Duration of Antibiotics for the Treatment of Gram-negative Bacilli Bacteremia

Duration of Antibiotics for the Treatment of Gram-negative Bacilli Bacteremia - a Randomized Controlled Trial

The investigators plan an open label randomized controlled trial to compare short-course antibiotic therapy (<=7 days) versus longer treatment (>7 days). The investigators will include hospitalized patients with gram-negative bacteremia. The investigators primary objective is to investigate the safety and efficacy of short-course antibiotics.

Study Overview

• Status: Completed
• Conditions: Gram Negative Bacteremia
• Intervention / Treatment: Drug: short-course antibiotic treatment; Drug: accepted prolonged antibiotic treatment

• Study Type: Interventional
• Enrollment (Actual): 604
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel
    • Rambam Health Care Center
  • Petah Tikvah, Israel
    • Rabin Medical Center, Beilinson Hospital
• Italy
  • Emilia Romagna
    • Modena, Emilia Romagna, Italy
      • Policlinico di Modena, Italy

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• patients with gram-negative aerobic bacilli bacteremia, defined as growth of a single gram-negative microorganism in one or more blood cultures, associated with evidence of infection (hyper- or hypothermia, a localized infection, sepsis or septic shock).
• We will include patients receiving appropriate antibiotic treatment for 7 days and are afebrile / not hypothermic for the last 48 hours. Both community and hospital acquired gram-negative bacteremias will be included, regardless of antibiotic susceptibility patterns. We will allow the inclusion of patients receiving less than 7 days if clinically stable and discharge from hospital is considered. We will then recruit the patient before discharge, if stable at least for 48 hours before randomization.

We will include the following sources of bacteremia:

1. Primary bacteremia / unknown source
2. Urinary tract
3. Abdominal
4. Respiratory tract
5. Central venous catheter(CVC), when the catheter was removed before randomization
6. Skin and soft tissue, including surgical site infection

Exclusion Criteria:

1. Gram-negative bacteremia due to specific infections as detailed here:

   1. Endocarditis / endovascular infections
   2. Necrotizing fasciitis
   3. Osteomyelitis
   4. Abdominal abscesses and other unresolved abdominal sources requiring surgical intervention (e.g., cholecystitis)
   5. Central nervous system infections
   6. Empyema
   7. CVC- related or CVC-associated bloodstream infections when the catheter is retained. We will permit the inclusion of patients with retained CVCs in whom the source of the bacteremia is not the CVC.
2. Polymicrobial growth in blood cultures involving gram-positive or anaerobes in addition to gram-negatives (defined as either growth of two or more different species of microorganisms in the same blood culture, or growth of different species in two or more separate blood cultures within the same episode (< 48 h) and with clinical or microbiological evidence of the same source).

3. Specific pathogens including:

   1. Salmonella spp.
   2. Brucella spp.

4. Immunosuppression, including:

   1. HIV infection
   2. Hematopoietic stem-cell transplantation
   3. Neutropenia on day of randomization or in the 48 hours prior to randomization. Patients with neutropenic fever at presentation that are afebrile and non-neutropenic in the 48 hours before randomization will be included.
5. Clinical instability during the 48 hours before randomization, defined as mean blood pressure<60 mmHg despite adequate fluid resuscitation or vasopressors support.
6. Repeated positive blood cultures for the same organism separated by at least 24 hours, regardless of antibiotic treatment. Patients with repeated isolates on the first 24 hours will be included.
7. Uncontrolled focus of infection: e.g. an abscess that was not drained sufficiently; non-drained moderate to severe hydronephrosis in a patient with bacteremia of urinary source; deep seated intra-abdominal infections that were not drained properly.
8. Fever > 38.0C measured at least twice in the 48 h prior to recruitment; or > 38.5C once during the 48 h; or hypothermia <35.5C measured once during the 48 h.
9. Previous enrollment in this trial
10. Concurrent participation in another clinical trial

