Tedizolid Research Articles

Comparative In Vivo Efficacy of Human-Simulated Exposures of Tedizolid (TZD) in Neutropenic (I-) versus Immunocompetent (I+) Murine Streptococcus pneumoniae Lung Infection Model

Comparative In Vivo Efficacy of Human-Simulated Exposures of Tedizolid (TZD) in Neutropenic (I-) versus Immunocompetent (I+) Murine Streptococcus pneumoniae Lung Infection Model

Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans

1. Fluorine plays a key role in the design of new drugs and recent FDA approvals included two fluorinated drugs, tedizolid phosphate and vorapaxar, both of which contain the fluorophenyl pyridyl moiety.2. To investigate the likely phase-I (oxidative) metabolic fate of this group, various fluorinated phenyl pyridine carboxylic acids were incubated with the fungus Cunninghamella elegans, which is an established model of mammalian drug metabolism.3. 19F NMR spectroscopy established the degree of biotransformation, which varied depending on the position of fluorine substitution, and gas chromatography–mass spectrometry (GC–MS) identified alcohols and hydroxylated carboxylic acids as metabolites. The hydroxylated metabolites were further structurally characterised by nuclear magnetic resonance spectroscopy (NMR), which demonstrated that hydroxylation occurred on the 4′ position; fluorine in that position blocked the hydroxylation.4. The fluorophenyl pyridine carboxylic acids were not biotransformed by rat liver microsomes and this was a consequence of inhibitory action, and thus, the fungal model was crucial in obtaining metabolites to establish the mechanism of catabolism.

Tedizolid and Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections of the Lower Extremity versus Non-Lower-Extremity InfectionsPooled Analysis of Two Phase 3 Trials.

Tedizolid phosphate, the prodrug of the oxazolidinone tedizolid, has been approved in a number of countries, including the United States, those in the European Union, and Canada, for treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Two phase 3 trials demonstrated the noninferior efficacy of tedizolid (200 mg once daily for 6 days) to linezolid (600 mg twice daily for 10 days) in patients with ABSSSI. Because of the challenges of treating lower-extremity ABSSSI, the efficacy and safety of tedizolid and linezolid for treating lower-extremity versus non-lower-extremity infections were compared. This was a post hoc analysis of pooled data from patients with lower-extremity infections enrolled in two phase 3 studies, ESTABLISH-1 (NCT01170221) and ESTABLISH-2 (NCT01421511), comparing tedizolid to linezolid in patients with ABSSSI. Lower-extremity ABSSSI were present in 40.7% of tedizolid-treated and 42.2% of linezolid-treated patients. Methicillin-resistant Staphylococcus aureus (MRSA) was present in 34.7% of all patients with a baseline causative pathogen. Early clinical responses at 48 to 72 hours and investigator-assessed responses at the post-therapy evaluation were similar between tedizolid and linezolid, regardless of ABSSSI type. With both treatments, the early clinical response was slightly higher in patients with non-lower-extremity infection than in those with lower-extremity ABSSSI (tedizolid, 84.8% versus 77.0%; linezolid, 81.4% versus 76.6%, respectively); however, by the post-therapy evaluation visit, response rates were similar (tedizolid, 87.1% versus 86.3%; linezolid, 86.6% versus 87.2%, respectively). Gastrointestinal adverse events and low platelet counts were observed more frequently with linezolid treatment. Post-therapy evaluations showed that the clinical response of lower-extremity ABSSSI to tedizolid and linezolid was comparable to that of ABSSSI in other locations. A short 6-day course of once-daily tedizolid was as effective as a 10-day course of twice-daily linezolid in treating patients with lower-extremity ABSSSI.

