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1.  Activity of Tedizolid Phosphate (TR-701) in Murine Models of Infection with Penicillin-Resistant and Penicillin-Sensitive Streptococcus pneumoniae 
The in vitro activity of tedizolid (previously known as torezolid, TR-700) against penicillin-resistant Streptococcus pneumoniae (PRSP) clinical isolates and the in vivo efficacy of tedizolid phosphate (torezolid phosphate, TR-701) in murine models of PRSP systemic infection and penicillin-susceptible S. pneumoniae (PSSP) pneumonia were examined using linezolid as a comparator. The MIC90 against 28 PRSP isolates was 0.25 μg/ml for tedizolid, whereas it was 1 μg/ml for linezolid. In mice infected systemically with a lethal inoculum of PRSP 1 h prior to a single administration of either antimicrobial, oral tedizolid phosphate was equipotent to linezolid (1 isolate) to 2-fold more potent than linezolid (3 isolates) for survival at day 7, with tedizolid phosphate 50% effective dose (ED50) values ranging from 3.19 to 11.53 mg/kg of body weight/day. In the PSSP pneumonia model, the ED50 for survival at day 15 was 2.80 mg/kg/day for oral tedizolid phosphate, whereas it was 8.09 mg/kg/day for oral linezolid following 48 h of treatment with either agent. At equivalent doses (10 mg/kg once daily tedizolid phosphate or 5 mg/kg twice daily linezolid), pneumococcal titers in the lungs at 52 h postinfection were approximately 3 orders of magnitude lower with tedizolid phosphate treatment than with linezolid treatment or no treatment. Lung histopathology showed less inflammatory cell invasion into alveolar spaces in mice treated with tedizolid phosphate than in untreated or linezolid-treated mice. These results demonstrate that tedizolid phosphate is effective in murine models of PRSP systemic infection and PSSP pneumonia.
doi:10.1128/AAC.00346-12
PMCID: PMC3421900  PMID: 22713339
2.  In Vitro Activity and Microbiological Efficacy of Tedizolid (TR-700) against Gram-Positive Clinical Isolates from a Phase 2 Study of Oral Tedizolid Phosphate (TR-701) in Patients with Complicated Skin and Skin Structure Infections 
Tedizolid (TR-700, formerly torezolid) is the active moiety of the prodrug tedizolid phosphate (TR-701), a next-generation oxazolidinone, with high potency against Gram-positive species, including methicillin-resistant Staphylococcus aureus (MRSA). A recently completed randomized, double-blind phase 2 trial evaluated 200, 300, or 400 mg of oral tedizolid phosphate once daily for 5 to 7 days in patients with complicated skin and skin structure infections. This report examines the in vitro activity of tedizolid and Zyvox (linezolid) against Gram-positive pathogens isolated at baseline and describes the microbiological and clinical efficacy of tedizolid. Of 196 isolates tested, 81.6% were S. aureus, and of these, 76% were MRSA. The MIC50 and MIC90 of tedizolid against both methicillin-susceptible S. aureus (MSSA) and MRSA were 0.25 μg/ml, compared with a MIC50 of 1 μg/ml and MIC90 of 2 μg/ml for linezolid. For coagulase-negative staphylococci (n = 7), viridans group streptococci (n = 15), and beta-hemolytic streptococci (n = 3), the MICs ranged from 0.03 to 0.25 μg/ml for tedizolid and from 0.12 to 1 μg/ml for linezolid. The microbiological eradication rates at the test-of-cure visit (7 to 14 days posttreatment) in the microbiologically evaluable population (n = 133) were similar in all treatment groups, with overall eradication rates of 97.7% for all pathogens, 97.9% for MRSA, and 95.7% for MSSA. The clinical cure rates for MRSA and MSSA infections were 96.9% and 95.7%, respectively, across all dose groups. This study confirms the potent in vitro activity of tedizolid against pathogenic Gram-positive cocci, including MRSA, and its 4-fold-greater potency in comparison with linezolid. All dosages of tedizolid phosphate showed excellent microbiological and clinical efficacy against MRSA and MSSA.
doi:10.1128/AAC.00458-12
PMCID: PMC3421864  PMID: 22687509
3.  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 ▿ 
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.
