SUPPLEMENT ARTICLE
Tedizolid Phosphate for the Management of Acute Bacterial Skin and Skin Structure Infections: Efficacy Summary William O’Riordan,1 Sinikka Green,1 Purvi Mehra,1 Carisa De Anda,2 Edward Fang,2 and Philippe Prokocimer2 1
eStudySite, and 2Cubist Pharmaceuticals, San Diego, California
Keywords.
Downloaded from http://cid.oxfordjournals.org/ at Georgetown University on October 5, 2014
The novel oxazolidinone tedizolid phosphate is in late-stage development for acute bacterial skin and skin structure infections (ABSSSIs). Preclinical and phase 1 trials have shown that 200-mg once-daily tedizolid phosphate dosing achieves the appropriate pharmacokinetic goals for optimal antimicrobial effect, and a randomized phase 2 dose-ranging trial confirmed that tedizolid phosphate may be an option for the treatment of ABSSSIs at the 200-mg dose, the lowest effective dose, over a mean of 6.4 days of therapy. In the first of two phase 3 trials, 6 days of 200-mg once-daily oral tedizolid phosphate ( plus 4 days of placebo) was noninferior to 10 days of 600-mg twice-daily oral linezolid when evaluated at both the early (48- to 72-hour assessment) and test-of-cure (7–14 days after the last dose of active or placebo agent was given) time points. Initial results from the second phase 3 trial (intravenous to oral therapy design) confirm the study met all primary and secondary endpoints and continues to add insight into the clinical utility of tedizolid phosphate. tedizolid phosphate; ABSSSI; MRSA; Staphylococcus aureus; efficacy.
Acute bacterial skin and skin structure infections (ABSSSIs) are a frequent indication for antibiotic therapy and an increasing cause of hospitalization [1, 2]. The majority of ABSSSIs are caused by aerobic Grampositive cocci, including Staphylococcus aureus, and beta-hemolytic streptococci [3]. Since 1960, methicillin resistance in S. aureus has become a critical problem in healthcare and community settings [2, 4–6], and the numbers of patients with methicillin-resistant S. aureus (MRSA) skin infections seen in emergency departments have increased in recent years, as have cases of skin abscess [2, 7, 8]. Despite the availability of newer antimicrobial agents [9], updated recommendations for vancomycin administration [10], and increased active surveillance and other infection control practices [4], resistant Gram-positive pathogens continue to challenge the management of ABSSSIs [3, 6] and highlight the
Correspondence: Philippe Prokocimer, Cubist Pharmaceuticals, 6310 Nancy Ridge Dr, Ste 101, San Diego, CA 92121 ([email protected]). Clinical Infectious Diseases 2014;58(S1):S43–50 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/cit617
critical need for new therapeutic options to combat these multidrug-resistant pathogens. S. aureus has become the most common pathogen encountered in serious skin infections; it has been estimated that >90% of MRSA infections involve ABSSSIs [11]. Once recognized for distinctive antibiotic susceptibility patterns in community or hospital settings [12, 13], these niches are increasingly cross-populated, rendering the classic phenotypic assessment of empiric pathogen identification less reliable for clinical use [13, 14]. Novel clones of MRSA with increasing resistance to a broad range of antibiotics continue to emerge in many parts of the world [6, 14]. Despite the workhorse status of vancomycin [1, 10], the emergence of strains with rising minimal inhibitory concentrations (MICs), as well as vancomycin-intermediate and vancomycin-resistant S. aureus strains, can compromise the clinical efficacy of vancomycin. As demonstrated in a survey of isolates from clinical trials, treatment failure rates were 48% for isolates with a vancomycin MIC of 0.5 µg/mL and increased to >90% when the MIC was >2.0 µg/mL [15]. Challenges to the implementation of drug-level monitoring and newer dosing recommendations for optimal trough
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Table 1. Summary of Phase 1 Trials That Address Dosing and Administration of Tedizolid Phosphate in Healthy Subjects and Special Patient Populations [29–31] Study Population
PK/PD Study Goals
Administration and Dose
Elderly subjects
Subjects aged >65 y
Single oral 200-mg dose
Adolescents
Subjects aged 12–17 y
Single 200-mg intravenous or oral dose 200 mg oral once-daily dose for 7 d
Hepatic Moderate (Child-Pugh impairment 7–9); Severe (Child-Pugh 10–15)
200 mg intravenous oncedaily dose for 7 d
Healthy control
Administration with or without meals
Single 600-mg oral dose
Healthy control
Administration with tyramine
Single 200-mg oral dose
Healthy control
Single and multiple (21 d) Single dose; 200–1200 ascending dose of mg tedizolid phosphate Multidose; 200, 300, 400 disodium mg
Abbreviations: HD, hemodialysis; PD, pharmacodynamic; PK, pharmacokinetic.
