scholarly journals A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study)

2020 ◽  
Author(s):  
Ivan Titov ◽  
Richard G Wunderink ◽  
Antoine Roquilly ◽  
Daniel Rodríguez Gonzalez ◽  
Aileen David-Wang ◽  
...  
Keyword(s):  
Clinical Response ◽  
Bacterial Pneumonia ◽  
Severe Renal Impairment ◽  
Apache Ii Score ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Gram Negative ◽  
Mitt Population ◽  
All Cause Mortality ◽  
Hospital Acquired

Abstract Background Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Methods This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7–14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7–14 days after completing therapy in the MITT population. Results Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, −5.3% [95% confidence interval {CI}, −11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, −3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively. Conclusions Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients. Clinical Trials Registration NCT02493764.

scholarly journals 1574. Multivariate Regression Analysis to Determine Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Trial

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S785-S786
Author(s):  
Robert Tipping ◽  
Jiejun Du ◽  
Maria C Losada ◽  
Michelle L Brown ◽  
Katherine Young ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Clinical Response ◽  
Treatment Outcomes ◽  
Multivariate Regression ◽  
Multivariate Regression Analysis ◽  
Apache Ii Score ◽  
Double Blind ◽  
Mitt Population ◽  
Study Results ◽  
All Cause Mortality

Abstract Background In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was non-inferior to PIP/TAZ for treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in the primary endpoint of Day 28 all-cause mortality (D28 ACM) and the key secondary endpoint of clinical response (CR) at early follow-up (EFU; 7-14 d after end of therapy). We performed a multivariate regression analysis to determine independent predictors of treatment outcomes in this trial. Methods Randomized, controlled, double-blind, phase 3, non-inferiority trial comparing IMI/REL 500 mg/250 mg vs PIP/TAZ 4 g/500 mg, every 6 h for 7-14 d, in adult patients (pts) with HABP/VABP. Stepwise-selection logistic regression modeling was used to determine independent predictors of D28 ACM and favorable CR at EFU, in the MITT population (randomized pts with ≥1 dose of study drug, except pts with only gram-positive cocci at baseline). Baseline variables (n=19) were pre-selected as candidates for inclusion (Table 1), based on clinical relevance. Variables were added to the model if significant (p < 0.05) and removed if their significance was reduced (p > 0.1) by addition of other variables. Results Baseline variables that met criteria for significant independent predictors of D28 ACM and CR at EFU in the final selected regression model are in Fig 1 and Fig 2, respectively. As expected, APACHE II score, renal impairment, elderly age, and mechanical ventilation were significant predictors for both outcomes. Bacteremia and P. aeruginosa as a causative pathogen were predictors of unfavorable CR, but not of D28 ACM. Geographic region and the hospital service unit a patient was admitted to were found to be significant predictors, likely explained by their collinearity with other variables. Treatment allocation (IMI/REL vs PIP/TAZ) was not a significant predictor for ACM or CR; this was not unexpected, since the trial showed non-inferiority of the two HABP/VABP therapies. No interactions between the significant predictors and treatment arm were observed. Conclusion This analysis validated known predictors for mortality and clinical outcomes in pts with HABP/VABP and supports the main study results by showing no interactions between predictors and treatment arm. Table 1. Candidate baseline variables pre-selected for inclusion Figure 1. Independent predictors of greater Day 28 all-cause mortality (MITT population; N=531) Figure 2. Independent predictors of favorable clinical response at EFU (MITT population; N=531) Disclosures Robert Tipping, MS, Merck & Co., Inc. (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Maria C. Losada, BA, Merck & Co., Inc. (Employee, Shareholder) Michelle L. Brown, BS, Merck & Co., Inc. (Employee, Shareholder) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Joan R. Butterton, MD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck & Co., Inc. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder)

scholarly journals 1460. Imipenem/Cilastatin (IMI)/Relebactam (REL) in Hospital-Acquired/Ventilator-Associated Bacterial Pneumonia (HABP/VABP): Subgroup Analyses of Critically Ill Patients in the RESTORE-IMI 2 Trial

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S732-S732
Author(s):  
Luke F Chen ◽  
Maria C Losada ◽  
Kathryn A Mahoney ◽  
Jiejun Du ◽  
Michelle L Brown ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Clinical Response ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Severe Renal Impairment ◽  
Study Drug ◽  
Apache Ii ◽  
Apache Ii Score ◽  
Double Blind ◽  
Mitt Population