doi:10.1128/AAC.01565-10
PMCID: PMC3122459  PMID: 21502615
4.  Comparative Efficacies of Human Simulated Exposures of Tedizolid and Linezolid against Staphylococcus aureus in the Murine Thigh Infection Model 
Tedizolid (formally torezolid) is an expanded-spectrum oxazolidinone with enhanced in vitro potency against Gram-positive pathogens, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The efficacies of human simulated exposures of tedizolid and linezolid against S. aureus in an immunocompetent mouse thigh model over 3 days were compared. Four strains of MRSA and one of MSSA with tedizolid and linezolid MICs ranging from 0.25 to 0.5 and from 2 to 4 μg/ml, respectively, were utilized. Tedizolid or linezolid was administered in a regimen simulating a human steady-state 24-h area under the free concentration-time curve of 200 mg every 24 h (Q24) or 600 mg Q12, respectively. Thighs were harvested after 4, 8, 12, 24, 36, 48, and 72 h, and efficacy was determined by the change in bacterial density. The mean bacterial density in control mice increased over the 3-day period. After 24 h of treatment, a reduction in bacterial density of ≥1 log CFU was observed for both the tedizolid and linezolid treatments. Antibacterial activity was enhanced for both agents with a reduction of ≥2.6 log CFU after 72 h of treatment. Any statistically significant differences (P ≤ 0.05) in efficacy between the agents were transient and did not persist throughout the 72-h treatment period. The tedizolid and linezolid regimens demonstrated similar in vivo efficacies against the S. aureus isolates tested. Both agents were bacteriostatic at 24 h and bactericidal on the third day of treatment. These data support the clinical utility of tedizolid for skin and skin structure infections caused by S. aureus, as well as the bactericidal activity of the oxazolidinones after 3 days of treatment.
doi:10.1128/AAC.00122-12
PMCID: PMC3421595  PMID: 22687504
5.  Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model 
Antimicrobial Agents and Chemotherapy  2012;56(11):5916-5922.
Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug (converted to the active form tedizolid [TR-700]) with potent Staphylococcus aureus activity. The current studies characterized and compared the in vivo pharmacokinetic/pharmacodynamic (PD) characteristics of TR-701/TR-700 and linezolid against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in the neutropenic murine pneumonia model. The pharmacokinetic properties of both drugs were linear over a dose range of 0.625 to 40 mg/kg of body weight. Protein binding was 30% for linezolid and 85% for TR-700. Mice were infected with one of 11 isolates of S. aureus, including MSSA and community- and hospital-acquired MRSA strains. Each drug was administered by oral-gastric gavage every 12 h (q12h). The dosing regimens ranged from 1.25 to 80 mg/kg/12 h for linezolid and 0.625 to 160 mg/kg/12 h for TR-701. At the start of therapy, mice had 6.24 ± 0.40 log10 CFU/lungs, which increased to 7.92 ± 1.02 log10 CFU/lungs in untreated animals over a 24-h period. A sigmoid maximum-effect (Emax) model was used to determine the antimicrobial exposure associated with net stasis (static dose [SD]) and 1-log-unit reduction in organism relative to the burden at the start of therapy. The static dose pharmacodynamic targets for linezolid and TR-700 were nearly identical, at a free drug (non-protein-bound) area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) of 19 and 20, respectively. The 1-log-unit kill endpoints were also similar, at 46.1 for linezolid and 34.6 for TR-700. The exposure targets were also comparable for both MSSA and MRSA isolates. These dosing goals support further clinical trial examination of TR-701 in MSSA and MRSA pneumonia.
doi:10.1128/AAC.01303-12
PMCID: PMC3486526  PMID: 22964254
6.  Pharmacokinetics of Tedizolid Following Oral Administration: Single and Multiple Dose, Effect of Food, and Comparison of Two Solid Forms of the Prodrug 
Pharmacotherapy  2013;34(3):240-250.
Objectives
The single- and multiple-dose pharmacokinetics (PK) of tedizolid were examined after oral administration of tedizolid phosphate disodium (TPD), including the effect of food on PK. The relative bioavailability of TPD to the free acid tedizolid phosphate was determined to bridge the results of these and other studies to the solid form of the prodrug selected for further development.
Design
Randomized placebo-controlled, double-blind single- and multiple-ascending dose studies and randomized open-label, crossover food effect and relative bioavailability studies.
Setting
Clinical Research Units.
Participants
Healthy subjects.
Intervention
Study TR701-101 enrolled 40 subjects in single-ascending dose (200–1200 mg TPD or placebo) and 40 subjects in 21-day multiple-ascending dose (200, 300, or 400 mg TPD once/day; 600 mg linezolid twice/day; or placebo) arms. Study TR701-103 was a food-effect study in 12 subjects administered 600 mg TPD. Study TR701-108 was a relative bioavailability study in 12 subjects administered 150-mg tedizolid equivalents as TPD or tedizolid phosphate.