levels [16, 17] continue to present clinical challenges for appropriate use of vancomycin. Recent evidence for daptomycin resistance through cross-resistance to vancomycin [18] and novel resistance pathways [19] raises concerns in clinical practice. Resistance to linezolid, the first member of the oxazolidinone class of antibiotics approved for ABSSSIs, has been reported among staphylococci and enterococci associated with 23S rRNA gene mutations and more recently through the chloramphenicol-florfenicol resistance (cfr) methyltransferase gene [20–22], with the potential for widespread dissemination through plasmid exchange [23]. For these reasons, new antimicrobial options that bypass these known resistance mechanisms are urgently needed to treat multidrug-resistant Gram-positive bacteria in both hospital and community settings. Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug currently being developed for the treatment of Grampositive infections [24], including those caused by MRSA, as well as vancomycin- and linezolid-resistant Gram-positive pathogens [20–22, 25]. With the active moiety, tedizolid, having 4- to 16-fold greater activity than linezolid against Grampositive species (including cfr-positive isolates), a convenient oral formulation with high bioavailability, and once-daily dosing, tedizolid phosphate is an attractive candidate for clinical evaluation in ABSSSIs [20, 23, 24, 26]. During the course of tedizolid phosphate development, US Food and Drug Administration (FDA) guidance on the conduct of skin infection clinical trials shifted from older guidance for complicated skin and soft tissue infection (cSSSI) to a revised and updated guidance
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EARLY STUDIES In a 21-day phase 1 safety trial in subjects aged >18 years, once-daily oral doses of 200, 300, or 400 mg of tedizolid phosphate were well tolerated throughout the study [34, 35], and hematologic changes similar to those seen with twice-daily 600 mg linezolid were only noted for the 400-mg dose between days 7 and 21 of exposure [35]. Based on extensive preclinical modeling and phase 1 safety results, a phase 2 dose-ranging study was designed to evaluate once-daily tedizolid phosphate on efficacy, safety, and tolerability in patients with cSSSIs [36]. This double-blind study included 188 patients aged 18–75 years who were randomized 1:1:1 to a 200-, 300-, or 400-mg once-daily tedizolid phosphate treatment arm for 5–7 days. Eligible patients presented with abscess, deep extensive cellulitis, or infected wounds (surgical or post-traumatic) that included at least 2 of the following signs and symptoms: drainage, erythema, fluctuance, warmth, pain, tenderness, and swelling, as well as a systemic sign of active infection (oral temperature >38°C, white blood cell count >10 000 cells/µL, or >10% immature neutrophils) when the lesion size was 37.6°C), which occurred in 8.1% of the tedizolid group and 10.4% of the linezolid group. There was high concordance (>80%) between the programmatic outcome at the 48- to 72-hour time point and the investigator assessment of clinical response at post-therapy evaluation [32]. A sustained clinical response was also observed at EOT by programmatic or investigator-based assessment (Table 4). Attributes