Seven versus 14 days of antimicrobial therapy for severe multidrug-resistant Gram-negative bacterial infections in intensive care unit patients (OPTIMISE): a randomised, open-label, non-inferiority clinical trial

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2024年12月18日

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Beatriz Arns,
Andre C. Kalil,
Guilherme G. L. Sorio,
Emerson Boschi,
Ana Carolina Peçanha Antonio,
Juliana Peçanha Antonio,
Daniella Cunha Birriel,
Daniel Haase Lanziotti,
Frederico da Cunha Abbott,
Glecia Carla Rocha,
Vanildes de Fátima Fernandes,
Vicente Cés de Souza Dantas,
Graciele Fátima da Silva Medeiros,
Verônica de França Diniz Rocha,
Francielle Constantino Pereira,
André Luiz Nunes Gobatto,
Valéria Paes Lima,
Fábio Holanda Lacerda,
Cláudia Maria Dantas de Maio Carrilho,
Kairo Daniel Nunes de Oliveira Cardozo,
Vivian Menezes Irineu,
Pedro Kurtz,
Jaqueline Driemeyer Correia Horvath,
Guilhermo Prates Sesin,
Crepin Aziz Jose Oluwafoumi Agani,
Tiago Marcon dos Santos,
Liliane Spencer Bittencourt Brochier,
Bruna Silveira da Rosa,
Bruno Martins Tomazini,
Bruno Adler Maccagnan Pinheiro Besen,
Adriano Jose Pereira,
Viviane Cordeiro Veiga,
Giovana Marssola Nascimento,
Alexandre P. Zavascki,
Jaysa Pizzi,
Thaissa Torrezini,
Euclimeire da Silva Neves,
Jamile Freire Barreto dos Santos,
Jaime Paula Pessoa Linhares Filho,
Marcos de Almeida e Pontes Vieira,
René Rodrigues Pereira,
Cassia Righy,
Ricardo Turon,
Bruno Gonçalves

摘要

Background

Shorter courses of antimicrobial therapy have been shown to be non-inferior to longer durations for the management of several infections. However, data on critically ill patients with severe infections by multidrug-resistant Gram-negative bacteria (MDR-GNB) are scarce. In the duratiOn of theraPy in severe infecTIons by MultIdrug-reSistant gram-nEgative bacteria (OPTIMISE) trial, we assessed the non-inferiority of 7-day versus 14-day antimicrobial therapy for patients with intensive care unit (ICU)-acquired severe infections by MDR-GNB.

Methods

This was a randomised multicenter, open-label, parallel controlled, non-inferiority trial. Adult patients with severe infections by MDR-GNB initiated ≥ 48 h of ICU admission were eligible if they were hemodynamically stable and without fever > 48 h on the 7th day of appropriate antimicrobial therapy. Patients were 1:1 randomised to discontinue antimicrobial therapy on the 7th (± 1) day or to continue for a total of 14 (± 1) days. The primary outcome was clinical failure, defined as death or relapse of infection within 28 days of randomisation. An upper edge of the two-tailed 95% confidence interval (CI) of the delta between the clinical failure rate in the 7- and the 14-day lower than 10% in both intention-to-treat (ITT) and per protocol (PP) analyses was set as the non-inferiority criteria.

Results

A total of 106 patients composed the ITT population: 59 and 47 allocated to 7- and 14-day groups, respectively. The PP population included 75 patients: 47 and 28 in the 7- and 14-day groups, respectively. Clinical failure occurred in 42.4% and 44.7% of the ITT population in 7- and 14-day groups, respectively, (risk difference (RD) − 2.3, 95%CI − 21.3 to 16.7), and in 46.8% and 50.0% of the PP population in 7- and 14-day groups, respectively (RD − 3.2, 95%CI − 26.6 to 20.2). Most infections were of the respiratory tract (73/68.9%) and caused by carbapenem-resistant Enterobacterales (42/39.6%). The study was interrupted before reaching planned sample size due to low recruitment rate.

Conclusion

The OPTIMISE trial could not determine the non-inferiority of 7-day compared to 14-day therapy for severe infections caused by MDR-GNB due to early termination related to the low recruitment rate.

Trial registration: NCT05210387 on January 13, 2022.