Measurements and Main Results
Plasma concentrations of the prodrug tedizolid phosphate, its active moiety tedizolid, and/or linezolid were collected. After administration of 200 to 600 mg TPD, tedizolid values increased approximately dose proportionally in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax). Tedizolid half-life values were approximately 2-fold greater compared with linezolid. TPD administration with food delayed tedizolid absorption and reduced Cmax relative to the fasted state but did not alter AUC. Minimal accumulation was predicted and observed for tedizolid, whereas observed accumulation of linezolid exceeded predictions based on single-dose PK. Comparable PK of tedizolid was observed following oral administration of either TPD or tedizolid phosphate. In the multiple-ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8 linezolid subjects (low reticulocyte count).
Conclusions
Overall, tedizolid has a favorable PK profile, a half-life that supports once daily administration, and no nonlinearities at steady state. Tedizolid phosphate can be administered without regard to food.
doi:10.1002/phar.1337
PMCID: PMC4238735  PMID: 23926058
tedizolid phosphate disodium; tedizolid phosphate free acid; TR-700; TR-701; TR-701 FA; pharmacokinetics; food effect; relative bioavailability
7.  Profile of tedizolid phosphate and its potential in the treatment of acute bacterial skin and skin structure infections 
Tedizolid phosphate is the first once-daily oxazolidinone approved by the United States Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections (ABSSSI). It is more potent in vitro than linezolid against methicillin-resistant Staphylococcus aureus (MRSA) and other gram-positive pathogens causing ABSSSI, even retaining activity against some linezolid-resistant strains. Tedizolid is approximately 90% protein bound, leading to lower free-drug concentrations than linezolid. The impact of the effect of food, renal or hepatic insufficiency, or hemodialysis on tedizolid’s pharmacokinetic have been evaluated, and no dosage adjustment is needed in these populations. In animal and clinical studies, tedizolid’s effect on bacterial killing is optimized by the free-drug area under the curve to minimum inhibitory concentration ratio (fAUC/MIC). The 200 mg once-daily dose is able to achieve the target fAUC/MIC ratio in 98% of simulated patients. Two Phase III clinical trials have demonstrated the noninferiority of tedizolid 200 mg once daily for 6 days to linezolid 600 mg twice daily for 10 days. In vitro, animal, and clinical studies have failed to demonstrate that tedizolid inhibits monoamine oxidase to a clinically relevant extent. Tedizolid has several key advantages over linezolid including once daily dosing, decreased treatment duration, minimal interaction with serotonergic agents, possibly associated with less adverse events associated with the impairment of mitochondrial protein synthesis (eg, myelosuppression, lactic acidosis, and peripheral/optic neuropathies), and retains in vitro activity against linezolid-resistant gram-positive bacteria. Economic analyses with tedizolid are needed to describe the cost-effectiveness of this agent compared with other options used for ABSSSI, particularly treatment options active against MRSA.
doi:10.2147/IDR.S56691
PMCID: PMC4411017  PMID: 25960671
tedizolid; oxazolidinone; ABSSSI; MRSA; VRE; monoamine oxidase
8.  Potential role of tedizolid phosphate in the treatment of acute bacterial skin infections 
Tedizolid phosphate (TR-701), a prodrug of tedizolid (TR-700), is a next-generation oxazolidinone that has shown favorable results in the treatment of acute bacterial skin and skin-structure infections in its first Phase III clinical trial. Tedizolid has high bioavailability, penetration, and tissue distribution when administered orally or intravenously. The activity of tedizolid was greater than linezolid against strains of Staphylococcus spp., Streptococcus spp., and Enterococcus spp. in vitro studies, including strains resistant to linezolid and those not susceptible to vancomycin or daptomycin. Its pharmacokinetic characteristics allow for a once-daily administration that leads to a more predictable efficacy and safety profile than those of linezolid. No hematological adverse effects have been reported associated with tedizolid when used at the therapeutic dose of 200 mg in Phase I, II, or III clinical trials of up to 3 weeks of tedizolid administration. Given that the clinical and microbiological efficacy are similar for the 200, 300, and 400 mg doses, the lowest effective dose of 200 mg once daily for 6 days was selected for Phase III studies in acute bacterial skin and skin-structure infections, providing a safe dosing regimen with low potential for development of myelosuppression. Unlike linezolid, tedizolid does not inhibit monoamine oxidase in vivo, therefore interactions with adrenergic, dopaminergic, and serotonergic drugs are not to be expected. In conclusion, tedizolid is a novel antibiotic with potent activity against Gram-positive microorganisms responsible for skin and soft tissue infections, including strains resistant to vancomycin, linezolid, and daptomycin, thus answers a growing therapeutic need.
