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Efficacy and safety of tedizolid for the treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia in Japanese patients: Results from a subgroup analysis of a phase 3, randomized, double-blind study comparing tedizolid and linezolid

Open AccessPublished:June 16, 2022DOI:https://doi.org/10.1016/j.jiac.2022.04.027

      Abstract

      Introduction

      The results from the phase 3 study that evaluated the efficacy and safety of tedizolid phosphate, an oxazolidinone drug, for the treatment of gram-positive ventilated hospital-acquired bacterial pneumonia (vHABP)/ventilator-associated bacterial pneumonia (VABP) compared with linezolid (VITAL study), have been previously reported. We conducted a subgroup analysis to report the data obtained from Japanese patients enrolled in this study.

      Methods

      Patients aged ≥18 years with vHABP/VABP likely to be caused by gram-positive cocci were randomized 1:1 to tedizolid phosphate 200 mg once daily for 7 days or linezolid 600 mg twice daily for 10 days. In both treatment groups, patients with concurrent gram-positive bacteremia were treated for 14 days. Primary efficacy endpoints were day 28 all-cause mortality (ACM) and investigator-assessed clinical response at test-of-cure (TOC) in the intention-to-treat population. Safety outcomes included assessment of treatment-emergent adverse events.

      Results

      Fifty-three Japanese patients were randomized at received study drug (tedizolid, n = 28; linezolid, n = 25). Demographics and characteristics were generally similar between treatment groups. Rates of day 28 ACM were 10.7% and 20.0% with tedizolid and linezolid, respectively (difference, 9.3%; 95% CI, −10.1 to 28.7). Rates of investigator-assessed clinical cure at TOC were 78.6% and 72.0% with tedizolid and linezolid, respectively (difference, 6.6%; 95% CI, −16.7 to 29.8). Tedizolid phosphate was generally well tolerated and no new safety concerns were observed in the Japanese subgroup.

      Conclusion

      The results from this subgroup analysis suggest generally favorable efficacy and safety of tedizolid in adult Japanese patients with vHABP/VABP. (ClinicalTrials.gov identifier: NCT02019420).

      Keywords

      1. Introduction

      Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are among the most frequent nosocomial infections [
      • Magill S.S.
      • Edwards J.R.
      • Bamberg W.
      • Beldavs Z.G.
      • Dumyati G.
      • Kainer M.A.
      • et al.
      Multistate point-prevalence survey of health care-associated infections.
      ,
      • Magill S.S.
      • O'Leary E.
      • Janelle S.J.
      • Thompson D.L.
      • Dumyati G.
      • Nadle J.
      • et al.
      Changes in prevalence of health care-associated infections in U.S. hospitals.
      ,
      • Metersky M.L.
      • Wang Y.
      • Klompas M.
      • Eckenrode S.
      • Bakullari A.
      • Eldridge N.
      Trend in ventilator-associated pneumonia rates between 2005 and 2013.
      ,
      • Suetens C.
      • Latour K.
      • Karki T.
      • Ricchizzi E.
      • Kinross P.
      • Moro M.L.
      • et al.
      Prevalence of healthcare-associated infections, estimated incidence and composite antimicrobial resistance index in acute care hospitals and long-term care facilities: results from two European point prevalence surveys, 2016 to 2017.
      ]. HABP is an acute infection characterized by a new or progressive pulmonary infiltrate in a patient hospitalized >48 hours or within 7 days of discharge; the clinical signs and symptoms include fever or hypothermia, chills, rigors, cough, purulent sputum production, chest pain, or dyspnea [
      US Food and Drug Administration Center for Drug Evaluation and Research (CDER)
      Guidance for industry hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia: developing drugs for treatment.
      ]. VABP is associated with the same clinical syndrome as HABP and new or progressive infiltrate and increased oxygen requirements in patients receiving mechanical ventilation for at least 48 hours [
      US Food and Drug Administration Center for Drug Evaluation and Research (CDER)
      Guidance for industry hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia: developing drugs for treatment.
      ]. VABP is the leading cause of morbidity and mortality in intensive care units (ICU), with mortality rates ranging from 20% to 75% and incidence ranging from 7% to 70% [
      • Alp E.
      • Voss A.
      Ventilator associated pneumonia and infection control.
      ]. In mechanically ventilated patients and patients in the ICU, development of VABP is associated with longer hospital and ICU stays, increased costs, and increased mortality [
      • Giuliano K.K.
      • Baker D.
      • Quinn B.
      The epidemiology of nonventilator hospital-acquired pneumonia in the United States.
      ,
      • Micek S.T.
      • Kollef M.H.
      • Torres A.
      • Chen C.
      • Rello J.
      • Chastre J.
      • et al.
      Pseudomonas aeruginosa nosocomial pneumonia: impact of pneumonia classification.
      ].
      Globally, the gram-positive pathogen Staphylococcus aureus is one of the most frequently identified causative pathogens in HABP/VABP [
      • Magill S.S.
      • Edwards J.R.
      • Bamberg W.
      • Beldavs Z.G.
      • Dumyati G.
      • Kainer M.A.
      • et al.
      Multistate point-prevalence survey of health care-associated infections.
      ,
      • Magill S.S.
      • O'Leary E.
      • Janelle S.J.
      • Thompson D.L.
      • Dumyati G.
      • Nadle J.
      • et al.
      Changes in prevalence of health care-associated infections in U.S. hospitals.
      ,
      • Sievert D.M.
      • Ricks P.
      • Edwards J.R.
      • Schneider A.
      • Patel J.
      • Srinivasan A.
      • et al.
      Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2009-2010.
      ,
      • Jones R.N.
      Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.
      ], and methicillin-resistant S. aureus (MRSA) comprises approximately 50% of the S. aureus isolates in patients with HABP [
      • Jones R.N.
      Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.
      ]. Gram-positive bacteria, specifically S. aureus, are a common cause of HABP in Japan and antibacterial resistance is an increasing concern [
      • Iwata K.
      • Igarashi W.
      • Honjo M.
      • Oka H.
      • Oba Y.
      • Yoshida H.
      • et al.
      Hospital-acquired pneumonia in Japan may have a better mortality profile than HAP in the United States: a retrospective study.
      ,
      • Mikasa K.
      • Aoki N.
      • Aoki Y.
      • Abe S.
      • Iwata S.
      • Ouchi K.
      • et al.
      JAID/JSC guidelines for the treatment of respiratory infectious diseases: The Japanese Association for Infectious Diseases/Japanese Society of Chemotherapy - The JAID/JSC guide to clinical management of infectious disease/guideline-preparing committee respiratory infectious disease WG.
      ]. Previous data suggested that MRSA accounted for approximately 50–70% of all S. aureus isolated from inpatients in Japanese hospitals; however, recent data suggest the percentage has decreased, although there is variability across hospitals [

