tedizolid-phosphate and Staphylococcal-Infections

The development of resistance to antibiotics has been ignored for a long time. But nowadays, increasing resistance is an important topic. For a decade no new antibiotics had been developed and it is not possible to quickly close this gap of new resistance and no new drugs. This work presents six new antibiotics (ceftaroline, ceftobiprole, solithromycin, tedizolid, ceftolozane/tazobactam, ceftazidime/avibactam). In part, only expert opinions are given due to lack of study results.The two 5th generation cephalosporins ceftaroline and ceftobiprole have beside their equivalent efficacy to ceftriaxone (ceftaroline) and cefipim (ceftobiprole) high activity against MRSA. The fluoroketolide solithromycin should help against macrolide-resistant pathogens and has been shown to be noninferior to the fluorochinolones. The oxazolidinone tedizolid is effective against linezolid-resistant MRSA. The two cephalosporins ceftolozane/tazobactam and ceftazidime/avibactam are not only effective against gram-negative pathogens, but they have a very broad spectrum. Due to the efficacy against extended-spectrum β‑lactamases, they can relieve the selection pressure of the carbapenems. We benefit from all new antibiotics which can take the selection pressure from other often used antibiotics. The increasing number of resistant gram-negative pathogens worldwide is alarming. Thus, focusing on the development of new drugs is extremely important.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Infections; Ceftaroline; Ceftazidime; Cephalosporins; Clinical Trials as Topic; Drug Approval; Drug Combinations; Drug Resistance, Multiple, Bacterial; Ephedrine; Humans; Macrolides; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Penicillanic Acid; Phenobarbital; Staphylococcal Infections; Tazobactam; Theophylline; Triazoles

Tedizolid, the active moiety of tedizolid phosphate, is approved in the United States, the European Union, Canada and a number of other countries for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This network meta-analysis (NMA) evaluates the comparative effectiveness of tedizolid and other antibacterials indicated for the treatment of ABSSSI caused by MRSA.. Systematic review of 10 databases was undertaken to inform an NMA to estimate the relative effectiveness of tedizolid and established monotherapy comparators (ceftaroline, daptomycin, linezolid, teicoplanin, tigecycline, vancomycin) for treating MRSA-associated ABSSSI. Randomized controlled trials enrolling adults with ABSSSI or complicated skin and skin structure infections caused by suspected/documented MRSA were eligible for inclusion. Networks were developed based on similarity of study design, patient characteristics, outcome measures and available data. Outcomes of interest included clinical response at end of therapy (EOT), post-therapy evaluation (PTE) or test-of-cure assessment and treatment discontinuations resulting from adverse events (AEs). Bayesian NMA was conducted for each outcome using fixed-effects and random effects models.. Literature searches identified 3,618 records; 15 trials met the inclusion criteria and were considered suitable for NMA comparison. In fixed-effects models, tedizolid had higher odds of clinical response at EOT (odds ratio [OR], 1.7; credible interval, 1.0, 3.0) and PTE than vancomycin (OR, 1.6; credible interval, 1.1, 2.5). No differences in odds of clinical response at EOT or PTE were observed between tedizolid and other comparators. There was no evidence of a difference among treatments for discontinuation due to AEs. Results from random effects and fixed-effects models were generally consistent.. Tedizolid was superior to vancomycin for clinical response at EOT and PTE. There was no evidence of a difference between tedizolid and other comparators and no evidence of a difference between tedizolid and all comparators when evaluating discontinuation due to AEs. These findings suggest that tedizolid provides an alternative option for the management of serious skin infections caused by suspected or documented MRSA. This study is subject to the limitations inherent in all NMAs, and the results should be interpreted accordingly.

