title: 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.
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
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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).
authors: CTU-HUVR, University Hospital Virgen del Rocío, Avda Manuel Siurot s/n, 787, 41013, Seville, Spain. claram.rosso.sspa@juntadeandalucia.es.
authors: Clara
authors: C
authors: Rosso-Fernández
authors: Unidad Clínica de Cuidados Críticos, Institute of Biomedicine of Seville (IBIS) Hospital Virgen del Rocío, Avda Manuel Siurot s/n, 41013, Seville, Spain. jgarnachom@gmail.com.
authors: José
authors: J
authors: Garnacho-Montero
authors: General Intensive Care Unit, Policlinico Universitario A Gemelli, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy. m.antonelli@rm.unicatt.it.
authors: Massimo
authors: M
authors: Antonelli
authors: Department of Critical Care, University Hospital ATTIKO, 1 Rimini Str., 12462, Athens, Greece. gdimop@med.uoa.gr.
authors: George
authors: G
authors: Dimopoulos
authors: Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío, Avda Manuel Siurot s/n, 41013, Seville, Spain. jmcisnerosh@gmail.com.
authors: José Miguel
authors: JM
authors: Cisneros
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols; D003091:Colistin / Q000009:adverse effects / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial; D005060:Europe / Q000453:epidemiology; D016905:Gram-Negative Bacterial Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology; D006801:Humans; D015994:Incidence; D000077731:Meropenem; D010330:Patents as Topic; D053717:Pneumonia, Ventilator-Associated / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology; D012107:Research Design; D013845:Thienamycins / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem; D003091:Colistin