      Japanese Society of Chemotherapy/Japanese Association for Infectious Diseases. Practical guidelines for the management and treatment of infections caused by MRSA, 2019 Edition. (Japanese).

      ]. The 2020 annual report of Japan Nosocomial Infections Surveillance stated that 99.8% of participating facilities reported at least 1 case of MRSA and that this percentage had remained constant over the prior 5 years (2016–2020); among all the resistant pathogens isolated annually from 2016 to 2020, MRSA consistently accounted for the highest percentage of isolates [
      Ministry of Health, Labor and Welfare
      Japan nosocomial infection surveillance (JANIS): annual Open Report 2020.
      ].
      Tedizolid phosphate is a prodrug that is converted in vivo by endogenous phosphatases to the active drug, tedizolid, which in turn, inhibits bacterial protein synthesis [
      SIVEXTRO (tedizolid phosphate
      US prescribing information.
      ,
      SIVEXTRO (tedizolid phosphate
      Summary of product characteristics.
      ]. Tedizolid phosphate is approved in multiple countries/regions, including the United States and Europe, as an oral or intravenous (IV) 200-mg dose administered once daily for the treatment of acute bacterial skin and skin structure infections caused by certain susceptible gram-positive bacteria, including MRSA [
      SIVEXTRO (tedizolid phosphate
      US prescribing information.
      ,
      SIVEXTRO (tedizolid phosphate
      Summary of product characteristics.
      ]. It has been approved for use in Japan in patients with skin and soft tissue infections (SSTI) caused by MRSA, and had clinical cure and microbiologic eradication reported in >92% of patients and a favorable safety profile in a multicenter phase 3 study that enrolled Japanese adults [
      • Mikamo H.
      • Takesue Y.
      • Iwamoto Y.
      • Tanigawa T.
      • Kato M.
      • Tanimura Y.
      • et al.
      Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan – Results of a randomised, multicentre phase 3 study.
      ]. In the lung, tedizolid has demonstrated efficient penetration in healthy adults and high epithelial lining fluid concentrations (∼40-fold epithelial lining fluid-to-plasma penetration ratio) [
      • Housman S.T.
      • Pope J.S.
      • Russomanno J.
      • Salerno E.
      • Shore E.
      • Kuti J.L.
      • et al.
      Pulmonary disposition of tedizolid following administration of once-daily oral 200-milligram tedizolid phosphate in healthy adult volunteers.
      ].
      A randomized, double-blind, double-dummy, global phase 3 non-inferiority study (VITAL) was conducted to compare a 7-day course of tedizolid phosphate with a 10-day linezolid course for the treatment of ventilated HABP (vHABP)/VABP [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. Tedizolid was non-inferior to linezolid for day 28 all-cause mortality (ACM) for the treatment of vHABP/VABP caused by gram-positive bacteria; however, non-inferiority was not demonstrated for investigator-assessed clinical response at test-of-cure (TOC) [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. Tedizolid phosphate was generally well tolerated and no new safety concerns emerged in this population [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. We conducted this subgroup analysis to report the data obtained from Japanese patients enrolled in the VITAL study.