doi:10.2147/DDDT.S30728
PMCID: PMC3622392  PMID: 23589680
oxazolidinone; TR-700; TR-701 FA; tedizolid; skin and soft tissue infections; linezolid resistance
9.  Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers 
Plasma concentrations of antimicrobial drugs have long been used to correlate exposure with effect, yet one cannot always assume that unbound plasma and tissue concentrations are similar. Knowledge about unbound tissue concentrations is important in the development of antimicrobial drugs, since most infections are localised in tissues. Therefore, a clinical microdialysis study was conducted to evaluate the distribution of tedizolid (TR-700), the active moiety of the antimicrobial prodrug tedizolid phosphate (TR-701), into interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissues following a single oral 600 mg dose of tedizolid phosphate in fasting conditions. Twelve healthy adult subjects were enrolled. Two microdialysis probes were implanted into the thigh of each subject, one into the vastus medialis muscle and one into subcutaneous adipose tissue. Probes were calibrated using retrodialysis. Dialysate samples were collected every 20 min for 12 h following a single oral dose of 600 mg tedizolid phosphate, and blood samples were drawn over 24 h. Unbound tedizolid levels in plasma were similar to those in muscle and adipose tissue. The ratios of unbound (free) AUC in tissues over unbound AUC in plasma (fAUCtissue/fAUCplasma) were 1.1 ± 0.2 and 1.2 ± 0.2 for adipose and muscle tissue, respectively. The median half-life was 8.1, 9.2 and 9.6 h for plasma, adipose tissue and muscle tissue, respectively. Mean protein binding was 87.2 ± 1.8%. The study drug was very well tolerated. The results of this study show that tedizolid distributes well into ISF of adipose and muscle tissues. Unbound levels of tedizolid in plasma, adipose tissue and muscle tissue were well correlated. Free plasma levels are indicative of unbound levels in the ISF of muscle and adipose tissues.
doi:10.1016/j.ijantimicag.2012.03.006
PMCID: PMC3789129  PMID: 22584101
Microdialysis; Tissue distribution; Tedizolid; Pharmacokinetics
10.  Tedizolid Population Pharmacokinetics, Exposure Response, and Target Attainment 
Antimicrobial Agents and Chemotherapy  2014;58(11):6462-6470.
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.
doi:10.1128/AAC.03423-14
PMCID: PMC4249359  PMID: 25136028
11.  New developments in the management of severe skin and deep skin structure infections – focus on tedizolid 
Tedizolid, a novel oxazolidinone, is approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs). Tedizolid offers several potential advantages over current ABSSSI treatment options. First, tedizolid has a prolonged half-life, which allows for once-daily dosing. Second, tedizolid has broad spectrum activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, and enterococci. Third, tedizolid, available in both intravenous and oral formulations, has high oral bioavailability, allowing for easy oral step-down therapy. Fourth, in patients who have been prescribed selective serotonin reuptake inhibitors or monoamine oxidase inhibitors, tedizolid may have fewer drug interactions than linezolid. Finally, tedizolid may have fewer or comparatively delayed onset side effects than linezolid, including thrombocytopenia and nausea. This review covers the microbiology, pharmacology, mode of action, and pharmacokinetics of tedizolid as well as patient-focused perspectives such as quality of life, patient satisfaction/acceptability, adherence, and uptake and provides expert opinion on the current use of tedizolid for ABSSSIs and potential future therapeutic applications.
doi:10.2147/TCRM.S64553
PMCID: PMC4447168  PMID: 26045667
cellulitis; new antibiotics; oxazolidinones; infectious diseases; MRSA
12.  Analysis of the Phase 3 ESTABLISH Trials of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections 
Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy [EOT]), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by Staphylococcus aureus. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%; P = 0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm3 at the EOT (tedizolid, 4.9%; linezolid, 10.8%; P = 0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%; P = 0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.)