Pharmacokinetics and Safety of Tedizolid after Single and Multiple Intravenous/Oral Sequential Administrations in Healthy Chinese Subjects

PurposeTedizolid phosphate is a new antibacterial agent under investigation for the treatment of Gram-positive infections in China. This study was conducted to assess the pharmacokinetic (PK) properties, oral bioavailability, and safety of once daily tedizolid phosphate 200 mg in Chinese subjects to support its further clinical development in China. MethodsThis Phase I single-center study, conducted in 16 healthy Chinese male subjects, consisted of a single-dose administration, 1:1 randomized, two-way, intravenous (IV)/oral (PO) crossover of tedizolid phosphate 200 mg (Part 1) and, after a 7-day washout, a nonrandomized, multiple-dose, 7-day tedizolid phosphate 200 mg once daily administration (IV for 3 days, PO for 4 days; Part 2). Blood samples were collected for up to 72 hours after single dosing and for up to 2 hours on Day 3 and 72 hours on Day 7 of multiple dosing to determine PK parameters. Adverse events (AEs) were recorded throughout the entire study. FindingsThe Cmax and AUC of tedizolid (the active moiety of tedizolid phosphate) were 3.02 µg/mL and 30.50 µg • h/mL after single IV dosing of tedizolid phosphate, and 2.25 µg/mL and 26.10 µg • h/mL after single PO dosing, respectively, and the mean half-life was 10.1 hours for both administration routes. The oral bioavailability of tedizolid was 85.5%. PK parameters of tedizolid were similar after single and multiple dosing of tedizolid phosphate, indicating no time dependency. Only minor accumulation of tedizolid was observed after multiple dosing (expressed as accumulation ratios RAAUC: 1.18 for PO dosing, and RACmax: 1.16 and 1.05 for IV and PO dosing, respectively). Steady state of tedizolid was reached after about 3 days, and trough concentrations remained constant when switching from IV to PO dosing. Tedizolid phosphate was well tolerated with 6 subjects (37.5%) in Part 1 and 5 subjects (31.3%) in Part 2 experiencing an AE; all AEs but one were related to the study drug assessed by the investigator. All AEs were of mild intensity and had recovered or resolved by the end of the study. No serious AEs were observed, and no subjects prematurely discontinued the study due to an AE. ImplicationsThe results of this Phase I study conducted in Chinese male subjects indicate that no dosage adjustment of tedizolid phosphate 200 mg would be required when switching administration routes in this population. Tedizolid phosphate was well tolerated in healthy Chinese subjects. China Food and Drug Administration clinical trial permission numbers 2014L00360 and 2014L00361.

Comparative Efficacies of Tedizolid Phosphate, Linezolid, and Vancomycin in a Murine Model of Subcutaneous Catheter-Related Biofilm Infection Due to Methicillin-Susceptible and -Resistant Staphylococcus aureus.

Tedizolid, a novel oxazolidinone, exhibits bacteriostatic activity through inhibition of protein synthesis. The efficacies of tedizolid, linezolid, and vancomycin were compared in a murine catheter-related biofilm infection caused by methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) strains engineered for bioluminescence. We observed significantly improved efficacy in terms of decreased S. aureus densities and bioluminescent signals in the tedizolid-treated group versus the linezolid- and vancomycin-treated groups in the model of infection caused by the MSSA and MRSA strains.

Effects of therapeutic and supratherapeutic doses of oral tedizolid phosphate on cardiac repolarisation in healthy volunteers: a randomised controlled study

Drug-induced prolongation of the QT interval on the electrocardiogram (ECG) infrequently results in Torsades de pointes, a potentially fatal arrhythmia. Therefore, thorough QT analysis of new drugs is a regulatory requirement. The objective of this phase 1 study was to assess the effects of oral tedizolid phosphate on the QT interval corrected with Fridericia's formula (QTcF) in healthy adult subjects. A single therapeutic dose (200 mg) and a supratherapeutic dose (1200 mg) of tedizolid phosphate were administered to characterise QTc changes following typical systemic exposure and with markedly higher exposures, respectively. This was a four-way crossover study with 48 subjects randomly assigned to receive therapeutic and supratherapeutic doses of tedizolid phosphate, moxifloxacin (positive control for QT interval prolongation) and placebo (negative control). A continuous 12-lead ECG was recorded from 1 h before drug administration to 23 h after administration. Adverse events, which were generally mild, occurred most frequently with moxifloxacin or with a supratherapeutic dose of tedizolid phosphate; however, all treatments were well tolerated. This study demonstrated that therapeutic or supratherapeutic doses of the antibacterial tedizolid had no clinically significant effect on QT interval in healthy adults [ClinicalTrials.gov registration no.: NCT01461460].