      2. Patients and methods

      2.1 Study design

      Protocol MK-1986-002 (VITAL; ClinicalTrials.gov identifier: NCT02019420) was a randomized, double-blind, phase 3, non-inferiority study conducted at 122 sites (27 sites in Japan) in 32 countries from June 2014 to June 2018. In this current analysis, the efficacy and safety of tedizolid was assessed in a subgroup of adult Japanese patients. The study was conducted in accordance with principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. Written informed consent was provided by a legally acceptable representative before study enrollment.
      The inclusion criteria for this subgroup analysis included Japanese ethnicity, age ≥18 years, and a diagnosis of vHABP or VABP likely caused by gram-positive cocci. The full inclusion and exclusion criteria, as well as the study design and procedures for assessing bacterial isolates, have been previously reported [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. Briefly, patients were stratified by geographic region, age (18–64 years and ≥65 years), and underlying diagnosis (trauma or nontrauma admitting diagnosis), and randomized 1:1 using block randomization through an interactive voice response system to receive either tedizolid phosphate 200 mg once daily as a 60-min IV infusion for 7 days or linezolid 600 mg twice daily as a 60-min IV infusion for 10 days (patients with concurrent gram-positive bacteremia received 14-day treatment in both treatment groups). Patients received matching placebo infusions unique to each active treatment. Gram-negative adjunctive therapy was provided based on gram stain results or a rapid diagnostic test and adjusted according to microbiologic assessment. A central laboratory confirmed the identification and susceptibility testing of bacterial isolates obtained from the infection site or blood using Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing susceptibility criteria [
      Clinical and Laboratory Standards Institute (CLSI)
      Performance Standards for Antimicrobial susceptibility testing. CLSI supplement M100.
      ,
      European Committee on Antimicrobial Susceptibility Testing
      Breakpoint tables for interpretation of MICs and zone diameters. Version 9.0.
      ].

      2.2 Outcome assessments

      The primary efficacy endpoints were day 28 ACM and investigator-assessed clinical response at TOC (7–14 days after the last study drug infusion or time of failure) in the intention-to-treat (ITT) population (all randomized patients). Secondary efficacy endpoints included day 28 ACM in the microbiologic ITT (mITT) population (patients who received study drug and had a confirmed gram-positive pathogen[s]); investigator-assessed clinical response at TOC in the clinically evaluable (CE) population (patients who received study drug and had no major confounding events or factors and had evaluable clinical outcomes at the TOC visit); and microbiologic response at TOC in the mITT population. Clinical cure at TOC was defined as survival with resolution of most or all baseline clinical signs and symptoms of vHABP/VABP, absence of new signs/symptoms/complications owing to vHABP/VABP, and no administration of antibacterial therapy for vHABP/VABP or gram-positive bacteremia with the exception of 14-day adjunctive therapy. A favorable microbiologic response was defined as absence of the baseline pathogen(s) or no source specimen to culture in a patient assessed as achieving clinical cure by the investigator.
      Evaluation of safety was based on rates of treatment-emergent adverse events (TEAE) and abnormal laboratory values. TEAEs were defined as an event that emerged, or a preexisting event that worsened any time after the start of study drug administration through the late follow-up visit (28–32 days after randomization). Serious adverse events were followed until the event stabilized or resolved/death occurred or until consent was withdrawn.

      2.3 Statistical analysis

      For clinical endpoints, the estimated difference in proportions between the tedizolid and linezolid groups and the unadjusted 2-sided 95%/97.5% CI for the difference were calculated using the method of Miettinen & Nurminen [
      • Miettinen O.
      • Nurminen M.
      Comparative analysis of two rates.
      ]. Descriptive statistics were calculated to describe safety events.

      3. Results

      3.1 Patient disposition

      A total of 53 Japanese patients were included in the ITT analysis population (tedizolid, n = 28; linezolid, n = 25). Patient disposition is shown in Fig. 1. Demographics and baseline characteristics were generally similar between treatment groups in the ITT population (Table 1). The majority of patients were ≥65 years of age (tedizolid, n = 20 [71.4%]; linezolid, n = 21 [84.0%]), male (tedizolid, n = 22 [78.6%]; linezolid, n = 18 [72.0%]), and were hospitalized for ≥5 days before the first dose of study treatment was administered (tedizolid, n = 23 [82.1%]; linezolid, n = 24 [96.0%]); approximately half were diagnosed with VABP (tedizolid, n = 15 [53.6%]; linezolid, n = 16 [64.0%]). The number of patients with diabetes was smaller in the tedizolid group (n = 2 [7.1%]) compared with the linezolid group (n = 10 [40.0%]). Patients were treated with tedizolid and linezolid for a mean (SD) of 6.8 (1.9) and 8.8 (2.3) days, respectively (Table 1).
      Fig. 1
      Fig. 1Patient disposition.
      CE: clinically evaluable; HABP: hospital-acquired bacterial pneumonia; ITT: intention-to-treat; mITT: microbiologic intention-to-treat; TOC: test of cure; VABP: ventilator-associated bacterial pneumonia.
      Table 1Patient demographics and baseline characteristics (ITT population).
      ParameterTedizolid

