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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Carbapenem-Resistant Enterobacteriaceae Infection, Bloodstream Infection, Severe Infection, Pseudomonas Aeruginosa, Acinetobacter Infections, Gram-Negative Bacterial Infections, Human, Carbapenem Resistant Bacterial Infection, Bacteremia, Sepsis

Intervention / Treatment
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* Other: Duration of therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 7-day adequate antibiotic therapy<br>Adequate antibiotic therapy is defined as antimicrobial treatment with at least one agent with in vitro susceptibility. | Other: Duration of therapy<br>* 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).<br>|
| Active Comparator: 14-day adequate antibiotic therapy<br>Adequate antibiotic therapy is defined as antimicrobial treatment with at least one agent with in vitro susceptibility. | Other: Duration of therapy<br>* 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).<br>|

What is the study measuring?
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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 |