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Safety and efficacy of colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia as part of a macro-project funded by the Seventh Framework Program of the European Commission studying off-patent antibiotics: study protocol for a randomized controlled trial.

Rosso-Fernández C, Garnacho-Montero J, Antonelli M, Dimopoulos G, Cisneros JM, MagicBullet study gro - Trials (2015)

Bottom Line: Inappropriate empiric antimicrobial treatment is associated with increased mortality.Currently, there is no study being undertaken which analyzes empiric treatment of (VAP) with a suspicion of multi-resistance.Colistin, an off-patent antibiotic commercialized for more than 60 years, could widen the antibiotic alternatives for a high-mortality illness aggravated by antibiotic resistance.

View Article: PubMed Central - PubMed

Affiliation: CTU-HUVR, University Hospital Virgen del Rocío, Avda Manuel Siurot s/n, 787, 41013, Seville, Spain. claram.rosso.sspa@juntadeandalucia.es.

ABSTRACT

Background: Ventilator-associated pneumonia (VAP) is one of the most common and severe hospital-adquired infections, and multidrugresistant gram-negative bacilli (MDR-GNB) constitute the main etiology in many countries. Inappropriate empiric antimicrobial treatment is associated with increased mortality. In this context, the empirical treatment of choice for VAP is unknown. Colistin, is now the antimicrobial with greatest in vitro activity against MDR-GNB.

Methods/design: The MagicBullet clinical trial is an investigator-driven clinical study, funded by the Seventh Framework Program of the European Commission. This is designed as a phase IV, randomized, controlled, open label, non-inferiority and international trial to assess the safety and efficacy of colistin versus meropenem in late onset VAP. The study is conducted in a total of 32 centers in three European countries (Spain, Italy and Greece) with specific high incidences of infections caused by MDR-GNB. Patients older than 18 years who develop VAP with both clinical and radiological signs, and are on mechanical ventilation for more than 96 hours, or less than 96 hours but with previous antibiotic treatment plus one week of hospitalization, are candidates for inclusion in the study. A total sample size of 496 patients will be randomized according to a severity clinical score (at the time of VAP diagnosis in a 1:1 ratio to receive either colistin 4.5 MU as a loading dose, followed by 3 MU every eight hours (experimental arm), or meropenem 2 g every eight hours (control arm), both combined with levofloxacin. Mortality from any cause at 28 days will be considered as the main outcome. Clinical and microbiological cure will be evaluated at 72 hours, eight days, the finalization of antibiotic treatment, and 28 days of follow-up. The efficacy evaluation will be performed in every patient who receives at least one study treatment drug, and with etiologic diagnosis of VAP, intention-to-treat population and per protocol analysis will be performed.

Discussion: Currently, there is no study being undertaken which analyzes empiric treatment of (VAP) with a suspicion of multi-resistance. Colistin, an off-patent antibiotic commercialized for more than 60 years, could widen the antibiotic alternatives for a high-mortality illness aggravated by antibiotic resistance.

Trial registration: This trial is registered with ClinicalTrials.gov (identifier: NCT01292031 ; registered on 29 June 2012) and EudraCT (identifier: 2010-023310-31; registered on 7 February 2011).

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Related in: MedlinePlus

Workflow of the general project. SME. Small medium enterprise, VAP; Ventilator associated Pneumonia, WP; work package, pK/pD: pharmacokinetic/pharmacodinamic, MDR-GNB: multidrug resistant gram-negative bacteria.
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Fig1: Workflow of the general project. SME. Small medium enterprise, VAP; Ventilator associated Pneumonia, WP; work package, pK/pD: pharmacokinetic/pharmacodinamic, MDR-GNB: multidrug resistant gram-negative bacteria.

Mentions: The clinical trial is one of the work packages of a macro project aimed at seeking solutions to MDR-GNB infections, so that the samples gathered from patients in the clinical trial (respiratory and rectal swaps samples) are re-directed to different collaborative laboratories in Spain (Seville, Barcelona and Coruña), France (Paris) and Germany (Cologne), in order to assess other specific objectives such as the evaluation of the impact of the antimicrobial treatment in the development of antimicrobial resistance and its specific mechanism of antibiotic use on the microbiome. Additionally two clinical centers (one in Spain and another in Greece) also participate in a pK/pD sub-study of colistin. A requirement of European Projects is the participation of small to medium enterprises, two of which are participating in this trial designing and evaluating simple, rapid and reliable procedures to determine antibiotic susceptibility, using a DNA fluorescent staining technique and a novel microencapsulation technology in relevant bacteria isolated from patients with VAP. In addition, a PCR-based technique for the early detection of the microorganism involved in VAP, and its use to measure the ability of antibiotic therapy to clear bacteria from the lung, is being developed as part of the project (Figure 1).Figure 1


Safety and efficacy of colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia as part of a macro-project funded by the Seventh Framework Program of the European Commission studying off-patent antibiotics: study protocol for a randomized controlled trial.