      (n = 28)
      Linezolid

      (n = 25)
      Median age (range), y75.5 (27.0–88.0)75.0 (34.0–88.0)
      Age group (stratification factor), n (%)
       <65 y8 (28.6)4 (16.0)
       ≥65 y20 (71.4)21 (84.0)
      Male, n (%)22 (78.6)18 (72.0)
      Race, n (%)
       Asian28 (100.0)25 (100.0)
      Underlying diagnosis (stratification factor)
      The data for trauma or nontrauma admitting diagnosis were collected as underlying diagnosis for use as one of the stratification factors.
      , n (%)
       Trauma7 (25.0)6 (24.0)
       Nontrauma21 (75.0)19 (76.0)
      Diagnosis, n (%)
       vHABP13 (46.4)9 (36.0)
       VABP15 (53.6)16 (64.0)
      Diabetes (key comorbidity), n (%)2 (7.1)10 (40.0)
      Gram-positive bacteremia at baseline, n (%)1 (3.6)1 (4.0)
      Gram-positive pathogen at baseline, n (%)13 (46.4)12 (48.0)
       MSSA6 (21.4)9 (36.0)
       MRSA6 (21.4)4 (16.0)
      Streptococcus pneumoniae2 (7.1)1 (4.0)
      Mean (SD) treatment duration, days6.8 (1.9)8.8 (2.3)
      Duration of mechanical ventilation before first dose of study drug, n (%)
       <5 days17 (60.7)12 (48.0)
       ≥5 days11 (39.3)13 (52.0)
      Duration of hospitalization before first dose of study drug, n (%)
       <5 days5 (17.9)1 (4.0)
       ≥5 days23 (82.1)24 (96.0)
      PaO2/FiO2 ratio, n (%)
       <24016 (57.1)15 (60.0)
      Acute Physiology and Chronic Health Evaluation II score
      Median (range)23.0 (12.0–33.0)25.0 (13.0–38.0)
       <20, n (%)8 (28.6)6 (24.0)
       ≥20, n (%)20 (71.4)19 (76.0)
      Median (range) Glasgow Coma Scale score9.0 (3.0–15.0)6.0 (3.0–14.0)
      Median (range) Clinical Pulmonary Infection Score8.0 (6.0–12.0)10.0 (5.0–13.0)
      Median (range) Sequential Organ Failure Assessment score6.0 (3.0–13.0)7.0 (3.0–12.0)
      FiO2: fraction of inspired oxygen; ITT: intention-to-treat; MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-susceptible Staphylococcus aureus; PaO2: partial pressure of oxygen in arterial blood; VABP: ventilator-associated bacterial pneumonia; vHABP: ventilated hospital-acquired bacterial pneumonia.
      a The data for trauma or nontrauma admitting diagnosis were collected as underlying diagnosis for use as one of the stratification factors.
      Within 72 hours before receiving the first infusion of study drug, 92.9% and 92.0% of patients randomized to tedizolid and linezolid, respectively, were treated with a systemic antibacterial agent; β-lactam/β-lactamase inhibitor combination agents were the most frequently used treatments (tedizolid, 57.1%; linezolid, 36.0%) for gram-negative adjunctive therapy. All evaluable baseline lower respiratory tract gram-positive pathogens were susceptible to tedizolid and linezolid. Tedizolid susceptibility testing results were not available for Streptococcus pneumoniae isolates from 2 patients.

      3.2 Efficacy outcomes

      Rates of day 28 ACM were 10.7% and 20.0% with tedizolid and linezolid, respectively, in the ITT population (difference, 9.3%; 95% CI, −10.1 to 28.7) and 15.4% and 33.3%, respectively, in the mITT population (difference, 17.9%; 95% CI, −15.2 to 51.1; Table 2). Clinical cure at TOC was achieved by 78.6% and 72.0% of patients in the ITT population receiving tedizolid and linezolid, respectively (difference, 6.6%; 95% CI, −16.7 to 29.8) and by 82.4% and 73.7% of patients in the CE population receiving tedizolid and linezolid, respectively (difference, 8.7%; 95% CI, −18.2 to 35.5; Table 2). A similar percentage of patients (76.9% and 75.0% for tedizolid and linezolid, respectively) had a favorable microbiologic response against baseline gram-positive pathogens at TOC. When stratified by specific baseline pathogens, a favorable microbiologic response was achieved with tedizolid and linezolid by 50.0% (3/6) and 75.0% (3/4) of patients with MRSA, respectively, and by 83.3% (5/6) and 66.7% (6/9) of patients with methicillin-susceptible S. aureus, respectively (Table 3).
      Table 2Efficacy outcomes by patient population.
      Efficacy outcomeTedizolid

