Impact of Specific Antimicrobials and MIC Values on the Outcome of Bloodstream Infections Due to Extended-spectrum Beta-lactamase (ESBL) or Carbapenemase-producing Enterobacteriaceae: an Observational Multinational Study (INCREMENT)

June 26, 2014 updated by: JESUS RODRIGUEZ BAÑO

Impact of Specific Antimicrobials and Minimal Inhibitory Concentration(MIC) Values on the Outcome of Bloodstream Infections Due to ESBL or Carbapenemase-producing Enterobacteriaceae: an Observational Multinational Study

Main objective: to observationally assess the efficacy of different antimicrobials in Bloodstream Infection (BSI) due to Enterobacteriaceae producing ESBLs or carbapenemases.

Specific objectives:

Bacteraemic infections due to ESBL-producing Enterobacteriaceae:

  • To demonstrate that β-lactam/β-lactam inhibitors are not associated with worse cure rate and mortality than carbapenems after controlling for confounders, both as empirical and definitive therapy.
  • To demonstrate that fluoroquinolones as definitive therapy are not associated with worse cure rate and mortality than carbapenems after controlling for confounders.
  • To demonstrate that empirical cephalosporins in monotherapy are associated with worse cure rate and mortality than carbapenems after controlling for confounders in infections others than urinary tract infections.
  • To demonstrate that the association of active aminoglycosides with cephalosporins or fluoroquinolines is not associated with worse cure rate and mortality than carbapenems after controlling for confounders.
  • To demonstrate that combination empirical and definitive therapy is not associated with better cure rate than monotherapy after controlling for confounders.
  • For tigecycline, colistin, and fosfomycin, no hypothesis. The objective is to provide adjusted estimations of their association with outcome variables in comparison with carbapenem monotherapy according to clinical situation and infection.

Bacteraemic infections due to carbapenemase-producing Enterobacteriaceae:

  • To demonstrate that combination therapy is associated with worse cure rate and mortality than monotherapy after controlling for confounders.
  • To show that carbapenems are associated with worse cure rate and mortality when used in infections other than urinary tract caused by isolates showing MIC <2 µg/mL for imipenem or meropenem in comparison to those caused by isolates with higher MIC, after controlling for confounders.
  • To show that colistin used at a dose >6 million IU per day is associated with improved outcomes in comparison with lower dose, after controlling for confounders.

Study Overview

Status

Completed

Conditions

Detailed Description

METHODS

Study design: multicentre, international retrospective cohort study.

Sites: multiple expert investigators from different countries are invited.

Conditions to fulfil to participate include availability of a database with the required data or ability to retrospectively collect the data in a timely manner.

Procedure

The participant centres are asked to include:

  • Previously published cases: all these cases should be included if possible. The fact that the case had been previously published should be specified in the database.

  • Additionally, participants are asked to include consecutive episodes detected by reviewing their databases (clinical, infection control or microbiological records) from January 2004 to June 2012, according to the following criteria:

    • For ESBL producers:

A minimum of 20 and a maximum of 50 cases should be included from each centre (the more recent ones should be selected).

  • Cases for which the enzyme is characterised at least to group level by polymerase chain reaction, PCR, (it is, CTX-M, SHV, TEM) should be prioritised despite the date of diagnosis.

  • If not enough number of cases with PCR-characterized enzymes are available, or PCR-characterisation has not been performed, the total number of cases should be completed by including cases in which ESBL-production was identified using a standard phenotypic method.

    • For carbapenemase-producers: only cases in which the carbapenemase was characterised by PCR should be included. All episodes up to a limit of 50 cases per centre may be included.

Overall, to avoid selection biases, consecutive cases according to previous criteria should be included.

Variables

A common online database has been designed. Individual access to the database will be provided.

Main outcome variable: Cure rate at day 14

Secondary outcome variables: Mortality at 72 hours, 7, 14 and 30 days, clinical improvement at 72 hours, clinical cure at day 28.

Explanatory variables:

  • Demographics
  • Severity of chronic underlying conditions: McCabe and Charlson index
  • Acute severity of underlying disease: Pitt score during the the day before BSI.
  • Type of acquisition
  • Source of BSI
  • Severity of SIRS at presentation
  • Microorganism, betalactamase, MICs
  • Empirical therapy
  • Definitive therapy

Quality of data. Data will be approved and signed by the responsible investigator in each center. All data will be centrally reviewed; queries will be sent for lacking data and those showing inconsistencies or discrepancies. Data will be analysed per center; those with data showing significant differences with the average will be requested for review.