Rosso-Fernández C, Garnacho-Montero J, Antonelli M, Dimopoulos G, Cisneros JM, MagicBullet study gro - Trials (2015)

Workflow of the general project. SME. Small medium enterprise, VAP; Ventilator associated Pneumonia, WP; work package, pK/pD: pharmacokinetic/pharmacodinamic, MDR-GNB: multidrug resistant gram-negative bacteria.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4374401&req=5

Fig1: Workflow of the general project. SME. Small medium enterprise, VAP; Ventilator associated Pneumonia, WP; work package, pK/pD: pharmacokinetic/pharmacodinamic, MDR-GNB: multidrug resistant gram-negative bacteria.
Mentions: The clinical trial is one of the work packages of a macro project aimed at seeking solutions to MDR-GNB infections, so that the samples gathered from patients in the clinical trial (respiratory and rectal swaps samples) are re-directed to different collaborative laboratories in Spain (Seville, Barcelona and Coruña), France (Paris) and Germany (Cologne), in order to assess other specific objectives such as the evaluation of the impact of the antimicrobial treatment in the development of antimicrobial resistance and its specific mechanism of antibiotic use on the microbiome. Additionally two clinical centers (one in Spain and another in Greece) also participate in a pK/pD sub-study of colistin. A requirement of European Projects is the participation of small to medium enterprises, two of which are participating in this trial designing and evaluating simple, rapid and reliable procedures to determine antibiotic susceptibility, using a DNA fluorescent staining technique and a novel microencapsulation technology in relevant bacteria isolated from patients with VAP. In addition, a PCR-based technique for the early detection of the microorganism involved in VAP, and its use to measure the ability of antibiotic therapy to clear bacteria from the lung, is being developed as part of the project (Figure 1).Figure 1

Bottom Line: Inappropriate empiric antimicrobial treatment is associated with increased mortality.Currently, there is no study being undertaken which analyzes empiric treatment of (VAP) with a suspicion of multi-resistance.Colistin, an off-patent antibiotic commercialized for more than 60 years, could widen the antibiotic alternatives for a high-mortality illness aggravated by antibiotic resistance.

View Article: PubMed Central - PubMed

Affiliation: CTU-HUVR, University Hospital Virgen del Rocío, Avda Manuel Siurot s/n, 787, 41013, Seville, Spain. claram.rosso.sspa@juntadeandalucia.es.

ABSTRACT

Background: Ventilator-associated pneumonia (VAP) is one of the most common and severe hospital-adquired infections, and multidrugresistant gram-negative bacilli (MDR-GNB) constitute the main etiology in many countries. Inappropriate empiric antimicrobial treatment is associated with increased mortality. In this context, the empirical treatment of choice for VAP is unknown. Colistin, is now the antimicrobial with greatest in vitro activity against MDR-GNB.

Methods/design: The MagicBullet clinical trial is an investigator-driven clinical study, funded by the Seventh Framework Program of the European Commission. This is designed as a phase IV, randomized, controlled, open label, non-inferiority and international trial to assess the safety and efficacy of colistin versus meropenem in late onset VAP. The study is conducted in a total of 32 centers in three European countries (Spain, Italy and Greece) with specific high incidences of infections caused by MDR-GNB. Patients older than 18 years who develop VAP with both clinical and radiological signs, and are on mechanical ventilation for more than 96 hours, or less than 96 hours but with previous antibiotic treatment plus one week of hospitalization, are candidates for inclusion in the study. A total sample size of 496 patients will be randomized according to a severity clinical score (at the time of VAP diagnosis in a 1:1 ratio to receive either colistin 4.5 MU as a loading dose, followed by 3 MU every eight hours (experimental arm), or meropenem 2 g every eight hours (control arm), both combined with levofloxacin. Mortality from any cause at 28 days will be considered as the main outcome. Clinical and microbiological cure will be evaluated at 72 hours, eight days, the finalization of antibiotic treatment, and 28 days of follow-up. The efficacy evaluation will be performed in every patient who receives at least one study treatment drug, and with etiologic diagnosis of VAP, intention-to-treat population and per protocol analysis will be performed.

Discussion: Currently, there is no study being undertaken which analyzes empiric treatment of (VAP) with a suspicion of multi-resistance. Colistin, an off-patent antibiotic commercialized for more than 60 years, could widen the antibiotic alternatives for a high-mortality illness aggravated by antibiotic resistance.

Trial registration: This trial is registered with ClinicalTrials.gov (identifier: NCT01292031 ; registered on 29 June 2012) and EudraCT (identifier: 2010-023310-31; registered on 7 February 2011).

Show MeSH
Related in: MedlinePlus