      n/N (%)
      Linezolid

      n/N (%)
      Difference

      % (95% CI)
      Day 28 ACM
       ITT population3/28 (10.7)5/25 (20.0)9.3 (−10.1 to 28.7)
      The estimated difference in proportions between the 2 groups and the unadjusted 2-sided 95% CI for the difference (linezolid minus tedizolid) in the day 28 ACM rates calculated using the method of Miettinen & Nurminen without stratification.
       mITT population2/13 (15.4)4/12 (33.3)17.9 (−15.2 to 51.1)
      The estimated difference in proportions between the 2 groups and the unadjusted 2-sided 95% CI for the difference (linezolid minus tedizolid) in the day 28 ACM rates calculated using the method of Miettinen & Nurminen without stratification.
      Investigator-assessed clinical cure at TOC
       ITT population22/28 (78.6)18/25 (72.0)6.6 (−16.7 to 29.8);

      (−20.0 to 33.2)
      Data correspond to the 97.5% CI for the difference (tedizolid minus linezolid) in the investigator-assessed clinical cure rates at TOC calculated using the method of Miettinen & Nurminen without stratification.
       CE population14/17 (82.4)14/19 (73.7)8.7 (−18.2 to 35.5);

      (−22.0 to 39.4)
      Data correspond to the 97.5% CI for the difference (tedizolid minus linezolid) in the investigator-assessed clinical cure rates at TOC calculated using the method of Miettinen & Nurminen without stratification.
      ACM: all-cause mortality; CE: clinically evaluable; CI: confidence interval; ITT: intention-to-treat; mITT: microbiologic intention-to-treat; TOC: test of cure.
      a The estimated difference in proportions between the 2 groups and the unadjusted 2-sided 95% CI for the difference (linezolid minus tedizolid) in the day 28 ACM rates calculated using the method of Miettinen & Nurminen without stratification.
      b Data correspond to the 97.5% CI for the difference (tedizolid minus linezolid) in the investigator-assessed clinical cure rates at TOC calculated using the method of Miettinen & Nurminen without stratification.
      Table 3Favorable per-patient microbiologic response at TOC by baseline pathogen from lower respiratory tract or blood (mITT population).
      Baseline pathogenTedizolid

      n/N (%)
      Linezolid

      n/N (%)
      Gram-positive pathogens10/13 (76.9)9/12 (75.0)
      Staphylococcus aureus8/11 (72.7)9/12 (75.0)
      MRSA3/6 (50.0)3/4 (75.0)
      MSSA5/6 (83.3)6/9 (66.7)
      Streptococcus pneumoniae2/2 (100.0)1/1 (100.0)
      mITT: microbiologic intention-to-treat; MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-susceptible Staphylococcus aureus; TOC: test of cure.

      3.3 Safety outcomes

      Overall, 96.4% (n = 27) and 100.0% (n = 25) of patients receiving tedizolid and linezolid reported a TEAE (Table 4). Discontinuation due to a TEAE occurred in 2 (7.1%) patients receiving tedizolid (decreased platelet count, n = 1; hepatic enzyme increase, n = 1) and 1 (4.0%) patient receiving linezolid (thrombocytopenia). The most frequently reported TEAEs (≥15% of patients) with tedizolid were diarrhea, generalized edema, hypokalemia, and urinary tract infection (17.9% [n = 5] for each) and for linezolid were diarrhea (28.0% [n = 7]), anemia and hypokalemia (24.0% [n = 6] for each), and hyponatremia and increased liver function test (20.0% [n = 5] for each), hematuria and septic shock (16.0% [n = 4] for each; Table 5). Of these most common TEAEs reported from patients who received tedizolid, only anemia and diarrhea were considered to be drug-related TEAEs (3.6% [n = 1] for each; Table 5).
      Table 4TEAE summary (safety population).
      TEAE category, n (%)Tedizolid

      (n = 28)
      Linezolid

      (n = 25)
      Any TEAE27 (96.4)25 (100.0)
       TEAEs leading to discontinuation of study drug2 (7.1)1 (4.0)
       TEAEs leading to death3 (10.7)5 (20.0)
      Serious TEAEs6 (21.4)11 (44.0)
       Serious TEAEs leading to discontinuation of study drug01 (4.0)
       Serious TEAEs leading to death3 (10.7)5 (20.0)
      Drug-related TEAE7 (25.0)9 (36.0)
       Drug-related serious TEAE01 (4.0)
       Drug-related TEAE leading to death01 (4.0)
      TEAE: treatment-emergent adverse event.
      Table 5Most common overall and drug-related TEAEs (safety population).
      TEAE SOC and preferred terms, n (%)
      Limited to TEAEs recorded in ≥15% of patients in either the tedizolid or linezolid treatment group.
      Tedizolid