Topics: Anti-Bacterial Agents; Bayes Theorem; Ceftaroline; Cephalosporins; Daptomycin; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Oxazolidinones; Skin Diseases, Bacterial; Staphylococcal Infections; Tetrazoles; Vancomycin

The emerging antibiotic resistance of Gram-positive pathogens represents a significant challenge to the management of human infections. The novel oxazolidinone tedizolid demonstrates antimicrobial activity across a broad range of Gram-positive pathogens and greater potency than linezolid against wild-type and drug-resistant pathogens, including linezolid-resistant Staphylococcus aureus strains possessing mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins L3 or L4. Strains harboring such mutations are also selected for much less frequently with tedizolid than with linezolid. In addition, tedizolid has a significant potency advantage over linezolid-resistant strains carrying the horizontally transferable cfr gene. Methylation of A2503 of 23S rRNA by the Cfr methyltransferase confers resistance to linezolid (and a variety of other 50S ribosomal subunit-targeted antibiotics) but not to tedizolid because of structural differences in A-ring C5 substituents between the 2 drugs. The greater potency and improved resistance profile of tedizolid provides the microbiologic basis for considering this molecule as an alternative to linezolid for the treatment of serious infections caused by Gram-positive pathogens.

Topics: Acetamides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Gene Transfer, Horizontal; Humans; Linezolid; Organophosphates; Oxazoles; Oxazolidinones; Point Mutation; Ribosomal Protein L3; Ribosomal Proteins; RNA, Ribosomal, 23S; Staphylococcal Infections; Staphylococcus aureus; tRNA Methyltransferases

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Humans; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Staphylococcal Infections; Teicoplanin

Antimicrobial resistance among gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) continues to limit therapeutic options. The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of serious MRSA and VRE infections. With increasing utilization of linezolid, resistant pathogens have once again begun to emerge. Tedizolid, a next-generation oxazolidinone, possesses a spectrum of activity including MRSA and VRE, with significantly enhanced potency also against linezolid-resistant strains. Preclinical and early clinical studies have reported positive results, demonstrating a favorable pharmacokinetic profile in combination with key potential safety advantages. In two phase III clinical trials, tedizolid was found noninferior to linezolid in the treatment of acute bacterial skin and skin structure infections. Investigations for treatment of ventilator-acquired and health care-associated pneumonia are currently underway. Tedizolid has been subjected to pharmacodynamics studies throughout its development that have highlighted properties unique to this agent. Considerable accumulations in epithelial lining fluid and antimicrobial activity greatly augmented by the presence of granulocytes suggest that slow but bactericidal activity may be possible in some clinical scenarios. Structural distinctions between tedizolid and linezolid suggest that tedizolid has decreased vulnerability to oxazolidinone resistance mechanisms. Tedizolid minimum inhibitory concentrations are essentially unchanged in organisms possessing the chloramphenicol-florfenicol resistance gene, a horizontally transferable linezolid resistance mechanism. Although the clinical experience with tedizolid remains limited, early data suggest a potential role in the treatment of serious infections due to multidrug-resistant gram-positive pathogens.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drugs, Investigational; Gram-Positive Bacterial Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Prodrugs; Staphylococcal Infections; Vancomycin-Resistant Enterococci

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.. The tedizolid and linezolid MICs for MRSA was 0.25 and 2 μg/ml. Tedizolid MIC for P. anaerobius was 0.12 μg/ml, and linezolid MICs for two P. anaerobius isolates were 0.5 and 1 μg/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.. 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.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Female; Gram-Positive Bacterial Infections; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Peptostreptococcus; Staphylococcal Infections; Thigh

We determined the MIC and minimum biofilm bactericidal concentration (MBBC) of tedizolid and vancomycin against 97 isolates of Staphylococcus aureus and 74 isolates of Staphylococcus epidermidis associated with prosthetic joint infection. All isolates were vancomycin susceptible in the planktonic state; all staphylococci studied had a tedizolid MIC ≤0.5 μg/mL. The MBBC90 was >32 and >128 μg/mL for tedizolid and vancomycin, respectively.