doi:10.1128/AAC.03688-14
PMCID: PMC4335893  PMID: 25421472
13.  Tedizolid Phosphate: a Next-Generation Oxazolidinone 
Treatment of multidrug-resistant Gram-positive infections continues to challenge clinicians as the emergence of new resistance mechanisms outpaces introduction of novel antimicrobial agents. Tedizolid phosphate is a next-generation oxazolidinone with activity against both methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. Tedizolid has consistently shown potency advantages over linezolid against Gram-positive microorganisms including those with reduced susceptibility to linezolid. Of particular significance, minimum inhibitory concentrations of tedizolid appear to be largely unaffected by the chloramphenicol–florfenicol resistance (cfr) gene, which has been implicated in a number of published linezolid-resistant organism outbreaks. Tedizolid phosphate also has been found to have a favorable pharmacokinetic profile allowing for once-daily dosing in both oral and intravenous forms. Potency and pharmacokinetic advantages have allowed for lower total daily doses of tedizolid, compared to linezolid, being needed for clinical efficacy in the treatment of acute bacterial skin and skin structure infections (ABSSSI). The decreased total drug exposure produced may in part be responsible for a decrease in the observed adverse effects including thrombocytopenia. Tedizolid phosphate is currently indicated for the treatment of ABSSSI and under investigation for the treatment of nosocomial pneumonia. Although much of the role of tedizolid remains to be defined by expanding clinical experience, tedizolid is likely a welcomed addition to the mere handful of agents available for the treatment of multidrug-resistant Gram-positive infections.
Electronic supplementary material
The online version of this article (doi:10.1007/s40121-015-0060-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s40121-015-0060-3
PMCID: PMC4363212  PMID: 25708156
Enterococcus; Gram-positive; Methicillin-resistant Staphylococcus aureus; Oxazolidinone; Staphylococcus; Tedizolid; Vancomycin-resistant enterococci
14.  In Vitro, In Vivo, and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase Interactions 
Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety, tedizolid, has improved potency against Gram-positive pathogens and pharmacokinetics, allowing once-daily administration. Given linezolid warnings for drug-drug and drug-food interactions mediated by monoamine oxidase (MAO) inhibition, including sporadic serotonergic toxicity, these studies evaluated tedizolid for potential MAO interactions. In vitro, tedizolid and linezolid were reversible inhibitors of human MAO-A and MAO-B; the 50% inhibitory concentration (IC50) for tedizolid was 8.7 μM for MAO-A and 5.7 μM for MAO-B and 46.0 and 2.1 μM, respectively, with linezolid. Tedizolid phosphate was negative in the mouse head twitch model of serotonergic activity. Two randomized placebo-controlled crossover clinical studies assessed the potential of 200 mg/day tedizolid phosphate (at steady state) to enhance pressor responses to coadministered oral tyramine or pseudoephedrine. Sensitivity to tyramine was determined by comparing the concentration of tyramine required to elicit a ≥30-mmHg increase in systolic blood pressure (TYR30) when administered with placebo versus tedizolid phosphate. The geometric mean tyramine sensitivity ratio (placebo TYR30/tedizolid phosphate TYR30) was 1.33; a ratio of ≥2 is considered clinically relevant. In the pseudoephedrine study, mean maximum systolic blood pressure was not significantly different when pseudoephedrine was coadministered with tedizolid phosphate versus placebo. In summary, tedizolid is a weak, reversible inhibitor of MAO-A and MAO-B in vitro. Provocative testing in humans and animal models failed to uncover significant signals that would suggest potential for hypertensive or serotonergic adverse consequences at the therapeutic dose of tedizolid phosphate. Clinical studies are registered at www.clinicaltrials.gov as NCT01539473 (tyramine interaction study conducted at Covance Clinical Research Center, Evansville, IN) and NCT01577459 (pseudoephedrine interaction study conducted at Vince and Associates Clinical Research, Overland Park, KS).
doi:10.1128/AAC.00431-13
PMCID: PMC3697335  PMID: 23612197
15.  Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment 
Antimicrobial Agents and Chemotherapy  2014;58(11):6471-6476.
Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].)
doi:10.1128/AAC.03431-14
PMCID: PMC4249404  PMID: 25136024
16.  Single- and Multiple-Dose Pharmacokinetics and Absolute Bioavailability of Tedizolid 
Pharmacotherapy  2014;34(9):891-900.
Objectives
Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate.
Design
Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies.
Setting
Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010.
Participants
Ninety healthy volunteers.
Intervention
Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100–400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days.
Measurements and Main Results
A dose-dependent increase was observed in the maximum plasma concentration (1.2–5.1 μg/ml) and the area under the concentration-time curve (17.4–58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100–400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores.