Statistical Analysis Plan

  • Subcohorts with patients treated with the treatment to be compared will be selected.
  • A propensity score to receive the 2 treatment types to compare will be calculated by obtaining a non-parsimonious multivariate model by logistic regression in which the outcome variable will be the treatment type. The explanatory variables will include age, gender, center, type of ward, acquisition, Charlson index, Pitt score, severity of SIRS and source.
  • After univariate analysis, multivariate analysis to investigate the adjusted association of treatment type with the main and secondary outcome variables will be performed by using logistic regression (for clinical response at day 14) and by Cox regression for mortality. If time until death is unavailable, logistic regression will be used for 30-day mortality. Logistic regression will also be used for 72-hour and 30-day clinical response. The propensity score will be added in all cases; also, Charlson score, Pitt score, severity of SIRS and source will be added. Finally, interaction between treatment type and source classified as urinary tract and others will be included.

Study Type

Observational

Enrollment (Actual)

1344

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
    • Andalucia
      • Seville, Andalucia, Spain, 41009
        • Virgen Macarena University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

- Episode of clinically-significant monomicrobial BSI due to ESBL or carbapenemase-producing Enterobacteriaceae, including community and nosocomial ones

Description

Inclusion Criteria:

  • Episode of clinically-significant monomicrobial BSI due to ESBL or carbapenemase-producing Enterobacteriaceae, including community and nosocomial ones.

    • For ESBL-producers, detection by standard phenotypic method as recommended by CLSI is enough (although PCR-based characterisation is preferred, see below).
    • For carbapenemase-producers, characterisation by at least PCR is necessary (isolates in which carbapenemase production is suspected based on antimicrobial susceptibility profile plus phenotypic tests alone is not acceptable, see below).
  • Subsequent episodes in a patient caused by the same microorganism may be included if the interval between them is >3 months.
  • No age limits.

Exclusion Criteria:

  • Polymicrobial or non-clinically significant episodes. Episodes in which a potential contaminant (e.g., coagulase-negative staphylococci) is isolated only in one set of blood cultures and there is not a typical source of infection for that kind of organism (e.g. catheter-related) may be included.
  • Unavailability of key data (such cases should be counted to analyse a potential selection bias)
  • Episode occurring before January 2004.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cure rate at day 14
Time Frame: within the first 14 days after treatment started
o Cure: resolution of all signs and symptoms related to the infection, and antibiotic therapy is no longer necessary
within the first 14 days after treatment started

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality at 72 hours
Time Frame: within the first 72 hours
Dead: death of the patient for whatever the reason.
within the first 72 hours
Mortality at 7 days
Time Frame: within 7 days after treatment started
Dead: death of the patient for whatever the reason.
within 7 days after treatment started
Mortality at 14 days
Time Frame: within 14 days after treatment started
Dead: death of the patient for whatever the reason.
within 14 days after treatment started
Mortality at 30 days
Time Frame: within 30 days after treatment started
Dead: death of the patient for whatever the reason.
within 30 days after treatment started
Clinical Improvement at 72 hours
Time Frame: within the first 72 hours after treatment started

Improvement: partial control or resolution of signs and symptoms related to the infection, or resolution but antibiotic therapy is still necessary.

Non-improvement or deterioration: clinical situation qualified as similar or worse in comparison to that at the diagnosis of bacteremia.
within the first 72 hours after treatment started
Clinical cure at 28 days
Time Frame: within 28 days after treatment started
Clinical Cure: resolution of all signs and symptoms related to the infection, and antibiotic therapy is no longer necessary.
within 28 days after treatment started

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

JESUS RODRIGUEZ BAÑO

Investigators

  • Study Chair: JESUS RODRIGUEZ BAÑO, MD, PhD, Spanish Network for Research in Infectious Diseases

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2013

Primary Completion (ACTUAL)

December 1, 2013

Study Completion (ACTUAL)

May 1, 2014

Study Registration Dates

First Submitted

December 26, 2012

First Submitted That Met QC Criteria

January 7, 2013

First Posted (ESTIMATE)

January 9, 2013

Study Record Updates

Last Update Posted (ESTIMATE)

June 27, 2014

Last Update Submitted That Met QC Criteria

June 26, 2014

Last Verified

June 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • REIPI-1WP701
  • JRB-ANT-2012-01 (OTHER: REIPI)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Clinically Significant Bacteremia

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Latvia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe