tedizolid and Gram-Positive-Bacterial-Infections

Enterococci with special resistance patterns (mainly vancomycin-resistant enterococci) play an important role in everyday clinical practice. Rising resistance rates to linezolid, daptomycin or tigecycline are also increasingly reported. Therapeutically, linezolid and daptomycin are the most important substances mainly in infections due to vancomycin-resistant enterococci. Several systematic meta-analyses of bloodstream infections showed discrepant results in the comparison of mortality of linezolid and daptomycin-treated bacteraemias. The containment of enterococci with special resistance patterns is currently receiving great attention. The key hygienic issue in all recommendations for dealing with multidrug-resistant enterococci can be summarized very simply: current scientific evidence is often inconsistent and studies that have clearly tested a single intervention for efficacy are lacking. The present work gives an insight into the current epidemiology and therapeutic strategies. Furthermore, the recently published German KRINKO recommendations are presented.

Topics: Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Enterococcus; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Oxazolidinones; Tetrazoles; Tigecycline; Vancomycin Resistance

Tedizolid is a second-generation oxazolidinone with activity against Gram-positive bacteria, including MRSA isolates resistant to linezolid. Pivotal clinical trials showed that tedizolid at 200 mg once-daily for 6 days is not inferior to linezolid 600 mg twice daily for 10 days in patients with SSTI. The comparison of adverse events is favorable to tedizolid under the circumstances of the clinical trials. This is a review of recent literature on tedizolid, its use in special populations and potential adverse effects.. Findings suggest that tedizolid can be used in SSTI in adolescents, those older than 65 years, obese individuals and patients with diabetic foot infections. Forthcoming research to determine the future uses of this drug in other clinical syndromes requires demonstration of tolerance whenever tedizolid is administered for longer than 6 days.We also speculate on missing data and potential future indications of tedizolid in the highly competitive field of the treatment of severe Gram-positive infections other than SSTI.. Tedizolid is a second-generation oxazolidinone, very convenient for treatment of SSTI, in search for other indications including nosocomial pneumonia and bone and joint infections. VIDEO ABSTRACT.

Topics: Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Gram-Positive Bacterial Infections; Humans; Oxazolidinones; Skin Diseases, Infectious; Soft Tissue Infections; Tetrazoles; Treatment Outcome

Oxazolidinones comprise an important class of antibacterial protein synthesis inhibitors. Myelosuppression and monoamine oxidase inhibition (MAOI) are key independent causes for limiting adverse effects in therapy with the sole approved drug of this class, linezolid. This annotation describes a novel oxazolidinone agent, (S)-5-((isoxazol-3-ylamino)methyl)-3-(2,3,5-trifluoro-4-(4-oxo-3,4-dihydropyridin-1(2H)-yl)phenyl)oxazolidin-2-one (MRX-I), distinguished by its high activity against Gram-positive pathogens coupled with markedly reduced potential for myelosuppression and MAOI. The medical need, medicinal chemistry rationale, preclinical data, and phase I clinical trial summary for this new agent are reviewed herein.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Bone Marrow Cells; Clinical Trials, Phase I as Topic; Drug Design; Drug Resistance, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Linezolid; Monoamine Oxidase Inhibitors; Oxazolidinones; Pyridones; Sepsis

The mechanism of action, pharmacokinetics, pharmacodynamics, and clinical efficacy and safety of an investigational second-generation oxazolidinone are reviewed.. Tedizolid is a protein synthesis inhibitor in clinical development for the treatment of gram-positive infections. Similar to linezolid, tedizolid works by binding to the 23S ribosomal RNA of the 50S subunit, thereby preventing the formation of the 70S initiation complex and inhibiting protein synthesis. Tedizolid has demonstrated potent in vitro activity against multidrug-resistant gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, and vancomycin-resistant enterococci (VRE), including some linezolid-resistant strains. Tedizolid has a favorable pharmacokinetic profile that allows for once-daily dosing and easy i.v.-to-oral conversion. Unlike linezolid, tedizolid has not been shown to interact with serotonergic agents in clinical studies. Two Phase III studies in patients with acute bacterial skin and skin structure infections have demonstrated the noninferiority of 6 days of tedizolid therapy (200 mg i.v. or orally once daily) relative to 10 days of linezolid therapy. In clinical trials to date, overall rates of treatment-related adverse effects with linezolid and tedizolid were comparable (40.8% versus 43.3%), with nausea being the most commonly reported adverse effect associated with tedizolid use (16% of patients). Planned studies will investigate tedizolid's potential role in the treatment of community-acquired bacterial pneumonia, hospital-acquired/ventilator-associated bacterial pneumonia, and bacteremia.. Tedizolid is an investigational oxazolidinone antibiotic for the treatment of multidrug-resistant gram-positive pathogens such as MRSA, Streptococcus pneumoniae, and VRE, including some linezolid-resistant strains.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Drug Interactions; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazolidinones; Tetrazoles

Linezolid, approved for clinical use since 2000, has become an important addition to the anti-Gram-positive infection armamentarium. This oxazolidinone drug has in vitro and in vivo activity against essentially all Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The in vitro activity of linezolid was well documented prior to its clinical application, and several ongoing surveillance studies demonstrated consistent and potent results during the subsequent years of clinical use. Emergence of resistance has been limited and associated with invasive procedures, deep organ involvement, presence of foreign material and mainly prolonged therapy. Non-susceptible organisms usually demonstrate alterations in the 23S rRNA target, which remain the main resistance mechanism observed in enterococci; although a few reports have described the detection of cfr-mediated resistance in Enterococcus faecalis. S. aureus isolates non-susceptible to linezolid remain rare in large surveillance studies. Most isolates harbour 23S rRNA mutations; however, cfr-carrying MRSA isolates have been observed in the United States and elsewhere. It is still uncertain whether the occurrences of such isolates are becoming more prevalent. Coagulase-negative isolates (CoNS) resistant to linezolid were uncommon following clinical approval. Surveillance data have indicated that CoNS isolates, mainly Staphylococcus epidermidis, currently account for the majority of Gram-positive organisms displaying elevated MIC results to linezolid. In addition, these isolates frequently demonstrate complex and numerous resistance mechanisms, such as alterations in the ribosomal proteins L3 and/or L4 and/or presence of cfr and/or modifications in 23S rRNA. The knowledge acquired during the past decades on this initially used oxazolidinone has been utilized for developing new candidate agents, such as tedizolid and radezolid, and as linezolid patents soon begin to expire, generic brands will certainly become available. These events will likely establish a new chapter for this successful class of antimicrobial agents.

Topics: Acetamides; Anti-Bacterial Agents; Bacterial Proteins; Drug Approval; Drug Resistance, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Linezolid; Microbial Sensitivity Tests; Mutation; Oxazolidinones; Ribosomal Protein L3; Ribosomal Proteins; RNA, Ribosomal, 23S; Tetrazoles

Tedizolid is a novel oxazolidinone antibiotic. Considering the higher antibacterial effect in immunocompetent compared with immunosuppressed animals, it is not recommended in immunocompromised patients.. In this study, we assessed the 'pure' pharmacokinetic-pharmacodynamic (PKPD) relationship for tedizolid against Enterococcus in the hollow-fibre infection model (HFIM).. Unbound plasma concentration time profiles (200-5000 mg/day IV) were simulated in the HFIM over 120 h against an Enterococcus faecalis strain and two clinical isolates of Enterococcus faecium (VRE-vanB and VRE-vanA). Next, a PKPD model describing tedizolid efficacy against bacterial isolates was developed. A population PK model was linked to the developed PKPD model and utilized to predict the bacterial kinetics in plasma and in target tissues [adipose, muscle, epithelial lining fluid (ELF) and sputum] over 120 h of therapy.. The PKPD model adequately described the bacterial kill kinetics for all bacterial populations. At the human recommended dose of 200 mg/day, bacterial growth was predicted in plasma and all tissues, except for ELF. Bacteriostasis was observed only at a higher dose of 1200 mg/day over 120 h. An fAUC/MIC of 80 related to stasis over 120 h. Subpopulations resistant to 3 × MIC were amplified in plasma and target tissues, except for ELF, at doses of 200-800 mg/day.. The human dose of 200 mg/day was insufficient to suppress bacterial growth in the HFIM, indicating that further components contribute to the clinical effect of tedizolid. This study supports the warning/precaution for tedizolid to limit its use in immunocompromised patients.

Topics: Animals; Anti-Bacterial Agents; Enterococcus; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Oxazolidinones; Tetrazoles

Multicenter surveillance of antimicrobial susceptibility was performed for 235 vancomycin-resistant Enterococcus faecium (VREfm) isolates from 18 Taiwanese hospitals. The minimum inhibitory concentrations (MICs) of eravacycline, omadacycline, lipoglycopeptides, and other comparator antibiotics were determined using the broth microdilution method. Nearly all isolates of VREfm were not susceptible to teicoplanin, dalbavancin, and telavancin, with susceptibility rates of 0.5%, 1.7% and 0.5%, respectively. Tigecycline and eravacycline were active against 93.2% and 89.7% of the VREfm isolates, respectively. Moreover, the susceptibility rates of quinupristin/dalfopristin, tedizolid, and linezolid were 59.1%, 84.2%, and 77.4%, respectively. Additionally, 94% of the VREfm isolates were classified as susceptible to daptomycin, and the MICs of omadacycline required to inhibit VREfm growth by 50% and 90% were 0.12 and 0.5 mg/L, respectively. Susceptibility rates of VREfm isolates to synthetic tetracyclines and daptomycin were slightly lower and to oxazolidinone-class antibiotics were much lower in Taiwan than those in other parts of the world. Continuous monitoring of VREfm resistance to novel antibiotics, including synthetic tetracyclines, oxazolidinone-class antibiotics, and daptomycin, is needed in Taiwan.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Daptomycin; Drug Resistance, Bacterial; Enterococcus faecium; Epidemiological Monitoring; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Microbial Sensitivity Tests; Oxazolidinones; Taiwan; Tetracyclines; Tetrazoles; Tigecycline; Vancomycin; Vancomycin-Resistant Enterococci; Virginiamycin

Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Daptomycin; Endocarditis, Bacterial; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Rats; Staphylococcal Infections; Tetrazoles; Vancomycin Resistance; Vancomycin-Resistant Staphylococcus aureus

Dalbavancin is a new antibiotic against multi-drug resistant Gram (+) bacteria. Dalbavancin has an extremely long half-life. Current indication is skin and soft tissue infections (ABSSSI), but researchers have successfully administered it off-label to osteomyelitis (OM) patients.. We present a case of successful treatment of diabetic foot (DF) OM.. A 53-year-old male presented to our DF clinic, with recently diagnosed diabetes mellitus, with very bad glycaemic control (HbA1c=12,5%). He had diabetic neuropathy, but no peripheral arteriopathy. Two months before, because of an accident with hot water, he presented left foot ulcer, followed by ABSSSI and 1. Dalbavancin, due to its extremely long half-life, could potentially be the drug of choice for OM caused by multi-drug resistant Gram (+) cocci, in order to avoid hospitalization, especially on non-complient patients. Further research is necessary.

Topics: Anti-Bacterial Agents; Burns; Daptomycin; Diabetes Mellitus, Type 2; Diabetic Foot; Drug Resistance, Multiple, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Linezolid; Male; Middle Aged; Osteomyelitis; Oxazolidinones; Teicoplanin; Tetrazoles; Tigecycline

In a mouse peritonitis model, tedizolid was comparable to linezolid and daptomycin against an

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Daptomycin; Disease Models, Animal; Enterococcus faecalis; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Linezolid; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Oxazolidinones; Peritonitis; Staphylococcus; Tetrazoles

Despite the advances in current healthcare, bone and joint infections (BJIs) are a major clinical challenge that frequently involve prolonged systemic antibiotic use. Healthcare providers consider tedizolid an attractive candidate for therapy in adults and children with BJI.. We tested tedizolid against a US and European collection of Gram-positive BJI isolates (n = 797) consecutively collected from 2014 to 2017.. Organisms were tested by broth microdilution susceptibility methods following current CLSI guidelines and interpreted by both CLSI and EUCAST breakpoint criteria.. Staphylococcus aureus (59.3%; 58.6% in the USA and 60.4% in Europe) was the most common pathogen with a 29.6% MRSA rate and tedizolid MIC50/90 of 0.12/0.25 mg/L (100% susceptible). CoNS (15.0% of BJI in adults and <5% in children) had tedizolid MIC50/90 values of 0.12/0.12 mg/L (99.1% susceptible). Tedizolid exhibited MIC50/90 values of 0.12/0.25 mg/L for all streptococci and enterococci. Overall, high susceptibility rates (>95%) for vancomycin, daptomycin and linezolid were observed and, based on MIC90 values, tedizolid (MIC90 0.12-0.25 mg/L) was 4- to 8-fold more potent than linezolid (MIC90 0.5-2  mg/L) against this collection of Gram-positive pathogens causing BJI.. This study showed that tedizolid had potent in vitro activity against contemporary Gram-positive cocci causing BJI in adults and children in US and European hospitals.