Conclusion
These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes.
doi:10.1002/phar.1458
PMCID: PMC4260119  PMID: 24989138
tedizolid phosphate; intravenous; pharmacokinetics
17.  Platelet Profile in Patients with Acute Bacterial Skin and Skin Structure Infections Receiving Tedizolid or Linezolid: Findings from the Phase 3 ESTABLISH Clinical Trials 
Antimicrobial Agents and Chemotherapy  2014;58(12):7198-7204.
Tedizolid, the active moiety of tedizolid phosphate, is a recently approved oxazolidinone antibacterial with activity against a wide range of Gram-positive pathogens, including resistant strains such as methicillin-resistant Staphylococcus aureus. To date, 6 days of 200 mg tedizolid once daily has been shown to be noninferior to 10 days of 600 mg linezolid twice daily in two randomized, double-blind phase 3 trials (ESTABLISH-1 and ESTABLISH-2) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). The intent of this study was to characterize the platelet profiles of patients receiving tedizolid relative to linezolid over the course of treatment using pooled data from these two trials. The occurrences of clinically defined and statistical analysis plan–specified reduced platelet counts were assessed at the study days 7 to 9 visit, the study days 11 to 13 visit, and the posttherapy evaluation (PTE) visit. At the study days 7 to 9 visit, incidences of reduced platelet counts were low and largely similar between the groups. The only notable difference was a lower incidence of thrombocytopenia (platelet counts, <150,000 cells/mm3) among patients who received tedizolid (3.2%) relative to those who received linezolid (5.6%). At the study days 11 to 13 visit, patients who received tedizolid had lower incidences of platelet counts of <150,000 cells/mm3 (−5.9%), <112,500 cells/mm3 (−2.4%), and <100,000 cells/mm3 (−1.9%) than patients in the linezolid group. Similar differences were noted at the PTE visit. Findings across the two phase 3 ABSSSI trials suggest that 6 days of 200 mg tedizolid daily confers a low potential for reduced platelet counts among patients with ABSSSIs. (The ESTABLISH-1 and ESTABLISH-2 trials have been registered at ClinicalTrials.gov under registration numbers NCT01170221 and NCT01421511, respectively.)
doi:10.1128/AAC.03509-14
PMCID: PMC4249542  PMID: 25246392
18.  Activity of Tedizolid (TR-700) against Well-Characterized Methicillin-Resistant Staphylococcus aureus Strains of Diverse Epidemiological Origins 
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.
doi:10.1128/AAC.00274-13
PMCID: PMC3716181  PMID: 23571550
19.  In Vivo Pharmacodynamic Characterization of a Novel Plectasin Antibiotic, NZ2114, in a Murine Infection Model ▿  
NZ2114 is a novel plectasin derivative with potent activity against gram-positive bacteria, including multiply drug-resistant strains. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of NZ2114 and determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy. Serum drug levels following administration of three fourfold-escalating single-dose levels of NZ2114 were measured by microbiologic assay. Single-dose time-kill studies following doses of 10, 40, and 160 mg/kg of body weight demonstrated concentration-dependent killing over the dose range (0.5 to 3.7 log10 CFU/thigh) and prolonged postantibiotic effects (3 to 15 h) against both Staphylococcus aureus and Streptococcus pneumoniae. Mice had 106.3 to 106.8 CFU/thigh of strains of S. pneumoniae or S. aureus at the start of therapy when treated for 24 h with 0.625 to 160 mg/kg/day of NZ2114 fractionated for 4-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD index best correlated with microbiologic efficacy. Efficacies of NZ2114 were similar among the dosing intervals (P = 0.99 to 1.0), and regression with the 24-h area under the concentration-time curve (AUC)/MIC index was strong (R2, 0.90) for both S. aureus and S. pneumoniae. The maximum concentration of drug in serum/MIC index regression was also strong for S. pneumoniae (R2, 0.96). Studies to identify the PD target for NZ2114 utilized eight S. pneumoniae and six S. aureus isolates and an every-6-h regimen of drug (0.156 to 160 mg/kg/day). Treatment against S. pneumoniae required approximately twofold-less drug for efficacy in relationship to the MIC than did treatment against S. aureus. The free drug 24-h AUCs/MICs necessary to produce a stasis effect were 12.3 ± 6.7 and 28.5 ± 11.1 for S. pneumoniae and S. aureus, respectively. The 24-h AUC/MIC associated with a 1-log killing endpoint was only 1.6-fold greater than that needed for stasis. Resistance to other antimicrobial classes did not impact the magnitude of the PD target required for efficacy. The PD target in this model should be considered in the design of clinical trials with this novel antibiotic.
doi:10.1128/AAC.01584-08
PMCID: PMC2704636  PMID: 19414576
20.  Quantitative effect of granulocytes on antibiotic treatment of experimental staphylococcal infection. 
The quantitative relation between granulocytopenia and antibiotic treatment was established for a short-term Staphylococcus aureus infection in the thighs of mice, using rifampin, benzylpenicillin, and erythromycin. Granulocytopenia was induced by total-body irradiation; the number of granulocytes decreased gradually during the first 5 days after irradiation to 10% of the number in normal mice. Experimental infections were established on each of the 5 days after irradiation. In animals not treated with antibiotics, the number of granulocytes in peripheral blood and the number of CFU at the site of infection exhibited a strong negative correlation. The influence of granulocytes on the effect of antibiotics on the number of CFU differed for the three antibiotics. For erythromycin the slope of the dose-effect relation was rather flat, but a decrease in the number of granulocytes caused a significant, nearly parallel, shift in the dose-effect relation, resulting in an increase in the number of CFU. For benzylpenicillin the slope of the dose-effect relation for normal mice was also flat, but as the number of granulocytes decreased the slope became significantly steeper, resulting in a diminishing influence of granulocytes at higher dosages. For rifampin the slope of the dose-effect relation, which was already steep for nonirradiated animals, increased significantly. Here too the effect of granulocytes decreased as the dose increased.
PMCID: PMC284214  PMID: 3619426
21.  In vitro and in vivo comparison of the anti-staphylococcal efficacy of generic products and the innovator of oxacillin 
BMC Infectious Diseases  2010;10:153.
Background
Oxacillin continues to be an important agent in the treatment of staphylococcal infections; many generic products are available and the only requirement for their approval is demonstration of pharmaceutical equivalence. We tested the assumption that pharmaceutical equivalence predicts therapeutic equivalence by comparing 11 generics with the innovator product in terms of concentration of the active pharmaceutical ingredient (API), minimal inhibitory (MIC) and bactericidal concentrations (MBC), and antibacterial efficacy in the neutropenic mouse thigh infection model.
Methods
The API in each product was measured by a validated microbiological assay and compared by slope (potency) and intercept (concentration) analysis of linear regressions. MIC and MBC were determined by broth microdilution according to Clinical and Laboratory Standard Institute (CLSI) guidelines. For in vivo efficacy, neutropenic ICR mice were inoculated with a clinical strain of Staphylococcus aureus. The animals had 4.14 ± 0.18 log10 CFU/thigh when treatment started. Groups of 10 mice per product received a total dose ranging from 2.93 to 750 mg/kg per day administered q1h. Sigmoidal dose-response curves were generated by nonlinear regression fitted to Hill equation to compute maximum effect (Emax), slope (N), and the effective dose reaching 50% of the Emax (ED50). Based on these results, bacteriostatic dose (BD) and dose needed to kill the first log of bacteria (1LKD) were also determined.
Results
4 generic products failed pharmaceutical equivalence due to significant differences in potency; however, all products were undistinguishable from the innovator in terms of MIC and MBC. Independently of their status with respect to pharmaceutical equivalence or in vitro activity, all generics failed therapeutic equivalence in vivo, displaying significantly lower Emax and requiring greater BD and 1LKD, or fitting to a non-sigmoidal model.
Conclusions
Pharmaceutical or in vitro equivalence did not entail therapeutic equivalence for oxacillin generic products, indicating that criteria for approval deserve review to include evaluation of in vivo efficacy.
doi:10.1186/1471-2334-10-153
PMCID: PMC2897798  PMID: 20525378
22.  Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection 
Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against Staphylococcus aureus. The objective of our study was to examine the in vivo activity of cefquinome against S. aureus strains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo postantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected with S. aureus strain ATCC 29213. The animals were treated by subcutaneous injection of cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and produced in vivo PAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T>MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additional S. aureus isolates. A sigmoid maximum effect (Emax) model was used to estimate the magnitudes of the ratios of the %T that the free-drug serum concentration exceeded the MIC (%T>fMIC) associated with net bacterial stasis, a 0.5-log10 CFU reduction from baseline, and a 1-log10 CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make cefquinome an attractive option for the treatment of infections caused by S. aureus.