for sustained clinical response at EOT included the primary endpoint criteria plus the absence of patient-reported pain and/or tenderness that was worse than “mild.” Sensitivity analysis was undertaken to test the robustness of the data and to correspond with evolving regulatory guidance. This analysis excluded temperature as an outcome determinant for the primary endpoint or the pain criteria for the EOT endpoint (Table 5). The analysis showed that excluding temperature and varying the lesion response definition from cessation of lesion spread to ≥20% reduction in lesion size did not change the outcome at the primary endpoint, and exclusion of the pain criteria (as reported in the 2010 ABSSSI draft guideline [27]) did not alter outcome at the EOT visit. A pathogen was isolated from the primary infection site in approximately 63% of patients. The most common pathogen isolated was S. aureus (82.8%), with MRSA accounting for 42.1% of infections in the tedizolid phosphate group and 43.1% of infections in the linezolid group [32]. Safety data were recorded for all patients who received at least 1 dose of study medication. Patients receiving 200-mg oral tedizolid phosphate once-daily experienced similar rates of overall adverse events and treatment-emergent adverse events compared with patients receiving 600-mg oral linezolid twicedaily in the phase 3 trial. A significant trend toward lower gastrointestinal treatment-emergent adverse events was observed in the tedizolid phosphate-treated group, and fewer abnormally low platelet counts were observed in the analysis of hematology laboratory data in the tedizolid phosphate group [37]. Initial data from the second phase 3 clinical trial, comparing the early clinical response rate of intravenous to oral 6-day tedizolid phosphate with that of intravenous to oral 10-day linezolid (48–72 hours after the first infusion of study drug) for the treatment of ABSSSIs [38], have recently been reported [33]. In this trial, patients start treatment with at least 2 intravenous doses and may receive intravenous therapy for the entire treatment duration. Patients aged >12 years were recruited and
Table 5.
Sensitivity Analysis for the Intent-to-Treat and the Clinically Evaluable at End-of-Treatment Analysis Sets From ESTABLISH-1 Clinical Success Rate No. (%) [95% CI] Tedizolid Phosphate (n = 332)
48- to 72-hours response in ITT ≥20% decrease in area, no fever
Linezolid (n = 335)
Absolute Treatment Difference (95% CI), %
259 (78.0) [73.2 to 82.4]
255 (76.1) [71.1 to 80.6]
1.9 (−4.5 to 8.3)
No increase in area, no fever
289 (87.0) [83.0 to 90.5]
286 (85.4) [81.1 to 89.0]
1.6 (−3.5 to 7.0)
Sustained response at EOT (ITT)a ITT analysis set
268 (80.7) [76.1 to 84.8]
271 (80.9) [76.3 to 85.0]
−0.2 (−6.2 to 5.8)
No pain criteria (ITT)
289 (87.0) [83.0 to 90.5]
294 (87.8) [83.8 to 91.1]
−0.8 (−5.8 to 4.4)
CE-EOT analysis set
(n = 273) 239 (87.5) [83.0 to 91.2]
(n = 286) 249 (87.1) [82.6 to 90.7]
0.4 (−5.2 to 6.0)
Adapted with permission from Prokocimer et al [32]. Copyright © 2013 American Medical Association. All rights reserved. Abbreviations: CE, clinically evaluable; CI, confidence interval; EOT, end of therapy; ITT, intent-to-treat. a
Indeterminate and treatment failures at 48- to 72-hour assessment were not carried forward.
