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A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia.

ABSTRACT: Ceftobiprole, the active moiety of ceftobiprole medocaril, is a novel broad-spectrum cephalosporin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant strains) and penicillin- and ceftriaxone-resistant pneumococci, and gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa.This was a double-blind, randomized, multicenter study of 781 patients with hospital-acquired pneumonia (HAP), including 210 with ventilator-associated pneumonia (VAP). Treatment was intravenous ceftobiprole 500 mg every 8 hours, or ceftazidime 2 g every 8 hours plus linezolid 600 mg every 12 hours; primary outcome was clinical cure at the test-of-cure visit.Overall cure rates for ceftobiprole vs ceftazidime/linezolid were 49.9% vs 52.8% (intent-to-treat [ITT], 95% confidence interval [CI] for the difference, -10.0 to 4.1) and 69.3% vs 71.3% (clinically evaluable [CE], 95% CI, -10.0 to 6.1). Cure rates in HAP (excluding VAP) patients were 59.6% vs 58.8% (ITT, 95% CI, -7.3 to 8.8), and 77.8% vs 76.2% (CE, 95% CI, -6.9 to 10.0). Cure rates in VAP patients were 23.1% vs 36.8% (ITT, 95% CI, -26.0 to -1.5) and 37.7% vs 55.9% (CE, 95% CI, -36.4 to 0). Microbiological eradication rates in HAP (excluding VAP) patients were, respectively, 62.9% vs 67.5% (microbiologically evaluable [ME], 95% CI, -16.7 to 7.6), and in VAP patients 30.4% vs 50.0% (ME, 95% CI, -38.8 to -0.4). Treatment-related adverse events were comparable for ceftobiprole (24.9%) and ceftazidime/linezolid (25.4%).Ceftobiprole is a safe and effective bactericidal antibiotic for the empiric treatment of HAP (excluding VAP). Further investigations are needed before recommending the use of ceftobiprole in VAP patients. Clinical Trials Registration. NCT00210964, NCT00229008.

SUBMITTER: Awad SS

PROVIDER: S-EPMC4305133 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia.

Awad Samir S SS Rodriguez Alejandro H AH Chuang Yin-Ching YC Marjanek Zsuszanna Z Pareigis Alex J AJ Reis Gilmar G Scheeren Thomas W L TW Sánchez Alejandro S AS Zhou Xin X Saulay Mikaël M Engelhardt Marc M

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20140409 1

<h4>Background</h4>Ceftobiprole, the active moiety of ceftobiprole medocaril, is a novel broad-spectrum cephalosporin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant strains) and penicillin- and ceftriaxone-resistant pneumococci, and gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa.<h4>Methods</h4>This was a double-blind, randomized, multicenter study of 781 patients with h ...[more]

PMID: 24723282

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Project description:High variability of linezolid blood concentrations with partial subtherapeutic levels was observed in critically ill patients who received a standard intravenous dose of linezolid, contributing to drug resistance and toxicity. Continuous infusions of linezolid have been suggested as an alternative and provide good serum and alveolar levels without fluctuations in trough concentration. This study aimed to assess the effectiveness and safety of continuous linezolid infusion versus the standard regimen in critically ill patients. A prospective randomized controlled study was conducted on 179 patients with nosocomial pneumonia. Patients were randomized into two groups. The first group received IV linezolid 600 mg twice daily, while the second group received 600 mg IV as a loading dose, followed by a continuous infusion of 1200 mg/day (50 mg/h) for at least 8−10 days. The continuous infusion group showed a higher clinical cure rate than the intermittent infusion group (p = 0.046). Furthermore, efficacy was proven by greater improvement of P/F ratio (p = 0.030) on day 7 of treatment, a lower incidence of developing sepsis after beginning treatment (p = 0.009), and a shorter time to reach clinical cure (p < 0.001). Hematological parameters were also assessed during the treatment to evaluate the safety between the two groups. The incidence of thrombocytopenia was significantly lower in the continuous infusion group than in the intermittent infusion group. In addition, a stepwise logistic regression model revealed that the intermittent infusion of linezolid was significantly associated with thrombocytopenia (OR =4.128; 95% CI = 1.681−10.139; p =0.001). The current study is the first to assess the clinical aspects of continuous infusion of linezolid beyond pharmacokinetic studies. Continuous infusion of linezolid outperforms intermittent delivery in safety and improves clinical effectiveness in critically ill patients with Gram-positive nosocomial pneumonia.

