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Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial.
Lancet Infect Dis. 2018 03; 18(3):285-295.LI

Abstract

BACKGROUND

Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE).

METHODS

Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7-14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21-25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than -12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96).

FINDINGS

Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference -4·2% [95% CI -10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference -0·7% [95% CI -7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related.

INTERPRETATION

Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens.

FUNDING

AstraZeneca.

Authors+Show Affiliations

Servei de Pneumologia, Hospital Clinic, University of Barcelona, Barcelona, Spain; Institut D'investigació August Pi I Sunyer, Barcelona, Spain; Ciber de Enfermedades Respiratorias, Spain. Electronic address: atorres@clinic.cat.State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.Charles University, Prague, Czech Republic.APHP Hôpital Bichat-Claude Bernard, Paris-Diderot University, Paris, France.Washington University School of Medicine, St Louis, MO, USA.AstraZeneca, Shanghai, China.AstraZeneca, Shanghai, China.Taylormade Health, Warrington, United Kingdom.Statistical Services Unit, University of Sheffield, Sheffield, UK.Pfizer, Groton, CT, USA.Pfizer, Collegeville, PA, USA.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29254862

Citation

Torres, Antoni, et al. "Ceftazidime-avibactam Versus Meropenem in Nosocomial Pneumonia, Including Ventilator-associated Pneumonia (REPROVE): a Randomised, Double-blind, Phase 3 Non-inferiority Trial." The Lancet. Infectious Diseases, vol. 18, no. 3, 2018, pp. 285-295.
Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18(3):285-295.
Torres, A., Zhong, N., Pachl, J., Timsit, J. F., Kollef, M., Chen, Z., Song, J., Taylor, D., Laud, P. J., Stone, G. G., & Chow, J. W. (2018). Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. The Lancet. Infectious Diseases, 18(3), 285-295. https://doi.org/10.1016/S1473-3099(17)30747-8
Torres A, et al. Ceftazidime-avibactam Versus Meropenem in Nosocomial Pneumonia, Including Ventilator-associated Pneumonia (REPROVE): a Randomised, Double-blind, Phase 3 Non-inferiority Trial. Lancet Infect Dis. 2018;18(3):285-295. PubMed PMID: 29254862.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. AU - Torres,Antoni, AU - Zhong,Nanshan, AU - Pachl,Jan, AU - Timsit,Jean-François, AU - Kollef,Marin, AU - Chen,Zhangjing, AU - Song,Jie, AU - Taylor,Dianna, AU - Laud,Peter J, AU - Stone,Gregory G, AU - Chow,Joseph W, Y1 - 2017/12/16/ PY - 2017/06/06/received PY - 2017/10/02/revised PY - 2017/10/16/accepted PY - 2017/12/20/pubmed PY - 2019/2/13/medline PY - 2017/12/20/entrez SP - 285 EP - 295 JF - The Lancet. Infectious diseases JO - Lancet Infect Dis VL - 18 IS - 3 N2 - BACKGROUND: Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE). METHODS: Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7-14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21-25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than -12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96). FINDINGS: Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference -4·2% [95% CI -10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference -0·7% [95% CI -7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related. INTERPRETATION: Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens. FUNDING: AstraZeneca. SN - 1474-4457 UR - https://www.unboundmedicine.com/medline/citation/29254862/Ceftazidime_avibactam_versus_meropenem_in_nosocomial_pneumonia_including_ventilator_associated_pneumonia__REPROVE_:_a_randomised_double_blind_phase_3_non_inferiority_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1473-3099(17)30747-8 DB - PRIME DP - Unbound Medicine ER -