Abstract Background HABP/VABP are serious infections associated with high mortality. Critically ill patients (pts) are at particularly high risk of adverse clinical outcomes. In the RESTORE-IMI 2 trial, IMI/REL was non-inferior to PIP/TAZ in primary and key secondary endpoints. We evaluated outcomes specifically in critically ill pts, according to several definitions, from that trial. Methods Randomized, controlled, double-blind, phase 3 trial in adult pts with HABP/VABP. Lower respiratory tract (LRT) specimens were obtained ≤48 hours prior to screening. Pts were randomized 1:1 to IMI/REL 500 mg/250 mg or PIP/TAZ 4 g/500 mg, given IV every 6 h for 7-14 d. The primary endpoint was Day 28 all-cause mortality (ACM) and the key secondary endpoint was clinical response at early follow-up (EFU; 7-14 d after completing therapy) in the modified intent-to-treat (MITT) population (randomized pts with ≥1 dose of study drug, excluding pts with only gram-positive cocci present on baseline Gram stain). This analysis assessed efficacy outcomes specifically in pts in the ICU and in pts with APACHE II score ≥15, both prespecified subgroups. In post-hoc analyses, outcomes were also specifically assessed in the subgroups of pts with moderate/severe renal impairment (creatinine clearance < 60 mL/min) and pts who received vasopressors. Results Of MITT pts (n=531) at baseline, 66.1% (175 IMI/REL, 176 PIP/TAZ) were in the ICU, 47.5% (125 IMI/REL, 127 PIP/TAZ) had APACHE-II score ≥15, and 24.7% (71 IMI/REL, 60 PIP/TAZ) had moderate/severe renal impairment. Further, 20.9% (54 IMI/REL, 57 PIP/TAZ) received vasopressors within 72 h of first dose of study drug and/or during the study. In each subgroup, baseline demographics, clinical characteristics, and causative LRT pathogens (mostly Enterobacterales, P. aeruginosa, and A. calcoaceticus-baumannii complex) were generally comparable between treatment arms. In pts with APACHE-II score ≥15, Day 28 ACM and clinical response rates with IMI/REL were favorable compared to PIP/TAZ (Table). Day 28 ACM was also favorable with IMI/REL in patients receiving vasopressors. Remaining outcomes were similar between treatment arms. Conclusion IMI/REL is an efficacious treatment option for critically ill pts with HABP/VABP. Table. Primary and key secondary efficacy outcomes by subgroup (MITT population) Disclosures Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Maria C. Losada, BA, Merck & Co., Inc. (Employee, Shareholder) Kathryn A. Mahoney, PharmD, Merck (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Michelle L. Brown, BS, Merck & Co., Inc. (Employee, Shareholder) Robert Tipping, MS, Merck & Co., Inc. (Employee, Shareholder) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Joan R. Butterton, MD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck & Co., Inc. (Employee, Shareholder)

scholarly journals 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

2021 ◽  
Author(s):  
Richard G Wunderink ◽  
Antoine Roquilly ◽  
Martin Croce ◽  
Daniel Rodriguez Gonzalez ◽  
Satoshi Fujimi ◽  
...  
Keyword(s):  
Clinical Response ◽  
Bacterial Pneumonia ◽  
Double Blind Study ◽  
Phase 3 ◽  
Gram Positive ◽  
Double Blind ◽  
Intention To Treat ◽  
The Difference ◽  
Hospital Acquired ◽  
Noninferiority Margin

Abstract Background Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP. Methods In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population. Results Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, –1.8%; 95% confidence interval [CI]: –8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, –7.6%; 97.5% CI: –15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively. Conclusions Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated. Clinical Trials Registration NCT02019420.

scholarly journals 1230. Clinical and Microbiologic Outcomes by Causative Pathogen in Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia (HABP/VABP) Treated with Imipenem/Cilastatin (IMI)/Relebactam (REL) Versus Piperacillin/Tazobactam (PIP/TAZ)

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S635-S635
Author(s):  
Maria C Losada ◽  
Alok Maniar ◽  
Jiejun Du ◽  
Michelle L Brown ◽  
Katherine Young ◽  
...  
Keyword(s):  
Clinical Response ◽  
Study Drug ◽  
Empiric Therapy ◽  
Causative Pathogen ◽  
Phase 3 ◽  
Double Blind ◽  
Mitt Population ◽  
Secondary Endpoints ◽  
Intent To Treat ◽  
Hospital Acquired

