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

Sponsor

Fundación Pública Andaluza para la gestión de la Investigación en Sevilla (Other)

Overall Status

Completed

CT.gov ID

NCT02795949

Collaborator

Spanish Network for Research in Infectious Diseases (Other)

344

Enrollment

Locations

Arms

Actual Duration (Months)

16.4

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Enterobacteriaceae Infections	Drug: Antipseudomonal beta-lactam antibiotic Drug: De-escalation(short-spectrum antibiotic)	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

344 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 1, 2016

Actual Primary Completion Date :

Jan 1, 2020

Actual Study Completion Date :

Jan 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Antipseudomonal beta-lactam antibiotic Pharmaceutical form: solution for infusion Other Names: Ampicillin Trimethoprim/sulfamethoxazole Cefuroxime Amoxicillin/clavulanate Ciprofloxacin Ertapenem
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	Drug: De-escalation(short-spectrum antibiotic) Pharmaceutical form: solution for infusion Other Names: Piperacillin/tazobactam Meropenem Imipenem Aztreonam Ceftazidime Cefepime

Arm

Intervention/Treatment

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.

Drug: Antipseudomonal beta-lactam antibiotic

Pharmaceutical form: solution for infusion

Other Names:

Ampicillin

Trimethoprim/sulfamethoxazole

Cefuroxime

Amoxicillin/clavulanate

Ciprofloxacin

Ertapenem

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

Drug: De-escalation(short-spectrum antibiotic)

Pharmaceutical form: solution for infusion

Other Names:

Piperacillin/tazobactam

Meropenem

Imipenem

Aztreonam

Ceftazidime

Cefepime

Outcome Measures

Primary Outcome Measures

Clinical cure at day 3-5 after treatment. [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 Outcome Measures

Early clinical and microbiological response. [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. [Day 60]
The infection was completely resolved at day 60 (patients without infection symptoms)
Mortality [At 7,14 and 30 days]
Death for any reason
Length of hospital stay [At 7,14 and 30 days]
Defined as the from admission to hospital discharge
Recurrences (relapse or reinfection) rate [Day 60 after treatment]
Safety of antibiotic treatment [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 [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. [It is not allowed treatment duration more than 28 days]
Evaluate the study treatment duration.
Secondary infections. [60 days]
Evaluate the development of secondary infections other than the initial bacteremia.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jerez de la Frontera Hospital	Jerez de la Frontera	Cádiz	Spain	11138
2	La Línea de La Concepción Hospital	La Línea de La Concepción	Cádiz	Spain
3	University Hospital Donostia	San Sebastian	Gipúzcoa	Spain	20080
4	Cruces Hospital	Baracaldo	País Vasco	Spain
5	San Juan de Dios del Aljarafe Hospital	Bormujos	Sevilla	Spain	41930
6	University General Hospital of Alicante	Alicante		Spain	03012
7	University Hospital Mutua de Tarrasa	Barcelona		Spain	08221
8	University Hospital of Bellvitge	Barcelona		Spain
9	University Hospital Puerta del Mar	Cádiz		Spain	11009
10	Puerto Real Hospital	Cádiz		Spain
11	La Coruña Hospital	La Coruña		Spain
12	Universitary Hospital of Leon	León		Spain
13	University Hospital La Princesa	Madrid		Spain	28002
14	University Hospital La Paz	Madrid		Spain	28046
15	Universitary Hospital of Orense	Orense		Spain
16	Son Espases Hospital	Palma de Mallorca		Spain	07010
17	University Clinic of Navarra	Pamplona		Spain	31008
18	University Hospital Marqués de Valdecilla	Santander		Spain	30008
19	University Hospital Virgen Macarena	Seville		Spain	41071
20	Universitary Hospital of Vigo	Vigo		Spain
21	University Hospital of Zaragoza	Zaragoza		Spain	28046