Switch to Oral Antibiotics in Gram-negative Bacteremia (SOAB)

Switch to Oral Antibiotics in Gram-negative Bacteremia (SOAB); a Randomized, Open-label, Clinical Trial.

Eligible subjects will be those age 18 years or more with mono-microbial blood stream infection caused by E. coli, Klebsiella species, Enterobacter species, Serratia species, Citrobacter species, or Proteus species, who have achieved adequate source control, are afebrile and hemodynamically stable for 48 hours or more and have received microbiologically active intravenous therapy for 3-5 days. The bloodstream isolate must be susceptible to amoxicillin, amoxicillin-clavulanate, fluoroquinolones, oral cephalosporins and/or trimethoprim-sulfamethoxazole and the subject must be able to take oral medication directly or through a feeding tube. Exclusions criteria include allergy to all in-vitro active antimicrobials which are available in oral formulations, pregnancy, infective endocarditis, central nervous system infection, terminal illness with expected survival less than 14 days, absolute neutrophil count less than 1,000/ml and hematopoietic or solid organ transplantation within the preceding 90 days. Randomization will be stratified by urinary versus non-urinary source of bacteremia. The primary outcome is treatment failure at 90-days with 10% margin for non-inferiority in the 95% confidence interval around the difference in outcome between the two study groups.

Study Overview

• Status: Completed
• Conditions: Escherichia Coli Bacteremia; Klebsiella Bacteraemia; Enterobacter Bacteraemia; Serratia Bacteraemia; Citrobacter Bacteraemia; Proteus Bacteraemia
• Intervention / Treatment: Other: IV antimicrobial therapy; Other: Step down to oral antimicrobial therapy

Detailed Description

Oral antimicrobial therapy mitigates vascular line associated complications such as infection, thrombosis and pain, facilitating early mobilization and discharge and reducing healthcare costs. Efficacy and safety of step-down to oral antimicrobial therapy in patients with Enterobacteriaceae bacteremia has never been confirmed in a randomized clinical trial. The aim of this clinical trial is to evaluate the safety and efficacy of oral step down strategy in patients with Gram-negative blood stream infections.

Eligible subjects will be those age 18 years or more with mono-microbial blood stream infection caused by E. coli, Klebsiella species, Enterobacter species, Serratia species, Citrobacter species, or Proteus species, who have achieved adequate source control, are afebrile and hemodynamically stable for 48 hours or more and have received microbiologically active intravenous therapy for 3-5 days. The bloodstream isolate must be susceptible to amoxicillin, amoxicillin-clavulanate, fluoroquinolones, oral cephalosporins and/or trimethoprim-sulfamethoxazole and the subject must be able to take oral medication directly or through a feeding tube. Exclusions criteria include allergy to all in-vitro active antimicrobials which are available in oral formulations, pregnancy, infective endocarditis, central nervous system infection, terminal illness with expected survival less than 14 days, absolute neutrophil count less than 1.0x109/L and hematopoietic or solid organ transplantation within the preceding 90 days.

The primary endpoint is treatment failure at 90-days, defined as a composite of the death from any cause, need for additional antimicrobial therapy with one or more microbiologically active agents before complete resolution of signs and symptoms of infection, microbiological relapse (same species from any clinical site) and infection-related re-admission.

Eligible subjects will be randomized using permuted blocks of variable sizes to full intravenous antimicrobial therapy course (IV Group) or intravenous followed by step-down to oral therapy (PO Group). Randomization will be stratified by urinary versus non-urinary source of bacteremia. The primary analysis will include all patients who were randomized and received at least one dose of the assigned treatment. The difference in primary outcome rate between the intervention and control groups will be presented alongside a 95% confidence interval (CI), adjusted by source of bacteremia. If the upper limit of the 95% CI for the difference in overall response is below 10%, non-inferiority will be concluded.

A Data and Safety Monitoring Board will oversee the trial. An interim analysis will be performed after the first 50% of the target sample have completed the 90-day study period. The Data and Safety Monitoring Board can make a binding recommendation to terminate the study if the results of the interim analysis indicate very high likelihood for positive effect or futility.