Abstract Background IMI/REL is a combination of IMI and the novel class A and class C β-lactamase inhibitor REL. Here we present per-pathogen outcomes from a recent phase 3 clinical trial (RESTORE-IMI 2), in which IMI/REL was shown to be non-inferior to piperacillin/tazobactam (PIP/TAZ) for empiric therapy of HABP/VABP, in both primary and key secondary endpoints. Methods Randomized, controlled, double-blind, multinational, phase 3, non-inferiority trial in adults with HABP/VABP. Lower respiratory tract specimens were obtained ≤48 hours prior to screening. Participants (pts) were randomized 1:1 to IMI/REL 500 mg/250 mg or PIP/TAZ 4 g/500 mg, given intravenously every 6 h for 7-14 d. Pts also received empiric linezolid until baseline cultures confirmed absence of MRSA. This analysis evaluated outcomes by causative LRT pathogen in modified intent to treat (MITT) pts (randomized pts with ≥1 dose of study drug, excluding pts with only gram-positive cocci present on baseline Gram stain) who had ≥1 baseline LRT pathogen susceptible (according to CLSI criteria) to both study drugs. Outcomes assessed were microbiologic response at end of therapy (EOT), clinical response at early follow-up (EFU; 7-14 d after EOT), and Day 28 all-cause mortality (ACM). Results Of 531 MITT pts, 51.4% (130 IMI/REL, 143 PIP/TAZ) had ≥1 baseline LRT pathogen susceptible to both study drugs. The most common causative pathogens in this analysis population were Klebsiella spp (30.4% of patients), Pseudomonas aeruginosa (22.3%), Escherichia coli (22.0%), and Haemophilus influenzae (9.2%), consistent with other recent trials in HABP/VABP and with surveillance data. Outcomes by pathogen were generally comparable between IMI/REL and PIP/TAZ (Table). In a separate subgroup analysis of the microbiologic MITT population, in pts with ≥1 ESBL-positive LRT pathogen (45 IMI/REL, 35 PIP/TAZ), microbiologic response at EOT was 82.2% (IMI/REL) vs 68.6%% (PIP/TAZ), clinical response at EFU was 64.4% vs 60.0%, and Day 28 ACM was 20.0% and 22.9%, respectively. In the IMI/REL arm, 8 pts had ≥1 confirmed KPC-positive baseline LRT pathogen; KPC status was not assessed in the PIP/TAZ arm. Conclusion IMI/REL is an efficacious treatment option for HABP/VABP, regardless of causative pathogen. Table. Primary and secondary efficacy outcomes in patients who were in the MITT population and had at least 1 baseline LRT pathogen susceptible to both study drugs Disclosures Maria C. Losada, BA, Merck & Co., Inc. (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Michelle L. Brown, BS, Merck & Co., Inc. (Employee, Shareholder) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Robert Tipping, MS, Merck & Co., Inc. (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Joan R. Butterton, MD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck & Co., Inc. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder)

scholarly journals 1271. Efficacy and Safety of Cefiderocol and Best Available Therapy in Patients with Serious Infections Caused by Carbapenem-Resistant Gram-Negative Infections: Results of the Pathogen-Focused Phase 3 CREDIBLE-CR Study

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S652-S653
Author(s):  
Matteo Bassetti ◽  
Roger Echols ◽  
Yuko Matsunaga ◽  
Simon Portsmouth ◽  
Mari Ariyasu ◽  
...  
Keyword(s):  
Panel Member ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Gram Negative ◽  
Mitt Population ◽  
Carbapenem Resistant ◽  
Serious Infections ◽  
All Cause Mortality ◽  
Acinetobacter Spp ◽  
Tract Infections

