Seven Versus 14 Days of Antibiotic Therapy for Multidrug-resistant Gram-negative Bacilli Infections (OPTIMISE)

Open-label, Randomized Clinical Trial to Assess the Non-inferiority of 7-day Antibiotic Therapy Compared to Conventional 14-day Treatment in Multidrug-resistant Gram-negative Bacilli Infections

Antimicrobial resistance is a major global problem, particularly in hospital-acquired infections (HAIs). Gram-negative bacilli (GNB), including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, are among the most common pathogens associated with multidrug resistance and HAIs. These bacteria are of special concern because few therapeutic options are available.

Traditionally, the duration of treatment for severe multidrug-resistant (MDR)-GNB infections is 14 days. Studies of severe infections by GNB, regardless of susceptibility profile, have shown that shorter antimicrobial treatments are not inferior to traditional durations of therapy and are associated with a lower incidence of adverse effects. However, there are currently no studies assessing whether shorter duration of antimicrobial treatment is effective for MDR-GNB.

This open-label, randomized clinical trial aims to assess the non-inferiority of 7-day antibiotic therapy compared to conventional 14-day treatment in severe infections by MDR-GNB.

Study Overview

• Status: Terminated
• Conditions: Sepsis; Gram-Negative Bacterial Infections; Bacteremia; Severe Infection; Bloodstream Infection; Acinetobacter Infections; Pseudomonas Aeruginosa; Human; Carbapenem-Resistant Enterobacteriaceae Infection; Carbapenem Resistant Bacterial Infection
• Intervention / Treatment: Other: Duration of therapy

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • Rio De Janeiro, Brazil
    • Hospital Naval Marcílio Dias
  • Rio De Janeiro, Brazil
    • Instituto Estadual do Cérebro Paulo Niemeyer (Pró Saúde- Associação Beneficente de Assistência Social e Hospitalar)
  • São Paulo, Brazil
    • Hospital A.C Camargo
  • Bahia
    • Feira De Santana, Bahia, Brazil, 44089-340
      • Hospital Cleriston de Andrade
    • Salvador, Bahia, Brazil
      • Hospital Couto Maia
    • Salvador, Bahia, Brazil
      • Hospital da Cidade
  • Ceará
    • Fortaleza, Ceará, Brazil
      • Hospital OTO clinica
  • Distrito Federal
    • Brasília, Distrito Federal, Brazil, 70840-901
      • Hospital Universitario de Brasilia
    • Brasília, Distrito Federal, Brazil, 70330-150
      • Instituto Hospital de Base do Distrito Federal
  • Espirito Santo
    • Vila Velha, Espirito Santo, Brazil, 29118-060
      • Hospital Evangélico de Vila Velha
  • Maranhão
    • São Luís, Maranhão, Brazil, 65040-450
      • Hospital Presidente Vargas
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-221
      • Santa Casa de Misericórdia de Belo Horizonte
    • Nova Lima, Minas Gerais, Brazil, 34000-000
      • Hospital Vila da Serra (Instituto Materno Infantil de Minas Gerais S/A)
    • Passos, Minas Gerais, Brazil, 37904-020
      • Irmandade da Santa Casa de Misericórdia de Passos
  • Paraná
    • Londrina, Paraná, Brazil, 86038-350
      • Hospital Universitário da Universidade Estadual de Londrina
    • Maringá, Paraná, Brazil, 87053-270
      • Hospital Municipal de Maringá
  • Pará
    • Santarém, Pará, Brazil
      • Hospital Regional Baixo Amazonas
  • Pernambuco
    • Olinda, Pernambuco, Brazil, 53120-420
      • Hospital do Tricentenário
  • Rio De Janeiro
    • Volta Redonda, Rio De Janeiro, Brazil
      • Hospital São João Batista
  • Rio Grande Do Sul
    • Bento Gonçalves, Rio Grande Do Sul, Brazil, 95700-068
      • Hospital Tacchini
    • Caxias Do Sul, Rio Grande Do Sul, Brazil, 95070-561
      • Hospital Geral Caxias do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Hospital de Clínicas de Porto Alegre
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90160-092
      • Hospital Ernesto Dornelles
    • Porto Alegre, Rio Grande Do Sul, Brazil
      • Hospital Nossa Senhora da Conceicao
    • Porto Alegre, Rio Grande Do Sul, Brazil
      • Hospital Sao Lucas da PUC
    • Santa Cruz Do Sul, Rio Grande Do Sul, Brazil, 96810-072
      • Hospital Santa Cruz
    • Santa Cruz Do Sul, Rio Grande Do Sul, Brazil, 96835-090
      • Hospital Ana Nery
  • Sergipe
    • Aracaju, Sergipe, Brazil
      • Hospital São Lucas Sergipe - Rede D´or São Luiz
  • São Paulo
    • Itapetininga, São Paulo, Brazil, 18.030-070
      • Hospital Dr. Léo Orsi Bernadres - HLOB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Infection's diagnosis while in the ICU
• Severe infection in any site (defined as the presence of sepsis/septic shock or bloodstream infection or pneumonia) associated with a positive culture by MRD-GNB (Acinetobacter baumannii complex, Pseudomonas aeruginosa, and Enterobacterales bacteria, only susceptible to carbapenems and/or polymyxins)
• Hemodynamically stable and afebrile (axillary temperature less than 37.8ºC) for at least 48 hours on day 7 of adequate antibiotic therapy
• Consent of the team providing care to the patient regarding their inclusion in the research

