and 2 mug/ml. Tedizolid MIC for P. anaerobius was 0.12 mug/ml, and linezolid MICs for two P. anaerobius isolates were 0.5 and 1 mug/ml. In mixed infection model, Tedizolid therapy showed similar antimicrobial activities for one MRSA and two P. anaerobius isolates evaluated, compared with linezolid therapy. Additionally, when comparing the activity of Tedizolid and linezolid monotherapy between single infection and mixed infection model, antimicrobial activities of both antimicrobials were attenuated when mixed infection model was used. CONCLUSION: In the neutropenic murine thigh infection model, human simulated exposures of Tedizolid and linezolid resulted in similar efficacies against MRSA, even though single and mixed infection models were used. These data support the clinical utility of Tedizolid for use against MRSA and P. anaerobius in the treatment of cSSSI.

Tedizolid (TR 700; Torezolid; DA-7157) is a novel oxazolidinone, acting through inhibition of bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA) of the 50S subunit of the ribosome.

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