Antimicrobial and immunomodulatory effects of tedizolid against methicillin-resistant Staphylococcus aureus in a murine model of hematogenous pulmonary infection

Tedizolid (TZD) is a second-generation oxazolidinone and demonstrates potent in-vitro activity against multidrug-resistant Gram-positive bacteria. Phase III studies in patients with acute bacterial skin and skin structure infections (ABSSSI) have demonstrated the non-inferiority of TZD to linezolid (LZD). However, there are only a few studies that show the effect of TZD in pulmonary infections. In this study, we investigated the effect of TZD in a murine model of hematogenous pulmonary infection caused by methicillin-resistant Staphylococcus aureus (MRSA). The mice were treated either twice daily with saline (control), 25mg/kg of vancomycin (low-VAN), 110mg/kg of vancomycin (high-VAN), 120mg/kg of LZD or once daily with 20mg/kg of TZD. As compared to the control, the low- and high-VAN treatment groups, LZD and TZD significantly improved the survival rate, reduced the bacterial count in the lungs. Furthermore, TZD decreased the area of central bacterial colony zone (CBCZ) at 36h post-inoculation, compared with the control. In addition, we investigated the immunomodulatory effect of TZD by evaluating the plasma concentrations of the inflammatory cytokines. Although there were no significant differences in the bacterial count in the lungs amongst the drugs at 26h post-inoculation, TZD and LZD significantly improved the plasma concentrations of TNF-alpha, IL-6 and MIP-2, in comparison with the control. In this study, both TZD and LZD demonstrated antimicrobial and immunomodulatory efficacy in a murine model of hematogenous pulmonary infection caused by MRSA.

A highly sensitive and efficient UPLC-MS/MS assay for rapid analysis of tedizolid (a novel oxazolidinone antibiotic) in plasma sample.

Tedizolid (TDZ) is a novel oxazolidinone class antibiotic, indicated for the treatment of acute bacterial skin and skin structure infections in adults. In this study a highly sensitive UPLC-MS/MS assay was developed and validated for the determination of TDZ in rat plasma using rivaroxaban as an internal standard (IS). Both TDZ and IS were separated on an Acquity UPLC BEH™ C18 column using an isocratic mobile phase comprising of acetonitrile-20 mm ammonium acetate (85:15, v/v), eluted at 0.3 mL/min flow rate. The plasma sample was processed by liquid liquid extraction technique using ethyl acetate as an extracting agent. The analyte and IS were detected in positive mode using electrospray ionization source. The precursor to product ion transitions at m/z 371.09>343.10 for TDZ and m/z 435.97>144.94 for IS were used for the quantification in multiple reaction monitoring mode. The calibration curve was linear in the concentration range of 0.74-1500 ng/mL and the lower limit of quantification was 0.74 ng/mL only. The developed assay was validated following standard guidelines for bioanalytical method validation (US Food and Drug Administration) and all the validation results were within the acceptable limits. The developed assay was successfully applied into a pharmacokinetic study in rats. Copyright © 2016 John Wiley & Sons, Ltd.

Pharmacokinetics of Tedizolid in Morbidly Obese and Covariate-Matched Nonobese Adults.

Tedizolid is a novel oxazolidinone antimicrobial administered in its prodrug form, tedizolid phosphate, as a fixed once-daily dose. The pharmacokinetics of tedizolid has been studied in a relatively small proportion of morbidly obese (body mass index [BMI] of ≥40 kg/m(2)) adults through population analyses with sparse sampling. The current study compared the intensively sampled plasma pharmacokinetics of tedizolid phosphate and tedizolid in 9 morbidly obese and 9 age-, sex-, and ideal body weight-matched nonobese (BMI, 18.5 to 29.9 kg/m(2)) healthy adult (18 to 50 years of age) volunteers after administration of a single intravenous dose of tedizolid phosphate. The median (range) weights were 72.6 kg (58.9 to 89.5 kg) and 117 kg (102 to 176 kg) for the mostly female (77.8%) nonobese and morbidly obese adults, respectively. Tedizolid phosphate concentrations were below the limit of quantitation in a majority of subjects after the 2-h time point. The tedizolid median (range) maximum concentration of drug in plasma (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-∞) were 2.38 (1.28 to 3.99) mg/liter and 26.3 (18.4 to 43.2) h · mg/liter, respectively, for morbidly obese subjects, and these were nonsignificantly different (P ≥ 0.214) from the values for nonobese subjects. Similarly, the volumes of distribution (Vz) (P = 0.110) and clearance (CL) values (P = 0.214) were comparable between groups. Nearly identical (P = 0.953) median tedizolid half-lives of approximately 12 h were observed for both groups. Tedizolid Vz and CL scaled with body weight, but not proportionately. The small and nonsignificant differences in tedizolid AUC0-∞ values between morbidly obese and nonobese subjects suggest that dose modification is not necessary for morbidly obese adults. (This study has been registered at ClinicalTrials.gov under number NCT02342418.).