      (n = 28)
      Linezolid

      (n = 25)
      OverallDrug-relatedOverallDrug-related
      Blood and lymphatic system disorders
       Anemia2 (7.1)1 (3.6)6 (24.0)2 (8.0)
      Gastrointestinal disorders
       Diarrhea5 (17.9)1 (3.6)7 (28.0)6 (24.0)
      General disorders and administration site conditions
       Generalized edema5 (17.9)000
      Infections and infestations
       Septic shock1 (3.6)04 (16.0)0
       Urinary tract infection5 (17.9)03 (12.0)0
      Investigations
       Increased liver function test1 (3.6)05 (20.0)2 (8.0)
      Metabolism and nutrition disorders
       Hypokalemia5 (17.9)06 (24.0)1 (4.0)
       Hyponatremia3 (10.7)05 (20.0)0
      Renal and urinary disorders
       Hematuria1 (3.6)04 (16.0)0
      SOC: system organ class; TEAE: treatment-emergent adverse event.
      a Limited to TEAEs recorded in ≥15% of patients in either the tedizolid or linezolid treatment group.
      Serious TEAEs occurred in 21.4% (n = 6) and 44.0% (n = 11) of patients receiving tedizolid and linezolid, respectively (Table 4). For tedizolid, serious TEAEs included acute respiratory distress syndrome, brain herniation, acute cholecystitis, pleural effusion, pneumatosis intestinalis, sepsis, and urinary tract infection (1 patient each). For linezolid, serious TEAEs included ascites, glossoptosis, hypoxia, pleural effusion, organizing pneumonia, pneumonia aspiration, and thrombocytopenia (1 patient each); acute kidney injury, penile ulceration (2 patients each); and septic shock (4 patients). One serious TEAE, thrombocytopenia, was considered likely to be related to the study drug, linezolid, and resolved. A second serious TEAE reported from the same patient, acute kidney injury, was considered to be possibly related to linezolid and was fatal. All other serious TEAEs were not considered related to treatment. Three deaths occurred in patients receiving tedizolid (10.7%) and were due to pneumatosis intestinalis, sepsis, and brain herniation (1 patient each); none were considered drug related. Five deaths occurred in patients receiving linezolid (20.0%) and were due to septic shock (3 patients) and acute kidney injury and organizing pneumonia (1 patient each); only the 1 death due to acute kidney injury was considered possibly drug related.