Topics: Anti-Bacterial Agents; Arthritis, Infectious; Europe; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Osteomyelitis; Oxazolidinones; Tetrazoles; United States

We evaluated the microbiological efficacy of tedizolid compared with that of linezolid against common and emerging pathogens using pooled data from 2 phase 3 trials (NCT01170221 and NCT01421511) in patients with acute bacterial skin and skin structure infections. Patients received tedizolid 200 mg once daily for 6 days (n = 664) or linezolid 600 mg twice daily for 10 days (n = 669). Favorable microbiological outcome in both treatment groups, defined as eradication or presumed eradication at the end of treatment and at the posttherapy evaluation, exceeded 85% for most pathogens, including methicillin-resistant Staphylococcus aureus. Favorable microbiological response was observed for staphylococci and streptococci at tedizolid minimal inhibitory concentration values ≤0.5 mg/L and 0.25 mg/L, respectively. The studies demonstrated positive microbiological outcomes against common pathogens with a 6-day, once-daily regimen of tedizolid phosphate in patients with acute bacterial skin and skin structure infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Clinical Trials, Phase III as Topic; Double-Blind Method; Female; Gram-Positive Bacterial Infections; Humans; Linezolid; Male; Middle Aged; Oxazolidinones; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Soft Tissue Infections; Tetrazoles; Treatment Outcome; Young Adult

Topics: Anti-Bacterial Agents; Asian People; Gram-Positive Bacterial Infections; Humans; In Vitro Techniques; Inpatients; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Tetrazoles

For effective antibacterial therapy, physicians require qualitative test results using susceptibility breakpoints provided by clinical microbiology laboratories. This article summarizes the key components used to establish the Clinical Laboratory Standards Institute (CLSI) breakpoints for tedizolid. First, in vitro studies using recent surveillance and clinical trial isolates ascertained minimal inhibitory concentration (MIC) distributions against pertinent organisms, including staphylococci, streptococci, and enterococci. Studies in animal models of infection determined rates of antibacterial efficacy and survival following administration of tedizolid phosphate at doses equivalent to those in humans. Pharmacokinetic and pharmacodynamic analyses examined the relationship between plasma concentrations and MICs against the target organism. Finally, clinical trials assessed clinical and microbiologic outcomes by MIC. All these data were evaluated and combined to obtain the ratified CLSI susceptibility criteria for tedizolid of ≤0.5μg/mL for Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Enterococcus faecalis and ≤0.25μg/mL for Streptococcus anginosus group.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Enterococcus faecalis; Gram-Positive Bacterial Infections; Humans; Linezolid; Mice; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcus aureus; Streptococcus agalactiae; Streptococcus pyogenes; Tetrazoles

Enterococcal infections have become one of the most challenging nosocomial problems. Tedizolid, the second oxazolidinone, is 4-fold to 8-fold more potent in vivo and in vitro than linezolid against enterococci. However, the characteristics of tedizolid related to enterococci isolates in China remain elusive. The aim of this study was to evaluate in vitro activity of tedizolid against enterococcal isolates from patients with infections at a teaching hospital in China and to investigate the correlations between in vitro tedizolid activity against enterococci and the distribution of multilocus sequence types (MLST), resistance genes and virulence factors. A total of 289 non-duplicate Enterococcus faecalis strains and 68 E. faecium strains were isolated. Tedizolid inhibited 95.24% of all enterococcal isolates with an MIC ≤ 0.5μg/ml. Seventeen E. faecalis strains had an MIC > 0.5 μg/ml, and all E. faecium were inhibited at MIC ≤ 0.5 μg/ml. The proportion of tedizolid non-susceptible E. faecalis strains with optrA genes was higher than that among tedizolid-susceptible strains. Tedizolid exhibited good in vitro activity against all E. faecium strains, including multidrug-resistant E. faecium carrying tet(M), tet(L), tet(U),erm(A), erm(B) and erm(C) genes. In summary, tedizolid has an advantage (higher sensitivity rate) compared to linezolid among enterococci, except for isolates expressing the plasmid-encoded optrA gene.

Topics: Anti-Bacterial Agents; China; Drug Resistance, Bacterial; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Genes, Bacterial; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Multilocus Sequence Typing; Oxazolidinones; Tetrazoles; Virulence Factors

A total of 248 Gram-positive isolates from cancer patients were tested for in-vitro susceptibility to tedizolid and 3 comparator agents using CLSI broth microdilution methodology. Tedizolid inhibited 97% of isolates at ≤0.5μg/ml. It was active against all Gram-positive species and consistently had 8 fold lower MICs than linezolid, although based on % susceptibility using CLSI breakpoints, most isolates were also susceptible to the comparators. Tedizolid was active against MRSA isolates with vancomycin MICs of ≥1.0μg/ml.

Topics: Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Linezolid; Microbial Sensitivity Tests; Microbial Viability; Oxazolidinones; Tetrazoles; Vancomycin