Study on Reduced Antibiotic Treatment vs Broad Spectrum Betalactam in Patients With Bacteremia by Enterobacteriaceae

Overview

The continuous increase in the bacterial resistance rate and the slow arrival of new therapeutic options have turned into an antibiotic crisis. One of the strategies proposed by stewardship programs to try to change this situation described worldwide is the use of antibiotics with the lowest possible antimicrobial spectrum.

Enterobacteriaceae bacteremia is a good example of how this strategy would be applied. The empirical treatment of nosocomial bacteremia by Enterobacteriaceae comprises in several cases one or two antibiotics with antipseudomonal activity, being much less common than desirable a subsequent change to narrower spectrum antibiotics based on susceptibility data ("de escalation"). This is because the safety of de escalation is based only on expert advice and some observational studies, so their efficacy and safety is questioned by many clinicians and therefore its use is lower than desired. In fact, a recent systematic review of the Cochrane Library concluded that randomized studies to support this practice are needed. Investigators propose a "real clinical practice-based" randomized trial to compare the efficacy and safety of continuing with an antipseudomonal agents vs. de-escalation according to a pre-specified rule, in patients with bacteraemia due to Enterobacteriaceae.

Full Title of Study: “Randomized, Multicenter, Phase III, Controlled Clinical Trial, to Demonstrate the no Inferiority of Reduced Antibiotic Treatment vs a Broad Spectrum Betalactam Antipseudomonal Treatment in Patients With Bacteremia by Enterobacteriaceae”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 2020

Interventions

  • Drug: Antipseudomonal beta-lactam antibiotic
    • Pharmaceutical form: solution for infusion
  • Drug: De-escalation(short-spectrum antibiotic)
    • Pharmaceutical form: solution for infusion

Arms, Groups and Cohorts

  • Experimental: Antipseudomonal beta-lactam antibiotic
    • Ampicillin 2g IV/6h Trimethoprim/sulfamethoxazole 160/800 mg IV/8 -12h Cefuroxime 750-1000 mg IV/8h Cefotaxime 1-2g IV/8h ó ceftriaxone 1 g/12-24h Amoxicillin/clavulanate 1000/125 mg IV/8h Ciprofloxacin 400 mg IV/12h Ertapenem 1-2g/24h.
  • Active Comparator: De-escalation(short-spectrum antibiotic)
    • Piperacillin/tazobactam 4/0.5 g IV/8h Meropenem 1-2 g IV/8h Imipenem 0.5 g IV/6h – 1g IV/6h Aztreonam 1-2 g IV/8h Ceftazidime 1-2 g IV/8h Cefepime 2 g IV/8-12h

Clinical Trial Outcome Measures

Primary Measures

  • Clinical cure at day 3-5 after treatment.
    • Time Frame: Day 3-5 after end of treatment.
    • Clinical cure: complete resolution of infection symptoms (bacteremia) present at the day on which the assessment is done and patient is alive.

Secondary Measures

  • Early clinical and microbiological response.
    • Time Frame: After 5 days of treatment
    • The infection was completely resolved after 5 days of treatment (patients without infection symptoms and a negative blood culture).
  • Late clinical and microbiological response.
    • Time Frame: Day 60
    • The infection was completely resolved at day 60 (patients without infection symptoms)
  • Mortality
    • Time Frame: At 7,14 and 30 days
    • Death for any reason
  • Length of hospital stay
    • Time Frame: At 7,14 and 30 days
    • Defined as the from admission to hospital discharge
  • Recurrences (relapse or reinfection) rate
    • Time Frame: Day 60 after treatment
  • Safety of antibiotic treatment
    • Time Frame: 60 days
    • Gathering any related adverse event from the informed consent form signature up to 60 days
  • Impact of the study treatment on intestinal microbiota
    • Time Frame: Screening, Day 7-14, Day 12-21, Day 30
    • Effect of study treatment on colonization of the intestinal tract with multi drug resistant gram negative bacilli
  • Treatment duration.
    • Time Frame: It is not allowed treatment duration more than 28 days
    • Evaluate the study treatment duration.
  • Secondary infections.
    • Time Frame: 60 days
    • Evaluate the development of secondary infections other than the initial bacteremia.

Participating in This Clinical Trial

Inclusion Criteria

1. ≥18 years old hospitalized patients with bacteremia from any source with isolation of an enterobacteria in blood cultures.

2. Active empiric treatment with antipseudomonal betalactamic at 48 hours from the symptoms of sepsis and the blood culture.The patient could have received any other type of antibiotic therapy up to 24 hours after blood extraction.

3. Microorganism susceptible at least one treatment from the experimental arm.

4. Patients with intravenous treatment at least 3 days from the randomization o 5 days from the initial blood culture.

5. Patients to sign the informed consent form.

Exclusion Criteria

1. Palliative care or life expectance < 90 days.

2. Pregnancy or lactation period.

3. To isolate the Extended-spectrum β-lactamases producing Enterobacteriaceae

4. Late randomization >48 hours after the enterobacteriaceae blood culture´s identification

5. Severe neutropenic (< 500 céls/mm3) at the randomization.

6. Treatment of infection > 28 days (endocarditis and osteomyelitis) or meningitis.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 90 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
  • Collaborator
    • Spanish Network for Research in Infectious Diseases
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Luis Eduardo Lopez Cortes, MD, PhD, Principal Investigator, Universitary Hospital Virgen Macarena

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