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(43.6%) before discharge, which on average was at 7.1 days. These characteristics of patients hospitalized with ABSSSIs are well matched to the emerging evidence that tedizolid may be an oral option for the management of ABSSSIs that was shown to be well tolerated in clinical trials. Notes Financial support. Medical writing support was provided by Bill Jacobs, PhD (Strategic HealthCOM, Somerville, NJ), funded by Cubist Pharmaceuticals. Supplement sponsorship. This article was published as part of a supplement entitled “Tedizolid: A Novel Oxazolidinone for Gram-Positive Infections,” funded by Cubist Pharmaceuticals. Potential conflicts of interest. W. O., S. G., and P. M. are employees of eStudySite, which has received grant funding from Cubist Pharmaceuticals; they were compensated for writing or reviewing this manuscript by Cubist Pharmaceuticals. C. D., E. F., and P. P. are employees and stockholders of Cubist Pharmaceuticals. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Lipsky BA, Moran GJ, Napolitano LM, Vo L, Nicholson S, Kim M. A prospective, multicenter, observational study of complicated skin and soft tissue infections in hospitalized patients: clinical characteristics, medical treatment, and outcomes. BMC Infect Dis 2012; 12:227. 2. Talan DA, Krishnadasan A, Gorwitz RJ, et al.; EMERGEncy ID Net Study Group. Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. Clin Infect Dis 2011; 53:144–9. 3. May AK, Stafford RE, Bulger EM, et al.; Surgical Infection Society. Treatment of complicated skin and soft tissue infections. Surg Infect (Larchmt) 2009; 10:467–99. 4. Jarvis WR, Jarvis AA, Chinn RY. National prevalence of methicillinresistant Staphylococcus aureus in inpatients at United States health care facilities, 2010. Am J Infect Control 2012; 40:194–200. 5. de Kraker ME, Wolkewitz M, Davey PG, Grundmann H; BURDEN Study Group. Clinical impact of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay related to
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Available data from phase 1, 2, and 3 trials have demonstrated the relative clinical efficacy and safety profile for tedizolid phosphate. These trials have also begun to illustrate the potential for attributes of tedizolid phosphate to improve the management of serious Gram-positive infections, including lower overall drug exposure, once-daily oral dosing (without regard to meals), predictable drug pharmacokinetics, and a favorable safety profile. The phase 2 dose-ranging study demonstrated comparable efficacy results across the 200-mg, 300-mg, and 400-mg tedizolid phosphate doses over 5–7 days of treatment for ABSSSIs [25], leading to the selection of the lowest effective dose of 200-mg once-daily for the phase 3 trials. Results from both phase 3 trials confirmed that 200-mg once-daily tedizolid phosphate met all noninferiority endpoint criteria as described by current FDA and EMA guidance for the treatment of ABSSSIs. The microbiologic response data are consistent with the documented in vitro activity profile for tedizolid, whereas the accumulating safety database has confirmed that tedizolid phosphate is a promising agent for clinical use. Although the overall patient populations in the phase 2 and 3 tedizolid phosphate trials may differ somewhat from those studied in the recently completed comparison of linezolid and vancomycin in complicated MRSA skin infections (which included diabetic foot infections but not cellulitis) [44], they are similar to the population in the ceftaroline registration trial [45] and a recent multicenter observational report [1]. In the later study, approximately 90% of patients presented with erythema, tenderness, pain, or local warmth, whereas only 8.2% were recorded to have a temperature >38°C, observations that are consistent with the patient demographics in the recently completed phase 3 trial population [32]. Although 88.8% of patients in the observation study were started on intravenous antibiotics (for 2– 3 days), most were either switched to another formulation (53.6%) or discontinued treatment based on improved infections
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methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother 2011; 55:1598–605. Stefani S, Chung DR, Lindsay JA, et al. Methicillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int J Antimicrob Agents 2012; 39:273–82. Pallin DJ, Egan DJ, Pelletier AJ, Espinola JA, Hooper DC, Camargo CA Jr. Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant Staphylococcus aureus. Ann Emerg Med 2008; 51:291–8. Qualls ML, Mooney MM, Camargo CA Jr, Zucconi T, Hooper DC, Pallin DJ. Emergency department visit rates for abscess versus other skin infections during the emergence of community-associated methicillin-resistant Staphylococcus aureus, 1997–2007. Clin Infect Dis 2012; 55:103–5. Bush K. Improving known classes of antibiotics: an optimistic approach for the future. Curr Opin Pharmacol 2012; 12:527–34. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm 2009; 66:82–98. Shlaes DM, Spellberg B. Overcoming the challenges to developing new antibiotics. Curr Opin Pharmacol 2012; 12:522–6. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298:1763–71. David MZ, Glikman D, Crawford SE, et al. What is communityassociated methicillin-resistant Staphylococcus aureus? J Infect Dis 2008; 197:1235–43. Chambers HF, DeLeo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 2009; 7:629–41. Moise-Broder PA, Sakoulas G, Eliopoulos GM, Schentag JJ, Forrest A, Moellering RC Jr. Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin Infect Dis 2004; 38:1700–5. Jeffres MN, Isakow W, Doherty JA, et al. Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care–associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest 2006; 130:947–55. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. Highdose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections. Arch Intern Med 2006; 166:2138–44. Sakoulas G, Brown J, Lamp KC, Friedrich LV, Lindfield KC. Clinical outcomes of patients receiving daptomycin for the treatment of Staphylococcus aureus infections and assessment of clinical factors for daptomycin failure: a retrospective cohort study utilizing the Cubicin® Outcomes Registry and Experience. Clin Ther 2009; 31: 1936–45. Fischer A, Yang SJ, Bayer AS, et al. Daptomycin resistance mechanisms in clinically derived Staphylococcus aureus strains assessed by a combined transcriptomics and proteomics approach. J Antimicrob Chemother 2011; 66:1696–711. Locke JB, Hilgers M, Shaw KJ. Mutations in ribosomal protein L3 are associated with oxazolidinone resistance in staphylococci of clinical origin. Antimicrob Agents Chemother 2009; 53:5275–8. Locke JB, Hilgers M, Shaw KJ. Novel ribosomal mutations in Staphylococcus aureus strains identified through selection with the oxazolidinones linezolid and torezolid (TR-700). Antimicrob Agents Chemother 2009; 53:5265–74. Livermore DM, Mushtaq S, Warner M, Woodford N. Activity of oxazolidinone TR-700 against linezolid-susceptible and -resistant staphylococci and enterococci. J Antimicrob Chemother 2009; 63:713–5. Gu B, Kelesidis T, Tsiodras S, Hindler J, Humphries RM. The emerging problem of linezolid-resistant Staphylococcus. J Antimicrob Chemother 2013; 68:4–11.
bacterial pneumonia and acute bacterial skin and skin structure infections: update from the Biomarkers Consortium of the Foundation for the National Institutes of Health. Clin Infect Dis 2012; 55:1114–21. 40. Trius Therapeutics obtains special protocol assessment with FDA for phase 3 study of torezolid phosphate [ press release]. San Diego, CA: Canale Communications, 2010. 41. Trius Therapeutics obtains special protocol assessment with FDA for second phase 3 study of torezolid phosphate [ press release]. San Diego, CA: Canale Communications, 2011. 42. Sahre M, Sabarinath S, Grant M, et al. Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers. Int J Antimicrob Agents 2012; 40:51–4.
43. Drusano GL, Liu W, Kulawy R, Louie A. Impact of granulocytes on the antimicrobial effect of tedizolid in a mouse thigh infection model. Antimicrob Agents Chemother 2011; 55:5300–5. 44. Itani KM, Dryden MS, Bhattacharyya H, Kunkel MJ, Baruch AM, Weigelt JA. Efficacy and safety of linezolid versus vancomycin for the treatment of complicated skin and soft-tissue infections proven to be caused by methicillin-resistant Staphylococcus aureus. Am J Surg 2010; 199:804–16. 45. Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010; 51:641–50.
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Tedizolid Phosphate for the Management of Acute Bacterial Skin and Skin Structure Infections: Efficacy Summary William O’Riordan,1 Sinikka Green,1 Purvi Mehra,1 Carisa De Anda,2 Edward Fang,2 and Philippe Prokocimer2 1
eStudySite, and 2Cubist Pharmaceuticals, San Diego, California
Keywords.
Downloaded from http://cid.oxfordjournals.org/ at Georgetown University on October 5, 2014
The novel oxazolidinone tedizolid phosphate is in late-stage development for acute bacterial skin and skin structure infections (ABSSSIs). Preclinical and phase 1 trials have shown that 200-mg once-daily tedizolid phosphate dosing achieves the appropriate pharmacokinetic goals for optimal antimicrobial effect, and a randomized phase 2 dose-ranging trial confirmed that tedizolid phosphate may be an option for the treatment of ABSSSIs at the 200-mg dose, the lowest effective dose, over a mean of 6.4 days of therapy. In the first of two phase 3 trials, 6 days of 200-mg once-daily oral tedizolid phosphate ( plus 4 days of placebo) was noninferior to 10 days of 600-mg twice-daily oral linezolid when evaluated at both the early (48- to 72-hour assessment) and test-of-cure (7–14 days after the last dose of active or placebo agent was given) time points. Initial results from the second phase 3 trial (intravenous to oral therapy design) confirm the study met all primary and secondary endpoints and continues to add insight into the clinical utility of tedizolid phosphate. tedizolid phosphate; ABSSSI; MRSA; Staphylococcus aureus; efficacy.
