In vitro activity of tedizolid (TR-700) against linezolid-resistant staphylococci

Rodríguez-Avial, Iciar; Culebras, Esther; Betriú, Carmen; Morales, Glauco; Peña, Irene; Picazo, Juan J.

doi:10.1093/jac/dkr403

Cited by 67 publications

(49 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The results suggest that TR-701 would exhibit an efficacy similar to the efficacy of lin- ezolid for S. aureus pneumonia. An unanswered question in the current study is whether TR-701 would be expected to have the same efficacy for a linezolid-resistant isolate, as has been suggested by in vitro results (32,33,46,49). The results suggest further study of TR-701 in clinical trials of pneumonia due to S. aureus is warranted and may be especially useful given the increased burden of MSSA and MRSA pneumonia in the health care setting.…”

Section: Discussionmentioning

confidence: 73%

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

Lepak

Marchillo

Pichereau

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Staphylococcus aureus has become a leading cause of community-and hospital-acquired pneumonia. Furthermore, infection with community-and health care-acquired strains of methicillinresistant S. aureus (MRSA) is increasingly common and limits antimicrobial options (13,25,29,31). Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug. The active moiety, tedizolid (TR-700), exhibits potent activity against Gram-positive bacteria, including MRSA (48). The goals of our studies were to identify the pharmacodynamic (PD) target (AUC/MIC ratio) for TR-700 against methicillin-susceptible S. aureus (MSSA) and MRSA strains in a neutropenic murine pneumonia model and compare the PD targets of TR-700 to that of the only FDA-approved oxazolidinone antibiotic, linezolid. MATERIALS AND METHODSBacteria, media, and antibiotics. Eleven isolates of S. aureus were utilized for these experiments. The strains included four MSSA strains (ATCC 6538P, ATCC 25923, ATCC 29213, and ATCC Smith), one hospital-acquired MRSA strain (ATCC 33591), and six community-acquired MRSA strains (MW2, R2527, 04-045, 04-154, 05-051, and UW 307109). Organisms were grown, subcultured, and quantified in Mueller-Hinton broth (Difco Laboratories, Detroit, MI) and Mueller-Hinton agar (Difco Laboratories, Detroit, MI). Linezolid was obtained from the University of Wisconsin pharmacy. Tedizolid (TR-700) and tedizolid phosphate (TR-701) were supplied by the manufacturer (Trius Therapeutics, San Diego, CA). Prior to in vivo treatment studies, TR-701 was dissolved in sterile water at the appropriate drug concentrations. TR-700 was dissolved in sterile dimethyl sulfoxide (DMSO) and diluted with medium to the appropriate concentration for in vitro susceptibility testing.In vitro susceptibility studies. The MICs of linezolid and TR-700 were determined three times in duplicate using Clinical and Laboratory Standards Institute (CLSI) microdilution methods M07-A8 (15). The duplicates were identical, and the final results were reported as the median value of the three MIC tests (see Table 1).Murine infection model. All animal studies were approved by the Animal Research Committees of the University of Wisconsin and William S. Middleton Memorial VA Hospital. Six-week-old, specific-pathogenfree, female ICR/Swiss mice weighing between 24 and 27 g (Harlan Sprague-Dawley, Indianapolis, IN) were used for all studies. Three mice were utilized for each treatment and control group. Mice were rendered neutropenic (absolute neutrophil count of Ͻ100/mm 3 ) by injecting cyclophosphamide (Mead Johnson Pharmaceuticals, Evansville, IN) intraperitoneally 4 days (150 mg/kg of body weight) and 1 day (100 mg/kg) prior to experimental infection. Previous studies have shown that this regimen produces persistent neutropenia in this animal model for 5 days (3). Broth cultures of freshly plated bacteria were grown to logarithmic phase. The inoculum for each organism was diluted to a 0.3 absorbance at 580 nm. Viable plate count confirmation of the inoculum ranged from 10 6 to 10 7 CFU/ml. Anima...

show abstract

Section: Discussionmentioning

confidence: 73%

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

Lepak

Marchillo

Pichereau

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The introduction of TZD provides another potential antimicrobial with an efficacy against these organisms, and early MIC studies performed with bacterial species show that TZD has a 4-to 16-fold greater potency than LZD against some bacteria, including LZD-resistant organisms (2,15,16 50 and an MIC 90 of 64 g/ml for LZD, and isolates were not differentiated into subspecies (current subspecies designations were unknown at the time) as they were in this study of 81 isolates of M. abscessus subsp. abscessus (MIC 50 , 4 g/ml and MIC 90 , 8 g/ml for TZD; MIC 50 , 16 g/ml and MIC 90 , 32 g/ml for LZD).…”

Section: Discussionmentioning

confidence: 99%

“…Previous investigators have also reported that TZD has enhanced in vitro activity against bacterial strains, including linezolid (LZD)-resistant strains of Streptococcus pneumoniae and methicillin-susceptible and -resistant coagulase-negative and -positive Staphylococcus, Streptococcus pyogenes, and Streptococcus agalactiae (2,3,8). With this superior activity in mind, we undertook a large study to evaluate the in vitro MICs of TZD compared with the MICs of LZD and other comparator antimicrobials against isolates of NTM.…”

mentioning

confidence: 99%

In Vitro Susceptibility Testing of Tedizolid against Nontuberculous Mycobacteria

Brown‐Elliott

Wallace

2017

J Clin Microbiol

View full text Add to dashboard Cite

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...

show abstract

“…In a study of its activity against linezolid‐resistant staphylococci, tedizolid showed a more than 16‐fold improvement compared to linezolid 39. It also maintained activity against most of the tested isolates, including multidrug‐resistant ones, thus clearly demonstrating the benefit of the structure‐based approach.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 92%

Targeting Antibiotic Resistance

2016

View full text Add to dashboard Cite

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

show abstract

In vitro activity of tedizolid (TR-700) against linezolid-resistant staphylococci

Abstract: The results of this study confirm the activity of tedizolid against linezolid-resistant staphylococci. This new oxazolidinone could have an important role as a potential therapeutic agent against multidrug-resistant staphylococci.

Cited by 67 publications

References 9 publications

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

In Vitro Susceptibility Testing of Tedizolid against Nontuberculous Mycobacteria

Targeting Antibiotic Resistance

Contact Info

Product

Resources

About