Topics: Anti-Bacterial Agents; Arthritis, Infectious; Humans; Inhibitory Concentration 50; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Prosthesis-Related Infections; Staphylococcal Infections; Staphylococcus

We compared tedizolid alone and tedizolid with rifampin to rifampin and vancomycin plus rifampin in a rat model of methicillin-resistant Staphylococcus aureus (MRSA) foreign body-associated osteomyelitis. The study strain was a prosthetic joint infection-associated isolate. Steady-state pharmacokinetics for intraperitoneal administration of tedizolid, vancomycin, and rifampin were determined in uninfected rats. MRSA was inoculated into the proximal tibia, and a wire was implanted. Four weeks later, the rats were treated intraperitoneally for 21 days with tedizolid (n = 14), tedizolid plus rifampin (n = 11), rifampin (n = 16), or vancomycin plus rifampin (n = 13). Seventeen rats received no treatment. After treatment, quantitative bone cultures were performed. Blood was obtained for determination of drug trough concentrations in the tedizolid and tedizolid plus rifampin groups. The mean peak plasma concentration and mean area under the concentration-time curve from time zero to 24 h for tedizolid were 12 μg/ml and 60 μg · h/ml, respectively. The bacterial loads in all treatment groups were significantly lower than those in the control group; those in the tedizolid- plus rifampin-treated animals were not significantly different from those in the vancomycin- plus rifampin-treated animals. The range of mean plasma trough concentrations in the tedizolid group was 0.44 to 0.73 μg/ml. Although neither tedizolid nor vancomycin resistance was detected in isolates recovered from bones, rifampin resistance was detected in 10 animals (63%) in the rifampin group, 8 animals (73%) in the tedizolid plus rifampin group, and a single animal (8%) in the vancomycin plus rifampin group. Tedizolid alone or tedizolid combined with rifampin was active in a rat model of MRSA foreign body-associated osteomyelitis. The emergence of rifampin resistance was noted in animals receiving tedizolid plus rifampin.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Bone Wires; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Foreign Bodies; Injections, Intraperitoneal; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Organophosphates; Osteomyelitis; Oxazoles; Rats; Rats, Wistar; Rifampin; Staphylococcal Infections; Tibia; Vancomycin

Tedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid against Staphylococcus aureus in vitro. The in vivo efficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistant S. aureus strain COL (infection inoculum of 10(7) CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P = 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P = 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (10(8) CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0-24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0-24 for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin.

Topics: Animals; Anti-Bacterial Agents; Daptomycin; Drug Administration Schedule; Endocarditis; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Rabbits; Staphylococcal Infections; Treatment Outcome; Vancomycin

The cfr gene was identified in three linezolid-resistant USA300 methicillin-resistant Staphylococcus aureus (MRSA) isolates collected over a 3-day period at a New York City medical center in 2011 as part of a routine surveillance program. Each isolate possessed a plasmid containing a pSCFS3-like cfr gene environment. Transformation of the cfr-bearing plasmids into the S. aureus ATCC 29213 background recapitulated the expected Cfr antibiogram, including resistance to linezolid, tiamulin, clindamycin, and florfenicol and susceptibility to tedizolid.

Topics: Acetamides; Anti-Bacterial Agents; Bacterial Proteins; Clindamycin; Diterpenes; Drug Resistance, Multiple, Bacterial; Gene Transfer Techniques; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Sequence Data; New York; Organophosphates; Oxazoles; Oxazolidinones; Plasmids; Staphylococcal Infections; Thiamphenicol

Tedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0-24)], 7 to 50 μg · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against a Staphylococcus aureus strain for which the MIC was ≤0.5 μg/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Area Under Curve; Biological Availability; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Neutrophils; Organophosphates; Oxazoles; Oxazolidinones; Platelet Count; Prodrugs; Skin Diseases, Bacterial; Staphylococcal Infections; Tetrazoles; Young Adult

The in vitro activities of tedizolid and 10 antistaphylococcal agents were compared against 111 methicillin-resistant Staphylococcus aureus (MRSA) strains from 14 epidemiologically characterized groups. Tedizolid, tigecycline, and daptomycin were the most potent agents, with tedizolid 4-fold more potent than linezolid. Tedizolid, linezolid, and vancomycin were unaffected by epidemiological types. Tigecycline and daptomycin had reduced potency against ST80-MRSA-IV and ST239-MRSA-III, respectively. Overall, tedizolid was highly potent against all MRSA strain types, including those resistant to other classes of drugs.