      4. Discussion

      This report summarizes the efficacy and safety of tedizolid in the Japanese subgroup of patients with vHABP/VABP enrolled in the VITAL study. The primary results of the study have been reported by Wunderink et al. [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. Efficacy results from this subgroup analysis showed that rates of day 28 ACM in Japanese patients treated with tedizolid were comparable with linezolid in the ITT population (10.7% with tedizolid and 20.0% with linezolid). These results are consistent with the primary efficacy results of the full population in the VITAL study that demonstrated that tedizolid was non-inferior to linezolid for the day 28 ACM rate (28.1% and 26.4%, respectively; difference, −1.8%; 95% CI, −8.2 to 4.7) [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. Rates of investigator-assessed clinical cure at TOC in Japanese patients were comparable with tedizolid and linezolid in the ITT population (78.6% with tedizolid and 72.0% with linezolid). This observation is notable since non-inferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC in the full study population (56.3% for tedizolid vs 63.9% for linezolid; difference, −7.6%; 97.5% CI, −15.7 to 0.5) [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. A favorable microbiologic response at TOC was also comparable between patients receiving tedizolid and linezolid (76.9% and 75.0%, respectively) and those with MRSA also responded favorably; these findings were similar to those confirmed in the full study population [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. The efficacy results of this subgroup analysis were also consistent with the findings observed in a phase 3 study in Japanese patients with SSTI caused by MRSA; clinical cure rates at TOC were similar in the tedizolid (92.6%) and linezolid (88.9%) groups in the microbiologically evaluable (ME)-MRSA population [
      • Mikamo H.
      • Takesue Y.
      • Iwamoto Y.
      • Tanigawa T.
      • Kato M.
      • Tanimura Y.
      • et al.
      Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan – Results of a randomised, multicentre phase 3 study.
      ]. Likewise, microbiologic success rates at TOC were similar in the ME-MRSA population (tedizolid, 96.4%; linezolid, 100.0%) [
      • Mikamo H.
      • Takesue Y.
      • Iwamoto Y.
      • Tanigawa T.
      • Kato M.
      • Tanimura Y.
      • et al.
      Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan – Results of a randomised, multicentre phase 3 study.
      ].
      The efficacy of tedizolid was favorable in the Japanese population. Compared with the full study population, Japanese patients tended to be older, with a higher percentage of patients ≥65 years of age (71.4% and 84.0% for tedizolid and linezolid, respectively, compared with 39.6% and 40.6% in the full study population) [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. In addition, more Japanese patients had a baseline diagnosis of vHABP (46.4% and 36.0% for tedizolid and linezolid, respectively) compared with the full study population, in which approximately 26% had vHABP at baseline [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. This is notable because vHABP has higher mortality rates than non-ventilated HABP and VABP [
      • Talbot G.H.
      • Das A.
      • Cush S.
      • Dane A.
      • Wible M.
      • Echols R.
      • et al.
      Evidence-based study design for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.
      ]. Lastly, the proportion of patients who had an Acute Physiologic Assessment and Chronic Health Evaluation II score ≥20 was higher in the Japanese subgroup (tedizolid, 71.4%; linezolid, 76.0%) compared with the full study population (tedizolid, 48.4%; linezolid, 43.1%) [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. Owing to the small sample size of this Japanese subgroup analysis (tedizolid, n = 28; linezolid, n = 25), it was not possible to determine factors that may contribute to the reduced mortality and increased rate of favorable clinical response in Japanese patients who received tedizolid. However, potential factors may include the relatively small number of patients with diabetes and higher proportions of patients who had mechanical ventilation <5 days before the first dose of study therapy and who had stayed in the hospital <5 days before the first dose of study therapy compared with the full study population. For reference, a post hoc logistic regression model to assess potential factors that predict clinical response in patients treated with tedizolid and linezolid was included in the primary analysis and, although geographic region (North America vs other regions) was a significant predictor of clinical response for tedizolid, the model did not identify race as a potential predicting factor [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ].
      Day 28 ACM in Japanese patients treated with tedizolid in this analysis was also lower compared with day 30 mortality rate (19.8%; 268/1351) reported in a multicenter prospective survey that collected data from 1460 patients with hospital-acquired pneumonia across 254 institutions in Japan from 2002 to 2004 [
      • Watanabe A.
      • Yanagihara K.
      • Kohno S.
      • Matsushima T.
      HAP study group. Multicenter survey on hospital-acquired pneumonia and the clinical efficacy of first-line antibiotics in Japan.
      ]. In the survey, approximately 30% (249/816) of cases, in which causative organisms were identified, were attributed to gram-positive organisms. In cases with MRSA pneumonia, the day 30 mortality rate was (33.6% [46/137]) [
      • Watanabe A.
      • Yanagihara K.
      • Kohno S.
      • Matsushima T.
      HAP study group. Multicenter survey on hospital-acquired pneumonia and the clinical efficacy of first-line antibiotics in Japan.
      ]. In this nationwide survey, patients were comparable in age with those in the current analysis (81.0% were ≥65 years of age vs 71.4% for patients treated with tedizolid in the current analysis); first-line antibacterial agents used for treatment were carbapenems (61.7%), anti-pseudomonal cephems (17.3%), and clindamycin (9.3%); and patients had a wide range of illness severity ranging from mild to severe [
      • Watanabe A.
      • Yanagihara K.
      • Kohno S.
      • Matsushima T.
      HAP study group. Multicenter survey on hospital-acquired pneumonia and the clinical efficacy of first-line antibiotics in Japan.
      ].
      As for the safety findings, the proportion of patients who reported any TEAE was similar across treatment arms in both the Japanese and full study population (≥90%) [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. The proportion of patients who reported drug-related TEAE was higher in the Japanese population in both treatment arms (tedizolid, 25.0%; linezolid, 36.0%) compared with the full study population (tedizolid, 8.1%; linezolid, 11.9%). This finding may be related to a higher proportion of patients aged ≥65 years in the Japanese subgroup compared with the full study population. In the tedizolid arm of the Japanese subgroup, 25.0% of TEAEs were reported as drug related but no serious TEAEs or deaths were drug related. Anemia and diarrhea were reported in the current analysis and the phase 3 study in Japanese patients with SSTI caused by MRSA [
      • Mikamo H.
      • Takesue Y.
      • Iwamoto Y.
      • Tanigawa T.
      • Kato M.
      • Tanimura Y.
      • et al.
      Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan – Results of a randomised, multicentre phase 3 study.
      ]. As observed in that study, myelosuppression-related TEAEs were not a concern when tedizolid was administered [
      • Mikamo H.
      • Takesue Y.
      • Iwamoto Y.
      • Tanigawa T.
      • Kato M.
      • Tanimura Y.
      • et al.
      Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan – Results of a randomised, multicentre phase 3 study.
      ]. The results of this subgroup analysis revealed that the safety profile of tedizolid in Japanese patients with vHABP/VABP was comparable to one that has been observed in Japanese patients with SSTI [
      • Mikamo H.
      • Takesue Y.
      • Iwamoto Y.
      • Tanigawa T.
      • Kato M.
      • Tanimura Y.
      • et al.
      Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan – Results of a randomised, multicentre phase 3 study.
      ], and no new safety concerns were observed.
      Certain limitations should be considered when evaluating the results of this analysis. Patient numbers in the treatment arms were small and may affect the conclusions that can be drawn from these data. In addition, the treatment duration specified for tedizolid was shorter than that of linezolid owing to the study design and could contribute to outcomes; however, the difference in treatment duration was not considered an influential factor for safety or efficacy outcomes in the primary analysis [
      • Wunderink R.G.
      • Roquilly A.
      • Croce M.
      • Rodriguez Gonzalez D.
      • Fujimi S.
      • Butterton J.R.
      • et al.
      A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia.
      ]. In this study, gram-negative adjunctive therapy was allowed as an initial therapy before respiratory tract specimens were available from the screening visit culture results. However, susceptibilities for gram-negative pathogens were unavailable for confirmation of adjunctive therapy adequacy and this is a limitation of the study.
      In conclusion, the results from this subgroup analysis showed that tedizolid has generally favorable efficacy and safety in adult Japanese patients with vHABP/VABP. No new safety concerns related to tedizolid were observed in this patient population.

