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

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

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.

Study Overview

• Status: Completed
• Conditions: Enterobacteriaceae Infections
• Intervention / Treatment: Drug: Antipseudomonal beta-lactam antibiotic; Drug: De-escalation(short-spectrum antibiotic)

• Study Type: Interventional
• Enrollment (Actual): 344
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Alicante, Spain, 03012
    • University General Hospital of Alicante
  • Barcelona, Spain, 08221
    • University Hospital Mutua de Tarrasa
  • Barcelona, Spain
    • University Hospital of Bellvitge
  • Cádiz, Spain, 11009
    • University Hospital Puerta del Mar
  • Cádiz, Spain
    • Puerto Real Hospital
  • La Coruña, Spain
    • La Coruña Hospital
  • León, Spain
    • Universitary Hospital of Leon
  • Madrid, Spain, 28002
    • University Hospital La Princesa
  • Madrid, Spain, 28046
    • University Hospital La Paz
  • Orense, Spain
    • Universitary Hospital of Orense
  • Palma de Mallorca, Spain, 07010
    • Son Espases Hospital
  • Pamplona, Spain, 31008
    • University Clinic of Navarra
  • Santander, Spain, 30008
    • University Hospital Marqués de Valdecilla
  • Seville, Spain, 41071
    • University Hospital Virgen Macarena
  • Vigo, Spain
    • Universitary Hospital of Vigo
  • Zaragoza, Spain, 28046
    • University Hospital of Zaragoza
  • Cádiz
    • Jerez de la Frontera, Cádiz, Spain, 11138
      • Jerez de la Frontera Hospital
    • La Línea de La Concepción, Cádiz, Spain
      • La Linea de la Concepción Hospital
  • Gipúzcoa
    • San Sebastian, Gipúzcoa, Spain, 20080
      • University Hospital Donostia
  • País Vasco
    • Baracaldo, País Vasco, Spain
      • Cruces Hospital
  • Sevilla
    • Bormujos, Sevilla, Spain, 41930
      • San Juan de Dios del Aljarafe Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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: 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: Ciprofloxacin; Ampicillin; Trimethoprim/sulfamethoxazole; Cefuroxime; Amoxicillin/clavulanate; 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: Cefepime; Ceftazidime; Meropenem; Piperacillin/tazobactam; Imipenem; Aztreonam

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Collaborators: Spanish Network for Research in Infectious Diseases
• Investigators: Principal Investigator: Luis Eduardo Lopez Cortes, MD, PhD, Universitary Hospital Virgen Macarena

Publications and helpful links

General Publications

• Lopez-Cortes LE, Rosso-Fernandez C, Nunez-Nunez M, Lavin-Alconero L, Bravo-Ferrer J, Barriga A, Delgado M, Lupion C, Retamar P, Rodriguez-Bano J; SIMPLIFY Study Group. Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial. BMJ Open. 2017 Jun 9;7(6):e015439. doi: 10.1136/bmjopen-2016-015439.

Helpful Links

• Spanish Network for Research in Infectious Diseases (Red Española de Investigación en Patología Infecciosa)

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2016
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): January 1, 2020

Study Registration Dates

• First Submitted: April 1, 2016
• First Submitted That Met QC Criteria: June 6, 2016
• First Posted (Estimate): June 10, 2016

Study Record Updates

• Last Update Posted (Actual): July 17, 2020
• Last Update Submitted That Met QC Criteria: July 15, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Bacteremia; Recurrence; Bloodstream infection; Enterobacteriaceae; Bacterial resistance; Escalation
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Bacteremia; Enterobacteriaceae Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antitubercular Agents; Antimalarials; Folic Acid Antagonists; Cytochrome P-450 CYP1A2 Inhibitors; beta-Lactamase Inhibitors; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Renal Agents; Cytochrome P-450 CYP2C8 Inhibitors; Ampicillin; Anti-Bacterial Agents; Antibiotics, Antitubercular; Ciprofloxacin; Imipenem; Amoxicillin; Meropenem; Ertapenem; Trimethoprim; Sulfamethoxazole; Aztreonam; Clavulanic Acid; Amoxicillin-Potassium Clavulanate Combination; Cefuroxime; Piperacillin; Ceftazidime; Tazobactam; Piperacillin, Tazobactam Drug Combination; Lactams; Cefepime; beta-Lactams
• Other Study ID Numbers: SIMPLFY