Acute bacterial skin and skin structure infections (ABSSSIs) are a frequent indication for antibiotic therapy and an increasing cause of hospitalization [1, 2]. The majority of ABSSSIs are caused by aerobic Grampositive cocci, including Staphylococcus aureus, and beta-hemolytic streptococci [3]. Since 1960, methicillin resistance in S. aureus has become a critical problem in healthcare and community settings [2, 4–6], and the numbers of patients with methicillin-resistant S. aureus (MRSA) skin infections seen in emergency departments have increased in recent years, as have cases of skin abscess [2, 7, 8]. Despite the availability of newer antimicrobial agents [9], updated recommendations for vancomycin administration [10], and increased active surveillance and other infection control practices [4], resistant Gram-positive pathogens continue to challenge the management of ABSSSIs [3, 6] and highlight the
Correspondence: Philippe Prokocimer, Cubist Pharmaceuticals, 6310 Nancy Ridge Dr, Ste 101, San Diego, CA 92121 ([email protected]). Clinical Infectious Diseases 2014;58(S1):S43–50 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/cit617
critical need for new therapeutic options to combat these multidrug-resistant pathogens. S. aureus has become the most common pathogen encountered in serious skin infections; it has been estimated that >90% of MRSA infections involve ABSSSIs [11]. Once recognized for distinctive antibiotic susceptibility patterns in community or hospital settings [12, 13], these niches are increasingly cross-populated, rendering the classic phenotypic assessment of empiric pathogen identification less reliable for clinical use [13, 14]. Novel clones of MRSA with increasing resistance to a broad range of antibiotics continue to emerge in many parts of the world [6, 14]. Despite the workhorse status of vancomycin [1, 10], the emergence of strains with rising minimal inhibitory concentrations (MICs), as well as vancomycin-intermediate and vancomycin-resistant S. aureus strains, can compromise the clinical efficacy of vancomycin. As demonstrated in a survey of isolates from clinical trials, treatment failure rates were 48% for isolates with a vancomycin MIC of 0.5 µg/mL and increased to >90% when the MIC was >2.0 µg/mL [15]. Challenges to the implementation of drug-level monitoring and newer dosing recommendations for optimal trough
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Table 1. Summary of Phase 1 Trials That Address Dosing and Administration of Tedizolid Phosphate in Healthy Subjects and Special Patient Populations [29–31] Study Population
PK/PD Study Goals
Administration and Dose
Elderly subjects
Subjects aged >65 y
Single oral 200-mg dose
Adolescents
Subjects aged 12–17 y
Single 200-mg intravenous or oral dose 200 mg oral once-daily dose for 7 d
Hepatic Moderate (Child-Pugh impairment 7–9); Severe (Child-Pugh 10–15)
200 mg intravenous oncedaily dose for 7 d
Healthy control
Administration with or without meals
Single 600-mg oral dose
Healthy control
Administration with tyramine
Single 200-mg oral dose
Healthy control
Single and multiple (21 d) Single dose; 200–1200 ascending dose of mg tedizolid phosphate Multidose; 200, 300, 400 disodium mg
Abbreviations: HD, hemodialysis; PD, pharmacodynamic; PK, pharmacokinetic.