• Study Type: Interventional
• Enrollment (Actual): 176
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Bahrain
  • Manama, Bahrain
    • Bahrain Defense Forces Hospital
• Kuwait
  • Kuwait, Kuwait
    • Farwaniya Hospital
• Qatar
  • Doha, Qatar
    • Hamad Medical Corporation
• Turkey
  • Istanbul, Turkey
    • Istanbul Medipol University
  • Istanbul, Turkey
    • Marmara University School of Medicine
  • Istanbul, Turkey
    • Istanbul University Carrahpasa Medical School
  • Ordu, Turkey
    • Ordu University School of Medicine

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥18 years.
• Mono-microbial blood stream infection.
• Isolation of E. coli, Klebsiella species, Enterobacter species, Serratia species, Citrobacter species, or Proteus species from ≥1 blood culture(s).
• Adequate source control within ≤5 days of staring in-vitro active intravenous antimicrobial therapy.
• Afebrile (Tmax <38 degrees Celsius) for ≥48 hours.
• Hemodynamically stable for ≥48 hours (SBP ≥100 mmHg, no vasopressors).
• Microbiologically active intravenous therapy for 3-5 days.
• Bloodstreams isolate in-vitro susceptibility to amoxicillin, amoxicillin-clavulanate, fluoroquinolones, oral cephalosporins and/or trimethoprim-sulfamethoxazole.
• Ability to take oral medication directly or through a feeding tube.

Exclusion Criteria:

• Allergy to all in-vitro active antibiotics which are available in oral formulations.
• Pregnancy.
• Infective endocarditis.
• Central nervous system infection.
• Terminal illness with expected survival <14 days.
• Neutropenia (absolute neutrophil count <1.0x10^9/L).
• Hematopoietic or solid organ transplantation within the preceding 90 days.

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
Active Comparator: IV Group; Eligible patients randomized to complete their antimicrobial therapy course through intravenous (IV) administration.	Other: IV antimicrobial therapy; No step down from intravenous to oral antimicrobial therapy to complete the intended course of treatment.
Experimental: Oral Group; Eligible patients randomized to step down to oral antimicrobial therapy for the remainder of their treatment course.	Other: Step down to oral antimicrobial therapy; Step down from intravenous to oral antimicrobial therapy to complete the intended course of treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment failure.	Defined as death, need for additional active antibiotic therapy before resolution of all signs and symptoms of infection, microbiological relapse or infection-related re-admission within 90 days of commencement of active intravenous antimicrobial therapy.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death from any cause.	Death from any cause during follow up period.	90 days
Need for additional antimicrobial therapy with one or more microbiologically active agents before complete resolution of signs and symptoms of infection.	Need for additional active antimicrobial therapy before resolution of signs and symptoms of infection; defined as recovery from infection-related symptoms present at baseline (e.g.; urinary symptoms, abdominal pain, jaundice ..etc), no recurrence of fever (Tmax ≥38.0oC).	Up to 90 days
Microbiological relapse. 4)	Active infection in any site caused by the same species in the index blood culture.	90 days
Infection-related re-admission.	Re-admission to hospital because of any active infection.	90 days
Hospital length of stay from date of first positive blood culture.	Hospital length of stay from date of first positive blood culture.	Up to 90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment failure in the per-protocol (PP) population.	Treatment failure as defined above in per-protocol population (those who were randomized to either study arms and completed intended course of antimicrobial therapy and have documented final outcomes.	90 days
Treatment failure in the subgroup with urinary source of bacteremia	Treatment failure as defined above in subjects with urinary source of bacteremia	90 days
Treatment failure in the subgroup with non-urinary source of bacteremia	Treatment failure as defined above in subjects with non-urinary source of bacteremia	90 days
Survival analysis (Kaplan-Meier curve with log-rank test).	Kaplan-Meier survival in both treatment arms with log-rank test for statistically significant difference.	90 days

Collaborators and Investigators

• Sponsor: Hamad Medical Corporation
• Investigators: Study Director: Ali S Omrani, FRCP FRCPath, Hamad Medical Corporation

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2019
• Primary Completion (Actual): August 30, 2022
• Study Completion (Actual): July 30, 2023

Study Registration Dates

• First Submitted: October 20, 2019
• First Submitted That Met QC Criteria: October 29, 2019
• First Posted (Actual): October 31, 2019

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 10, 2023
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Enterobacteriaceae, bacteremia, step down oral therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Enterobacteriaceae Infections; Bacteremia; Escherichia coli Infections; Anti-Bacterial Agents; Anti-Infective Agents
• Other Study ID Numbers: MRC-01-19-254

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