doi:10.1128/AAC.01666-13
PMCID: PMC4068449  PMID: 24614373
23.  Generic Vancomycin Products Fail In Vivo despite Being Pharmaceutical Equivalents of the Innovator ▿  
Generic versions of intravenous antibiotics are not required to demonstrate therapeutic equivalence with the innovator because therapeutic equivalence is assumed from pharmaceutical equivalence. To test such assumptions, we studied three generic versions of vancomycin in simultaneous experiments with the innovator and determined the concentration and potency of the active pharmaceutical ingredient by microbiological assay, single-dose pharmacokinetics in infected mice, antibacterial effect by broth microdilution and time-kill curves (TKC), and pharmacodynamics against two wild-type strains of Staphylococcus aureus by using the neutropenic mouse thigh infection model. The main outcome measure was the comparison of magnitudes and patterns of in vivo efficacy between generic products and the innovator. Except for one product exhibiting slightly greater concentration, vancomycin generics were undistinguishable from the innovator based on concentration and potency, protein binding, in vitro antibacterial effect determined by minimal inhibitory or bactericidal concentrations and TKC, and serum pharmacokinetics. Despite such similarities, all generic products failed in vivo to kill S. aureus, while the innovator displayed the expected bactericidal efficacy: maximum antibacterial effect (Emax) (95% confidence interval [CI]) was 2.04 (1.89 to 2.19), 2.59 (2.21 to 2.98), and 3.48 (2.92 to 4.04) versus 5.65 (5.52 to 5.78) log10 CFU/g for three generics and the innovator product, respectively (P < 0.0001, any comparison). Nonlinear regression analysis suggests that generic versions of vancomycin contain inhibitory and stimulatory principles within their formulations that cause agonistic-antagonistic actions responsible for in vivo failure. In conclusion, pharmaceutical equivalence does not imply therapeutic equivalence for vancomycin.
doi:10.1128/AAC.01044-09
PMCID: PMC2916296  PMID: 20547818
24.  Early bacterial clearance from murine lungs. Species-dependent phagocyte response. 
Journal of Clinical Investigation  1980;66(2):194-199.
Two sets of phagocytic cells are available to defend the lung against inhaled bacteria. Both resident alveolar macrophages and granulocytes from the circulation have been observed in pulmonary air spaces after the deposition of bacteria; their functional roles, however, have been defined. We rendered mice selectively granulocytopenic with heterologous antiserum in order to ascertain the relative contributions of these two groups of cells in intrapulmonary bacterial killing. The clearance of Staphylococcus aureus was unimpaired in granulocytopenic animals, confirming the primary role of the alveolar macrophages in the killing of these organisms. In contrast, granulocytopenic animals cleared only 10.0+/-7.0% of an inoculum of Klebsiella pneumoniae compared with 33.0+/-4.0% clearance in normal animals (P < 0.02), and Pseudomonas aeruginosa proliferated to 513% of baseline levels in granulocytopenic animals, whereas normal mice cleared 26.8+/-10.6% of the inoculum. These findings indicate that circulating granulocytes play a major role in the clearance of the latter two organisms. This variation in cellular response to different bacterial species suggests that the defense of the lung against pathogenic bacteria is more complex than has been previously assumed.
PMCID: PMC371698  PMID: 6995480
25.  Impact of Burden on Granulocyte Clearance of Bacteria in a Mouse Thigh Infection Model ▿  
Antimicrobial Agents and Chemotherapy  2010;54(10):4368-4372.
We wished to delineate granulocytes' impact on the clearance of different bacterial burdens of Pseudomonas aeruginosa and Staphylococcus aureus in a granulocyte-replete mouse thigh infection model. A mouse thigh model was employed. Bacterial challenges from 105 to 3 × 107 CFU (S. aureus) and from 3 × 104 to 3 × 108 CFU (P. aeruginosa) were injected into murine posterior thighs. Organism quantitation was at baseline, 2 h (Pseudomonas only), and 24 h. A Michaelis-Menten population model was fit to the data for each organism. Breakpoints for microbial containment by granulocytes were identified. Bacterial burdens exceeding that breakpoint value resulted in organism multiplication. The Michaelis-Menten model fit the data well. For P. aeruginosa, the observed-predicted plot had a regression equation that explained over 98% of the variance (P ≪ 0.001). For S. aureus, this relationship explained greater than 94% of the variance (P ≪ 0.001). Maximal growth rate constants, maximal population burdens, and the bacterial loads at which granulocytes killed if half-saturated were not different. The kill rate constant for P. aeruginosa was almost 10 times that of S. aureus. Bacterial kill by granulocytes is saturable. No difference between saturation points of different isolates was seen. A higher bacterial burden means an increasing reliance on chemotherapy to drive bacterial clearance.
doi:10.1128/AAC.00133-10
PMCID: PMC2944594  PMID: 20516275

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