      Funding

      Funding for this research and medical writing support were provided by Merck Sharp & Dohme LLC , a subsidiary of Merck & Co., Inc. , Rahway, NJ, USA (MSD).

      Authorship statement

      All authors met ICMJE criteria for authorship. HM was involved in the conception and design of the Japanese subgroup analysis, the interpretation of data, and review and revision of this manuscript. MN, SK, and CDA were involved in the design of the phase 3 VITAL study. MN and SK were involved in the interpretation of data, and review and revision of this manuscript. SF was involved in acquisition and interpretation of data, and review and revision of this manuscript. NO was involved in analysis of data, and review and revision of this manuscript. CDA was involved in the conception and design of the Japanese subgroup analysis, the analysis and interpretation of data, and review and revision of this manuscript. AT was involved in the interpretation of data and drafting of this manuscript. All authors provided final approval of the version for publication and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

      Declaration of competing interest

      HM received grant support from Asahi Kasei Pharma Corporation, Shionogi & Co. Ltd., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., and FUJIFILM Toyama Chemical Co., Ltd.; and payment for lectures from Astellas Pharma Inc., MSD K·K., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., MIYARISAN Pharmaceutical Co., Ltd., Becton, Dickinson and Company Japan, and FUJIFILM Toyama Chemical Co. Ltd. MN and SK were medical experts in Japan for this study. SF was an investigator for this study. NO and AT are employees of MSD K.K., Tokyo, Japan and CDA is an employee of MSD, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA.

      Acknowledgments

      We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel. Investigators at the following study sites participated in the clinical study from Japan: Nobuhiro Inagaki (Almeida Memorial Hospital), Satoshi Fujimi (Osaka General Medical Center), Takeshi Takahashi (National Hospital Organization Kumamoto Medical Center), Kazuhiko Yamada (National Center for Global Health and Medicine), Kenji Shigemi (University of Fukui Hospital), Yutaka Takeda (Kansai Rosai Hospital), Eiji Kawamoto (Mie University Hospital), Ryosuke Tsuruta (Yamaguchi University Hospital), Masayasu Arai (Kitasato University Hospital), Takaaki Kikuno (National Hospital Organization Tokyo Medical Center), Yu Kasamatsu (Osaka City General Hospital), Tomotsugu Nakano (Tokyo Metropolitan Hiroo Hospital), Kazuhiro Osanai (Kanazawa Medical University Hospital), Shinsuke Fujiwara (National Hospital Organization Ureshino Medical Center), Tsuyoshi Nojima (Kochi Health Sciences Center), Yuji Nakamura (Shobara Red Cross Hospital), Yusuke Koizumi (Aichi Medical University Hospital), Tsukasa Kuwana (Nihon University Itabashi Hospital), Hirokazu Okubo (Oita Oka Hospital), Yosuke Nagayoshi (National Hospital Organization Nagasaki Medical Center), Hiroshi Kakeya (Osaka City University Hospital), Yuichi Fukuda (Sasebo City General Hospital), Kazuki Konishi (Morioka Tsunagi Onsen Hospital), Hiroshi Hinohara (Gunma University Hospital), Takefumi Saito (National Hospital Organization Ibarakihigashi National Hospital), Akinori Nakamura (National Hospital Organization Matsumoto Medical Center). We also thank Norihiro Aoyama for providing support for data interpretation. Medical writing and/or editorial assistance was provided by Susan E. DeRocco, PhD, and Madiha Khan, PharmD, of The Lockwood Group, Stamford, CT, USA. This assistance was funded by Merck Sharp & Dohme LLC , a subsidiary of Merck & Co., Inc. , Rahway, NJ, USA (MSD).

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