Exclusion criteria

• Inclusion in other experimental studies involving antimicrobial therapy
• Infections that have as the primary site: endocarditis/endovascular infection, necrotizing fasciitis, osteomyelitis, abdominal abscess or other abdominal infections requiring surgical intervention (except infections that have been treated surgically, with curative character within the first 3 days of appropriate antimicrobial therapy), central nervous system Infections, empyema, prosthetic infection;
• Immunosuppression defined as: neutrophil cells <1000/mm³ in the current hospitalization, HIV/AIDS diagnosis with last CD4 count <200/mm³, solid organ transplantation in the last year and/or need for increased immunosuppression due to acute rejection in the last year, hematopoietic stem cell transplantation in the last year, and/or current therapy for chronic graft-versus-host disease
• Positive blood cultures for the same pathogen within 48 hours prior to randomization, when collected
• Uncontrolled concomitant infection with another GNB (regardless of susceptibility profile)
• Previous inclusion in this study
• Known pregnancy
• Patient in palliative care who has already decided not to restart antimicrobials, if necessary, or hemodynamic support measures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 7-day adequate antibiotic therapy; Adequate antibiotic therapy is defined as antimicrobial treatment with at least one agent with in vitro susceptibility.	Other: Duration of therapy; In experimental group patients with severe infection caused by MDR-GNB and who present a clinical response on day 7 (±1) of adequate antimicrobial therapy, the therapy will be suspended. The active control group will continue therapy until day 14 (±1).
Active Comparator: 14-day adequate antibiotic therapy; Adequate antibiotic therapy is defined as antimicrobial treatment with at least one agent with in vitro susceptibility.	Other: Duration of therapy; In experimental group patients with severe infection caused by MDR-GNB and who present a clinical response on day 7 (±1) of adequate antimicrobial therapy, the therapy will be suspended. The active control group will continue therapy until day 14 (±1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical failure	Incidence of clinical failure. Clinical failure is a composite outcome defined by the presence of one of the following: Infection relapse (infection anywhere in the body by the same MDR-GNB) or Death	28 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive and free from hospitalization	Number of days in which patients are alive and out of the hospital	28 days after randomization
Days alive and free from any antibiotic therapy	Number of days in which patients are alive and free from any antibiotic therapy	28 days after randomization
Occurrence of infections caused by other MRD-GNB or other bacteria	Incidence of infections caused by other MRD-GNB or other bacteria	28 days after randomization
Length of intensive care unit stay	Number of days in which patients stayed at intensive care unit	28 days after randomization
Acute kidney injury	Incidence of acute kidney injury, according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria	28 days after randomization
Diarrhea for any cause	Incidence of any diarrhea. Diarrhea is defined as 3 or more episodes per day.	28 days after randomization
Confirmed infection by Clostridioides difficile	Incidence of Clostridioides difficile infection	28 days after randomization
Hemodynamic instability lasting more than 6 hours	Incidence of hemodynamic instability lasting more than 6 hours. Hemodynamic instability is defined as hypotension that requires the use of doses of dopamine above 15 mcg/kg/min, epinephrine above 0.1 mcg/kg/min, or norepinephrine above 0.1 mcg/kg/min	14 days after randomization
Other adverse events related to antimicrobial therapy	Incidence of any other adverse event related to antimicrobial therapy	28 days after randomization

Collaborators and Investigators

• Sponsor: Hospital Moinhos de Vento
• Investigators: Principal Investigator: Alexandre Prehn Zavascki, Hospital Moinhos de Vento

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2022
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: December 31, 2021
• First Submitted That Met QC Criteria: January 13, 2022
• First Posted (Actual): January 27, 2022

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Bacterial Infections and Mycoses; Moraxellaceae Infections; Sepsis; Infections; Communicable Diseases; Bacteremia; Bacterial Infections; Gram-Negative Bacterial Infections; Acinetobacter Infections; Enterobacteriaceae Infections
• Other Study ID Numbers: 47366621.1.1001.5330

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No