Project description:ObjectiveHospital-acquired pneumonia remains the most lethal and expensive nosocomial infection worldwide. Optimal therapy remains controversial. We aimed to compare mortality and clinical response outcomes in patients treated with either linezolid or vancomycin.DesignSystematic review and meta-analysis.Data sourcesPubMed, EMBASE, Cochrane Library, American College of Physicians Journal Club, Evidence-based Medicine BMJ and abstracts from infectious diseases and critical care meetings were searched through April 2013.Eligibility criteria for selecting studiesAll randomised clinical trials comparing linezolid to vancomycin for hospital-acquired pneumonia.Data extractionPreferred reporting items for systematic reviews and meta-analyses guidelines were followed. One author extracted the data and two authors rechecked and verified all data.ResultsNine randomised trials with a total of 4026 patients were included. The adjusted absolute mortality risk difference (RD) between linezolid and vancomycin was 0.01% (95% CI -2.1% to 2.1%; p=0.992; I(2)=13.5%. The adjusted absolute clinical response difference was 0.9% (95% CI -1.2% to 3.1%; p=0.409; I(2)=0%. The risk of both microbiological (RD=5.6%, 95% CI -2.2% to 13.3%; p=0.159; I(2)=0%) and methicillin-resistant Staphylococcus aureus (RD=6.4%, 95% CI -4.1% to 16.9%; p=0.230; I(2)=0%) eradication were not different between linezolid and vancomycin. Gastrointestinal side effects were more frequent with linezolid (RD=0.8% (95% CI 0% to 1.5%; p=0.05), but no differences were found with renal failure, thrombocytopenia and drug discontinuation due to adverse events. Our sample size provided 99.9% statistical power to detect differences between drugs regarding clinical response and mortality.ConclusionsLinezolid and vancomycin have similar efficacy and safety profiles. The high statistical power and the near-zero efficacy difference between both antibiotics demonstrates that no drug is superior for the treatment of hospital-acquired pneumonia.

Project description:BackgroundImipenem 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).MethodsThis 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.ResultsOf 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.ConclusionsImipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients.Clinical trials registrationNCT02493764.

Project description:BackgroundWhen combined with ceftazidime, the novel non-β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239).MethodsThe primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%.ResultsCeftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups.ConclusionsCeftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone.Clinical trials registrationNCT01499290 and NCT01500239.

Project description:BackgroundSocial and hospital environmental factors that may be associated with hospital-acquired pneumonia (HAP) have not been evaluated. Comprehensive risk assessment for the incidence of HAP including sociodemographic, clinical, and hospital environmental factors was conducted using national health insurance claims data.MethodsThis is a population-based retrospective cohort study of adult patients who were hospitalized for more than 3 days from the Health Insurance Review and Assessment Service-National Inpatient Sample data between January 1, 2016 and December 31, 2018 in South Korea. Multivariable logistic regression analyses were conducted to identify the factors associated with the incidence of HAP.ResultsAmong the 512,278 hospitalizations, we identified 25,369 (5.0%) HAP cases. In multivariable analysis, well-known risk factors associated with HAP such as older age (over 70 vs. 20-29; adjusted odds ratio [aOR], 3.66; 95% confidence interval [CI] 3.36-3.99), male sex (aOR, 1.35; 95% CI 1.32-1.39), pre-existing lung diseases (asthma [aOR, 1.73; 95% CI 1.66-1.80]; chronic obstructive pulmonary disease [aOR, 1.62; 95% CI 1.53-1.71]; chronic lower airway disease [aOR, 1.79; 95% CI 1.73-1.85]), tube feeding (aOR, 3.32; 95% CI 3.16-3.50), suctioning (aOR, 2.34; 95% CI 2.23-2.47), positioning (aOR, 1.63; 95% CI 1.55-1.72), use of mechanical ventilation (aOR, 2.31; 95% CI 2.15-2.47), and intensive care unit admission (aOR, 1.29; 95% CI 1.22-1.36) were associated with the incidence of HAP. In addition, poverty (aOR, 1.08; 95% CI 1.04-1.13), general hospitals (aOR, 1.54; 95% CI 1.39-1.70), higher bed-to-nurse ratio (Grade ≥ 5; aOR, 1.45; 95% CI 1.32-1.59), higher number of beds per hospital room (6 beds; aOR, 3.08; 95% CI 2.77-3.42), and ward with caregiver (aOR, 1.19; 95% CI 1.12-1.26) were related to the incidence of HAP.ConclusionsThe incidence of HAP was associated with various sociodemographic, clinical, and hospital environmental factors. Thus, taking a comprehensive approach to prevent and treat HAP is important.

Dataset Information

A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia.

Publications

A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia.

Similar Datasets

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