Topics: Anti-Bacterial Agents; Daptomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Minocycline; Organophosphates; Oxazoles; Staphylococcal Infections; Tigecycline

Torezolid phosphate (TR-701) is the phosphate monoester prodrug of the oxazolidinone TR-700 which demonstrates potent in vitro activity against Gram-positive bacteria, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The pharmacodynamics of TR-701 or TR-700 (TR-701/700) against S. aureus is incompletely defined. Single-dose pharmacokinetic studies were conducted in mice for TR-701/700. Forty-eight-hour dose range and 24-hour dose fractionation studies were conducted in a neutropenic mouse thigh model of S. aureus infection using MRSA ATCC 33591 to identify the dose and schedule of administration of TR-701/700 that was linked with optimized antimicrobial effect. Additional dose range studies compared the efficacies of TR-701/700 and linezolid for one MSSA strain and one community-associated MRSA strain. In dose range studies, TR-701/700 was equally bactericidal against MSSA and MRSA. Mean doses of 37.6 and 66.9 mg/kg of body weight/day of TR-701/700 resulted in stasis and 1 log CFU/g decreases in bacterial densities, respectively, at 24 h, and mean doses of 35.3, 46.6, and 71.1 mg/kg/day resulted in stasis and 1 and 2 log CFU/g reductions, respectively, at 48 h. Linezolid administered at doses as high as 150 mg/kg/day did not achieve stasis at either time point. Dose fractionation studies demonstrated that the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the pharmacodynamic index for TR-701/700 that was linked with efficacy. TR-701/700 was highly active against MSSA and MRSA, in vivo, and was substantially more efficacious than linezolid, although linezolid's top exposure has half the human exposure. Dose fractionation studies showed that AUC/MIC was the pharmacodynamic index linked with efficacy, indicating that once-daily dosing in humans is feasible.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Female; Humans; Linezolid; Methicillin; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Oxazolidinones; Serum; Staphylococcal Infections; Staphylococcus aureus; Tetrazoles; Thigh

Tedizolid (TR-700, formerly torezolid) is the active component of the new oxazolidinone prodrug tedizolid phosphate (TR-701). We had previously demonstrated that tedizolid possessed potent antistaphylococcal activity superior to that of linezolid in a neutropenic mouse thigh infection model (A. Louie, W. Liu, R. Kulawy, and G. L. Drusano, Antimicrob. Agents Chemother. 55:3453-3460, 2011). In the current investigation, we used a mouse thigh infection model to delineate the effect of an interaction of TR-700 and granulocytes on staphylococcal cell killing. We compared the antistaphylococcal killing effect of doses of TR-701 equivalent to human exposures ranging from 200 to 3,200 mg/day in both granulocytopenic and normal mice. The mice were evaluated at 24, 48, and 72 h after therapy initiation. In granulocytopenic mice, a clear exposure response in which, depending on the time point of evaluation, stasis was achieved at "human-equivalent" doses of slightly below 2,300 mg/day (at 24 h) to slightly below 2,000 mg/day (at 72 h) was observed. In immune-normal animals, stasis was achieved at human-equivalent doses of slightly greater than 100 mg/day or less. The variance in bacterial cell killing results was attributable to the presence of granulocytes (without drug), the direct effect of TR-700 on Staphylococcus aureus, and the effect of the drug on Staphylococcus aureus mediated through granulocytes. The majority of the bacterial cell killing in normal animals was attributable to the effect of TR-700 mediated through granulocytes. Additional studies need to be undertaken to elucidate the mechanism underlying this observation.

Topics: Animals; Anti-Infective Agents; Female; Granulocytes; Mice; Microbial Sensitivity Tests; Models, Theoretical; Organophosphates; Oxazoles; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Tetrazoles; Thigh