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: short-course; antibiotic treatment stopped on day 7 if the patient has been afebrile for 48 hours and clinically stable. Continued hospitalization will be left to the discretion of the treating physician. Antibiotics will be restarted if fever recurs in at least 2 consecutive measurements above 38 or in cases of clinically or microbiologically documented infections.	Drug: short-course antibiotic treatment; On day 7 of appropriate intravenous or oral antibiotic treatment for the bacteremic episode (day 1 is the first day of appropriate antibiotic therapy), patients will be randomized to: Intervention group - antibiotic treatment stopped on day 7; Control group - antibiotic treatment continued for 14 days according to accepted hospital local guidelines.
Active Comparator: accepted prolonged antibiotic treatment; antibiotic treatment continued for 14 days according to accepted hospital local guidelines. Duration of hospital stay will also be left to the discretion of the treating physician. Type of empiric antibiotic treatment and later, specific antibiotic treatment, will be chosen by the treating physicians in consultation with the infectious diseases unit. The decision on timing of switch to oral antibiotic therapy will also be left to the discretion of the treating physician.	Drug: accepted prolonged antibiotic treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
composite of the following	The primary outcome is a composite of the following outcome measures	Until day 90 after randomization
All -cause mortality	All- cause mortality	Until day 90 after randomization
Treatment Failure	Failure including any of the following: Relapse: a recurrent bacteraemia due to the same microorganism occurring from day of randomization and until day 9013; Local suppurative complication that was not present at infection onset (e.g. renal abscess in pyelonephritis, empyema in pneumonia); Distant complications of initial infection, defined by growth of the same bacteria as in the initial bacteremia	Until day 90 after randomization
Hospital re-admissions or extended hospitalization	We will define re-admission as a new hospitalization for any cause occurring more than14 days from start of appropriate antibiotic treatment. Patients hospitalized after day 14 (were never discharged or 7-day regimen who were readmitted between days 7-14) will be counted as failures for this outcome. We will define re-admission as a new hospitalization for any cause occurring more than14 days from start of appropriate antibiotic treatment. Patients hospitalized after day 14 (were never discharged or 7-day regimen who were readmitted between days 7-14) will be counted as failures for this outcome.	Until day 90 after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clostridium difficile associated diarrhea	Clostridium difficile associated diarrhea	Until day 30 after randomization
Development of Antibiotic resistance	Development of resistance, defined as clinical isolates resistant to antibiotics previously used in the bacteremia episode. Surveillance sampling will not be conducted.	Until day 30 after randomization
Carriage of carbapenem resistant Klebsiella pneumonia.	Carriage of carbapenem resistant Klebsiella pneumonia (screened routinely)	Until day 30 after randomization
Total in hospital days	Total in hospital days within 30 and 90 days	Until day 90 after randomization.
Total antibiotic days	Total antibiotic days	Until day 30 after randomization
Adverse events	Any diarrhea; Liver function test abnormalities, defined as elevated bilirubin x 1.5 of upper limit of normal or transaminases x 2.5 of upper limit of normal; Antibiotic rash; Acute kidney injury - defined according to RIFLE criteria as increased creatinine level x 1.5 from baseline or glomerular filtration rate (GFR) decrease >25% or urine output of <0.5 ml/kg/h for 6 hours22	Until day 30 after randomization
Infection caused by other than gram-negative bacteremia	Development of either clinically or microbiologically documented infection other than gram-negative bacteremia. We will use the 2008 CDC/NHSN surveillance definitions of health-care associated infections for bacterial infections	Until day 90 after randomization
Number of hospital re-admissions	Number of hospital re-admissions until day 90	Until day 90 after randomization
Functional capacity and time to return to baseline activity	Functional capacity and time to return to baseline activity	Until day 30 after randomization

Collaborators and Investigators

• Sponsor: Rabin Medical Center
• Investigators: Principal Investigator: Dafna Yahav, MD, Rabin Medical Center

Publications and helpful links

General Publications

• Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, Neuberger A, Ghanem-Zoubi N, Santoro A, Eliakim-Raz N, Pertzov B, Steinmetz T, Stern A, Dickstein Y, Maroun E, Zayyad H, Bishara J, Alon D, Edel Y, Goldberg E, Venturelli C, Mussini C, Leibovici L, Paul M; Bacteremia Duration Study Group. Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial. Clin Infect Dis. 2019 Sep 13;69(7):1091-1098. doi: 10.1093/cid/ciy1054.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): March 4, 2018

Study Registration Dates

• First Submitted: November 14, 2012
• First Submitted That Met QC Criteria: November 26, 2012
• First Posted (Estimate): November 29, 2012

Study Record Updates

• Last Update Posted (Actual): April 9, 2019
• Last Update Submitted That Met QC Criteria: April 6, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: safety; efficacy; gram negative bacteremia; Duration of antibiotic treatment; short-course
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Bacteremia; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: 0258-12-RMC