Abstract Background The CREDIBLE-CR study assessed the efficacy and safety of cefiderocol (CFDC), a novel siderophore cephalosporin, in the treatment of serious infections due to carbapenem-resistant (CR) Gram-negative (GN) bacteria. Methods CREDIBLE-CR was an open-label, prospective, randomized 2:1, Phase 3 study (NCT02714595) in patients with nosocomial pneumonia (NP), bloodstream infections/sepsis (BSI/Sepsis), or complicated urinary tract infections (cUTI) with evidence of CR GN pathogens. Adults received intravenous CFDC 2 g, q8h, 3-h infusion or best available therapy (BAT; up to 3 drugs) for 7–14 days (extendable to 21 days). The primary endpoint at test of cure in the CR microbiological intent-to-treat (CR-MITT) population was clinical cure (NP, BSI/Sepsis) or microbiological eradication (cUTI). Secondary endpoints were clinical and microbiological outcomes, all-cause mortality (ACM) and safety. Only descriptive statistics were pre-specified. Results A total of 101 patients received CFDC and 49 received BAT (CR-MITT: CFDC n=80, BAT n=38): 50% had pneumonia, 31.4% BSI/Sepsis, and 18.6% cUTI (Table 1). Most frequent CR pathogens were Acinetobacter baumannii (45.8%), Klebsiella pneumoniae (37.3%), and Pseudomonas aeruginosa (23.7%). CFDC monotherapy was given to 83% of patients, while BAT monotherapy to 29% of patients. Primary outcome in the CFDC and BAT arms was achieved in 50.0% and 52.6% in NP, 43.5% and 42.9% in BSI/Sepsis, and 52.9% and 20.0% in cUTI patients (Figure). CFDC was highly efficacious vs CREs and NDM-producing pathogens. Day 28 ACM was 24.8% (25/101) with CFDC and 18.4% (9/49) with BAT. Rescue therapy was given more frequently in the BAT than CFDC arm. Mortality results by pathogen showed an imbalance in Acinetobacter spp. infections (Table 2) with a higher rate in the CFDC arm than BAT arm. ICU and shock at randomization were more frequent in the CFDC arm than in the BAT arm in Acinetobacter spp. infections (Table 2). No safety concerns related to CFDC emerged. Table 1. Baseline demographics and characteristics (CR-MITT population) Figure. CREDIBLE-CR study primary efficacy endpoints and secondary outcomes at test-of-cure visit in CR-MITT population. Table 2. All-cause mortality by baseline pathogen inpatients with or without Acinetobacter spp. infection (safety population) Conclusion Efficacy of CFDC was demonstrated in this descriptive pathogen-focused study, including CREs, metallo-NDM producers and CR non-fermenters. Baseline imbalances of ICU and shock in the subset of infections with Acinetobacter spp. may have contributed to the mortality difference between CFDC and BAT arms. Disclosures Matteo Bassetti, MD, Shionogi Inc. (Advisor or Review Panel member) Roger Echols, MD, Shionogi Inc. (Consultant) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

scholarly journals A Phase-3 Study to Compare Delafloxacin to Moxifloxacin for the Treatment of Adults with Community-acquired Bacterial Pneumonia (DEFINE-CABP)

2019 ◽  
Author(s):  
Juan P Horcajada ◽  
Robert A Salata ◽  
Rodolfo Álvarez-Sala ◽  
Floarea Mimi Nitu ◽  
Laura Lawrence ◽  
...  
Keyword(s):  
Clinical Response ◽  
Bacterial Pneumonia ◽  
Study Drug ◽  
The United States ◽  
Efficacy And Safety ◽  
Success Rates ◽  
Phase 3 ◽  
Double Blind ◽  
Atypical Pathogens ◽  
Intent To Treat

Abstract Background The clinical and economic burden of community-acquired bacterial pneumonia (CABP) is significant and is anticipated to increase as the population ages and pathogens become more resistant. Delafloxacin is a fluoroquinolone antibiotic approved in the United States for the treatment of adults with acute bacterial skin and skin structure infections. Delafloxacin’s shape and charge profile uniquely impacts its spectrum of activity and side effect profile. This phase 3 study compared the efficacy and safety of delafloxacin to moxifloxacin for the treatment of CABP. Methods A randomized, double-blind, comparator-controlled, multicenter, global Phase 3 study compared the efficacy and safety of delafloxacin 300 mg BID or moxifloxacin 400 mg QD in adults with CABP. The primary endpoint was early clinical response (ECR) defined as improvement at 96 (± 24) hours after first dose of study drug. Clinical response at test of cure (TOC) and microbiologic response were also assessed. Results In the intent-to-treat analysis population (ITT), ECR rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. Noninferiority of delafloxacin compared with moxifloxacin was demonstrated. At TOC in the ITT population, the success rates were similar between groups. Treatment-emergent adverse events considered at least possibly related to the study drug occurred in 65 subjects (15.2%) in the delafloxacin group and 54 (12.6%) in the moxifloxacin group. Conclusions IV/oral delafloxacin monotherapy is effective and well tolerated in the treatment of adults with CABP, providing coverage for grampositive, gramnegative, and atypical pathogens.