New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides.

The growing problem of antimicrobial resistance among bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), has reached a critical state. Tedizolid phosphate, dalbavancin, and oritavancin have recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and represent the next generation of oxazolidinones and lipoglycopeptides. All three agents exhibit in vitro activity and clinical efficacy against MRSA. Tedizolid phosphate and oritavancin demonstrate in vitro activity against VRE. These new Gram-positive agents are reviewed here.

In vitro activity of Tedizolid phosphate against multidrug-resistant Streptococcus pneumoniae isolates from Asian countries

Tedizolid phosphate is a second-generation oxazolidinone prodrug that is potential activity against a wide range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, penicillin-resistant streptococci, and vancomycin-resistant enterococci. The in vitro activity of tedizolid and other comparator agents against multidrug-resistant (MDR) pneumococci from various Asian countries were evaluated. Of the S. pneumoniae clinical pneumonia isolates collected during 2008 and 2009 from 8 Asian countries (Korea, Taiwan, Thailand, Hong Kong, Vietnam, Malaysia, Philippines, and Sri Lanka), 104 isolates of MDR pneumococci were included in this study. Antimicrobial susceptibility testing for 18 antimicrobial agents was performed by broth microdilution method. Tedizolid was highly active against pneumococci. All isolates tested were inhibited at a tedizolid minimum inhibitory concentration (MIC) value of ≤0.25μg/ml (ranged from ≤0.03μg/ml to 0.25μg/ml). The MIC50 and MIC90 of tedizolid against MDR pneumococci were both 0.12μg/ml, while MIC50 and MIC90 of linezolid were 0.5μg/ml and 1μg/ml, respectively. In addition, tedizolid maintained the activity against S. pneumoniae regardless of the extensively drug-resistant (XDR) phenotype of the isolates. The activity of tedizolid was excellent against all types of MDR pneumococci, exhibiting and maintaining at least 4-fold-greater potency compared to linezolid, regardless of resistance phenotypes to other commonly utilized agents. Tedizolid has the potential to be an agent to treat infections caused by MDR pneumococci in the Asia.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N=182) vs linezolid (N=171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p=0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Chiral separation of tedizolid using charge single isomer derivatives of cyclodextrins by capillary electrokinetic chromatography

A method to enantioseparate tedizolid (TED), the second analogue after linezolid (LIN) in a truly new class of antibacterial agents, the oxazolidinones, was developed based on capillary electrokinetic chromatography using cyclodextrin as chiral pseudophase (CD-cEKC). The single isomer R-tedizolid possesses one chiral centre at C5 of the oxazolidinone ring, which is associated with the antibacterial activity of the drug. Tedizolid enantiomers are non-charged and therefore require the use of charged cyclodextrins (CCDs) as carrier hosts to achieve a velocity difference during migration. During method development, hydrophilic anionic single-isomer and moderately hydrophobic and hydrophobic cyclodextrins were tested, including heptakis-(2,3-dihydroxy-6-sulfo)-β-cyclodextrin (HS-β-CD), heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD), oktakis-(2,3-diacetyl-6-sulfo)-γ-cyclodextrin (ODAS-γ-CD) and heptakis-(2,3-dimethyl-6-sulfo)-β-cyclodextrin (HDMS-β-CD). Only CDs that have acetyl groups at the C2 and C3 positions with seven (HDAS-β-CD) or eight (ODAS-γ-CD) residues of glucopyranose units provided baseline separation of the tedizolid enantiomers with the addition of organic solvent. During the experiments, different organic solvents were tested, such as methanol, acetonitrile, tetrahydrofuran, which varied in their abilities to donate or accept protons. The best enantiomer separation results were obtained using the CD-cEKC method with 37.5mM HDAS-β-CD dissolved in 50mM formic buffer (pH 4.0) with the addition of acetonitrile (81.4:18.6, v/v) at 27ºC, normal polarity, and 12kV. Finally, the apparent binding constants for each enantiomer—HDAS-β-CD pair were calculated. Moreover, in order to evaluate the behaviour of TED and LIN enantiomers relative to chiral selector, enantioselective interactions towards the precursors of TED and LIN isomers were also investigated.