levels [16, 17] continue to present clinical challenges for appropriate use of vancomycin. Recent evidence for daptomycin resistance through cross-resistance to vancomycin [18] and novel resistance pathways [19] raises concerns in clinical practice. Resistance to linezolid, the first member of the oxazolidinone class of antibiotics approved for ABSSSIs, has been reported among staphylococci and enterococci associated with 23S rRNA gene mutations and more recently through the chloramphenicol-florfenicol resistance (cfr) methyltransferase gene [20–22], with the potential for widespread dissemination through plasmid exchange [23]. For these reasons, new antimicrobial options that bypass these known resistance mechanisms are urgently needed to treat multidrug-resistant Gram-positive bacteria in both hospital and community settings. Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug currently being developed for the treatment of Grampositive infections [24], including those caused by MRSA, as well as vancomycin- and linezolid-resistant Gram-positive pathogens [20–22, 25]. With the active moiety, tedizolid, having 4- to 16-fold greater activity than linezolid against Grampositive species (including cfr-positive isolates), a convenient oral formulation with high bioavailability, and once-daily dosing, tedizolid phosphate is an attractive candidate for clinical evaluation in ABSSSIs [20, 23, 24, 26]. During the course of tedizolid phosphate development, US Food and Drug Administration (FDA) guidance on the conduct of skin infection clinical trials shifted from older guidance for complicated skin and soft tissue infection (cSSSI) to a revised and updated guidance
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EARLY STUDIES In a 21-day phase 1 safety trial in subjects aged >18 years, once-daily oral doses of 200, 300, or 400 mg of tedizolid phosphate were well tolerated throughout the study [34, 35], and hematologic changes similar to those seen with twice-daily 600 mg linezolid were only noted for the 400-mg dose between days 7 and 21 of exposure [35]. Based on extensive preclinical modeling and phase 1 safety results, a phase 2 dose-ranging study was designed to evaluate once-daily tedizolid phosphate on efficacy, safety, and tolerability in patients with cSSSIs [36]. This double-blind study included 188 patients aged 18–75 years who were randomized 1:1:1 to a 200-, 300-, or 400-mg once-daily tedizolid phosphate treatment arm for 5–7 days. Eligible patients presented with abscess, deep extensive cellulitis, or infected wounds (surgical or post-traumatic) that included at least 2 of the following signs and symptoms: drainage, erythema, fluctuance, warmth, pain, tenderness, and swelling, as well as a systemic sign of active infection (oral temperature >38°C, white blood cell count >10 000 cells/µL, or >10% immature neutrophils) when the lesion size was 37.6°C), which occurred in 8.1% of the tedizolid group and 10.4% of the linezolid group. There was high concordance (>80%) between the programmatic outcome at the 48- to 72-hour time point and the investigator assessment of clinical response at post-therapy evaluation [32]. A sustained clinical response was also observed at EOT by programmatic or investigator-based assessment (Table 4). Attributes for sustained clinical response at EOT included the primary endpoint criteria plus the absence of patient-reported pain and/or tenderness that was worse than “mild.” Sensitivity analysis was undertaken to test the robustness of the data and to correspond with evolving regulatory guidance. This analysis excluded temperature as an outcome determinant for the primary endpoint or the pain criteria for the EOT endpoint (Table 5). The analysis showed that excluding temperature and varying the lesion response definition from cessation of lesion spread to ≥20% reduction in lesion size did not change the outcome at the primary endpoint, and exclusion of the pain criteria (as reported in the 2010 ABSSSI draft guideline [27]) did not alter outcome at the EOT visit. A pathogen was isolated from the primary infection site in approximately 63% of patients. The most common pathogen isolated was S. aureus (82.8%), with MRSA accounting for 42.1% of infections in the tedizolid phosphate group and 43.1% of infections in the linezolid group [32]. Safety data were recorded for all patients who received at least 1 dose of study medication. Patients receiving 200-mg oral tedizolid phosphate once-daily experienced similar rates of overall adverse events and treatment-emergent adverse events compared with patients receiving 600-mg oral linezolid twicedaily in the phase 3 trial. A significant trend toward lower gastrointestinal treatment-emergent adverse events was observed in the tedizolid phosphate-treated group, and fewer abnormally low platelet counts were observed in the analysis of hematology laboratory data in the tedizolid phosphate group [37]. Initial data from the second phase 3 clinical trial, comparing the early clinical response rate of intravenous to oral 6-day tedizolid phosphate with that of intravenous to oral 10-day linezolid (48–72 hours after the first infusion of study drug) for the treatment of ABSSSIs [38], have recently been reported [33]. In this trial, patients start treatment with at least 2 intravenous doses and may receive intravenous therapy for the entire treatment duration. Patients aged >12 years were recruited and
Table 5.
