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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Enterobacteriaceae Infections

Intervention / Treatment
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* Drug: Antipseudomonal beta-lactam antibiotic
* Drug: De-escalation(short-spectrum antibiotic)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old hospitalized patients with bacteremia from any source with isolation of an enterobacteria in blood cultures. 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. Microorganism susceptible at least one treatment from the experimental arm. Patients with intravenous treatment at least 3 days from the randomization o 5 days from the initial blood culture. Patients to sign the informed consent form. Exclusion Criteria: Palliative care or life expectance < 90 days. Pregnancy or lactation period. To isolate the Extended-spectrum β-lactamases producing Enterobacteriaceae Late randomization >48 hours after the enterobacteriaceae blood culture´s identification Severe neutropenic (< 500 céls/mm3) at the randomization. Treatment of infection > 28 days (endocarditis and osteomyelitis) or meningitis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Antipseudomonal beta-lactam antibiotic<br>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. | Drug: Antipseudomonal beta-lactam antibiotic<br>* Pharmaceutical form: solution for infusion<br>* Other names: Ertapenem;|
| Active Comparator: De-escalation(short-spectrum antibiotic)<br>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 | Drug: De-escalation(short-spectrum antibiotic)<br>* Pharmaceutical form: solution for infusion<br>* Other names: Cefepime;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Enterobacteriaceae, Bacteremia, Escalation, Bacterial resistance, Bloodstream infection, Recurrence