Stability of Crushed Tedizolid Phosphate Tablets for Nasogastric Tube Administration.

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections. To determine whether the expected dose of tedizolid phosphate can be delivered via nasogastric tube in patients who have difficulty swallowing and in whom venous access is not suitable, this in vitro study evaluated the recovery of tedizolid phosphate 200-mg tablets after crushing, dispersion in water, and passage through a nasogastric tube. To analyze the chemical stability of the crushed tablet dispersed in water, the aqueous preparation was assayed initially after dispersion and again after 4 h at room temperature. Recovery of tedizolid phosphate after the crushed tablets were dispersed in water and passed through nasogastric tubes ranged from 92.5 to 97.1 %, which is within the specified acceptance criteria of 90 to 110 %. There was no significant change in recovery values after 4 h of storage at room temperature (93.9 % initially and 94.7 % after 4 h). The stability and recovery findings support the feasibility of administering an aqueous dispersion of crushed tedizolid phosphate tablets through a nasogastric tube in patients who have difficulty swallowing and in whom intravenous administration is not possible.

Tedizolid: A New Oxazolidinone Antibiotic for Skin and Soft Tissue Infections.

To review the chemistry, pharmacology, microbiology, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug interactions, dosing, and administration of tedizolid phosphate (TDZ). A search of PubMed using the terms "tedizolid," "torezolid," "TR-701," "TR-700," "DA-7157," and "DA-7218" was performed. The manufacturer's Web site was also reviewed to further identify relevant information. All English-language articles from 2006 to November 2014 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not uncovered in the searches. TDZ is the second oxazolidinone antibiotic with a spectrum of activity targeted against gram-positive organisms including methicillin-resistant Staphylococcus aureus . It is administered via intravenous infusion or orally without regard to food. The primary route of elimination is fecal excretion. Advanced age, hepatic dysfunction, or renal impairment does not alter its disposition. Phase III clinical trials have demonstrated that TDZ 200 mg daily for 6 days is noninferior to linezolid 600 mg twice daily for 10 days in the treatment of adults with skin and soft tissue infections caused or suspected to be caused by gram-positive organisms. TDZ has a side effect profile similar to that of linezolid and a lower potential for drug interactions. TDZ has been shown to be safe and effective for the treatment of adults with skin and soft tissue infections. Further research is needed to refine its role, particularly for the treatment of patients requiring a longer duration of therapy and in those receiving concomitant serotonergic agents.

Tedizolid: The First Once-Daily Oxazolidinone Class Antibiotic.

Tedizolid phosphate is the second commercially available oxazolidinone antibiotic, although the first one in class that is dosed once daily. It is a prodrug that is rapidly converted to the active compound tedizolid. Tedizolid has activity against a wide range of gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. It is approved to treat acute bacterial skin and skin structure infections (ABSSSIs). In 2 randomized controlled phase 3 trials, 6 days of tedizolid (200 mg once daily) has been proven to be noninferior to 10 days of linezolid (600 mg twice daily). These 2 ABSSSI studies have positioned tedizolid among the growing armamentarium of newer, novel, anti-gram-positive agents. Tedizolid appears to differ from linezolid in the incidence of gastrointestinal and hematologic side effects and appears to lack drug interactions with selective serotonin reuptake inhibitors. Conditions other than ABSSSI are currently being evaluated in clinical studies.

Tedizolid an Effective Option for Treating ABSSSI

Tedizolid an Effective Option for Treating ABSSSI

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.

Comparative efficacies of tedizolid phosphate, vancomycin, and daptomycin in a rabbit model of methicillin-resistant Staphylococcus aureus endocarditis.

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.

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 materialThe online version of this article (doi:10.1007/s40121-015-0060-3) contains supplementary material, which is available to authorized users.