Sensitivity Analysis for the Intent-to-Treat and the Clinically Evaluable at End-of-Treatment Analysis Sets From ESTABLISH-1 Clinical Success Rate No. (%) [95% CI] Tedizolid Phosphate (n = 332)
48- to 72-hours response in ITT ≥20% decrease in area, no fever
Linezolid (n = 335)
Absolute Treatment Difference (95% CI), %
259 (78.0) [73.2 to 82.4]
255 (76.1) [71.1 to 80.6]
1.9 (−4.5 to 8.3)
No increase in area, no fever
289 (87.0) [83.0 to 90.5]
286 (85.4) [81.1 to 89.0]
1.6 (−3.5 to 7.0)
Sustained response at EOT (ITT)a ITT analysis set
268 (80.7) [76.1 to 84.8]
271 (80.9) [76.3 to 85.0]
−0.2 (−6.2 to 5.8)
No pain criteria (ITT)
289 (87.0) [83.0 to 90.5]
294 (87.8) [83.8 to 91.1]
−0.8 (−5.8 to 4.4)
CE-EOT analysis set
(n = 273) 239 (87.5) [83.0 to 91.2]
(n = 286) 249 (87.1) [82.6 to 90.7]
0.4 (−5.2 to 6.0)
Adapted with permission from Prokocimer et al [32]. Copyright © 2013 American Medical Association. All rights reserved. Abbreviations: CE, clinically evaluable; CI, confidence interval; EOT, end of therapy; ITT, intent-to-treat. a
Indeterminate and treatment failures at 48- to 72-hour assessment were not carried forward.
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(43.6%) before discharge, which on average was at 7.1 days. These characteristics of patients hospitalized with ABSSSIs are well matched to the emerging evidence that tedizolid may be an oral option for the management of ABSSSIs that was shown to be well tolerated in clinical trials. Notes Financial support. Medical writing support was provided by Bill Jacobs, PhD (Strategic HealthCOM, Somerville, NJ), funded by Cubist Pharmaceuticals. Supplement sponsorship. This article was published as part of a supplement entitled “Tedizolid: A Novel Oxazolidinone for Gram-Positive Infections,” funded by Cubist Pharmaceuticals. Potential conflicts of interest. W. O., S. G., and P. M. are employees of eStudySite, which has received grant funding from Cubist Pharmaceuticals; they were compensated for writing or reviewing this manuscript by Cubist Pharmaceuticals. C. D., E. F., and P. P. are employees and stockholders of Cubist Pharmaceuticals. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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Available data from phase 1, 2, and 3 trials have demonstrated the relative clinical efficacy and safety profile for tedizolid phosphate. These trials have also begun to illustrate the potential for attributes of tedizolid phosphate to improve the management of serious Gram-positive infections, including lower overall drug exposure, once-daily oral dosing (without regard to meals), predictable drug pharmacokinetics, and a favorable safety profile. The phase 2 dose-ranging study demonstrated comparable efficacy results across the 200-mg, 300-mg, and 400-mg tedizolid phosphate doses over 5–7 days of treatment for ABSSSIs [25], leading to the selection of the lowest effective dose of 200-mg once-daily for the phase 3 trials. Results from both phase 3 trials confirmed that 200-mg once-daily tedizolid phosphate met all noninferiority endpoint criteria as described by current FDA and EMA guidance for the treatment of ABSSSIs. The microbiologic response data are consistent with the documented in vitro activity profile for tedizolid, whereas the accumulating safety database has confirmed that tedizolid phosphate is a promising agent for clinical use. Although the overall patient populations in the phase 2 and 3 tedizolid phosphate trials may differ somewhat from those studied in the recently completed comparison of linezolid and vancomycin in complicated MRSA skin infections (which included diabetic foot infections but not cellulitis) [44], they are similar to the population in the ceftaroline registration trial [45] and a recent multicenter observational report [1]. In the later study, approximately 90% of patients presented with erythema, tenderness, pain, or local warmth, whereas only 8.2% were recorded to have a temperature >38°C, observations that are consistent with the patient demographics in the recently completed phase 3 trial population [32]. Although 88.8% of patients in the observation study were started on intravenous antibiotics (for 2– 3 days), most were either switched to another formulation (53.6%) or discontinued treatment based on improved infections
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