scholarly journals LB4. Efficacy and Safety of Cefiderocol vs. High-Dose Meropenem in Patients with Nosocomial Pneumonia—Results of a Phase 3, Randomized, Multicenter, Double-Blind, Non-Inferiority Study

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S994-S994 ◽  
Author(s):  
Richard G Wunderink ◽  
Richard G Wunderink ◽  
Yuko Matsunaga ◽  
Mari Ari ◽  
Mari Ariyasu ◽  
...  
Keyword(s):  
Clinical Cure ◽  
Apache Ii Score ◽  
High Dose ◽  
Gram Negative Bacteria ◽  
Phase 3 ◽  
Double Blind ◽  
Gram Negative ◽  
Mitt Population ◽  
Prior Therapy ◽  
Gram Negative Bacteremia

Abstract Background Cefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. In this study, Day 14 all-cause mortality (ACM) rates were compared between CFDC and meropenem (MEM) in patients with nosocomial Gram-negative pneumonia. Methods The study (NCT03032380) was a Phase 3, international, double-blind, randomized, non-inferiority study in hospitalized patients with ventilator-associated, hospital-acquired, or healthcare-associated pneumonia caused by suspected Gram-negative bacteria. Patients were treated with CFDC (2 g, q8h) or MEM (2 g, q8h), both infused for 3 hours, for 7–14 days. Adjunctive linezolid (600 mg, q12h, ≥5 days) was given in both arms to cover Gram-positive bacteria. The primary endpoint was non-inferiority of CFDC to MEM for Day 14 ACM rate in the modified intent-to-treat population (mITT; non-inferiority margin: –12.5%). Key secondary endpoints were clinical and microbiological outcomes at test of cure (TOC), and Day 28 mortality. Safety was investigated up to 28 days after the end of treatment. Results In the ITT population, 148 patients were randomized to CFDC and 150 to MEM: 59.7% were ventilated, 32.6% had failure of prior therapy, the median APACHE II score was 15, and 6.0% had concomitant Gram-negative bacteremia at baseline. In the mITT population, non-inferiority of CFDC to MEM for Day 14 ACM was demonstrated; CFDC: 12.4% (18 out of 145 patients) vs. MEM: 11.6% (17 out of 146 patients); treatment difference: 0.8; 95% confidence interval: –6.6; 8.2. Comparable Day 28 ACM (CFDC: 21.0% vs. MEM: 20.5%), clinical cure (CFDC: 64.8% vs. MEM: 66.7%), and microbiological eradication (CFDC: 47.6% vs. MEM: 48.0%) rates were demonstrated in the mITT population at TOC. Clinical cure rates for major target pathogens at TOC were similar between CFDC and MEM arms (figure). The rates of treatment-emergent adverse events (TEAEs), drug-related TEAEs, serious AEs, discontinuation due to TEAEs, and deaths were similar between treatment arms (table). Conclusion This study demonstrated the non-inferiority of CFDC to high-dose MEM for the pre-specified endpoint of Day 14 ACM. No unexpected safety signals were observed in the study. Disclosures Richard G. Wunderink, MD, Merck (Consultant, Grant/Research Support), Shionogi Inc. (Consultant), Yuko Matsunaga, MD, Shionogi Inc. (Employee), Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee), Roger Echols, MD, Shionogi Inc. (Consultant), Anju Menon, PhD, Shionogi Inc. (Employee), Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee).

scholarly journals RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections

2019 ◽  
Vol 70 (9) ◽  
pp. 1799-1808 ◽  
Author(s):  
Johann Motsch ◽  
Cláudia Murta de Oliveira ◽  
Viktor Stus ◽  
Iftihar Köksal ◽  
Olexiy Lyulko ◽  
...  
Keyword(s):  
Clinical Response ◽  
Bacterial Infections ◽  
Infection Type ◽  
Complicated Urinary Tract Infection ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Overall Response ◽  
Dose Study ◽  
Intent To Treat ◽  
Hospital Acquired

Abstract Background The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. Methods Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. Results Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, –27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, –46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. Conclusions Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections. Clinical Trials Registration NCT02452047.

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