Cisneros, José M.Rosso-Fernández, Clara MaríaRoca-Oporto, CristinaDe Pascale, GennaroJiménez-Jorge, SilviaFernández-Hinojosa, EstebanMatthaiou, Dimitrios K.Ramírez, PaulaOrtiz Díaz-Miguel, RamónEstella, AngelAntonelli, MassimoDimopoulos, GeorgeGarnacho-Montero, José2020-08-182020-08-182019-11-28Cisneros JM, Rosso-Fernández CM, Roca-Oporto C, De Pascale G, Jiménez-Jorge S, Fernández-Hinojosa E, et al. Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial. Critical Care. 2019 23:3831364-8535http://hdl.handle.net/10668/3157Background: Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. Methods: A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7-14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. Results: A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of - 2.16 (- 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). Conclusions: This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination.enColistinVentilator-associated pneumoniaMultidrug-resistant bacteriaCarbapenem-resistant gram-negative bacilliColistinaNeumonía asociada al ventiladorDrug resistance, bacterialFarmacorresistencia BacterianaGram-negative bacteriaBacterias gramnegativasCarbapenem-resistant enterobacteriaceaeEnterobacteriaceae resistentes a los carbapenémicosMedical Subject Headings::Persons::Persons::Age Groups::Adult::AgedMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial AgentsMedical Subject Headings::Chemicals and Drugs::Polycyclic Compounds::Macrocyclic Compounds::Peptides, Cyclic::Polymyxins::ColistinMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Persons::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Diseases::Bacterial Infections and Mycoses::Infection::Cross Infection::Pneumonia, Ventilator-AssociatedMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective StudiesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcomeresearch article31779711open access10.1186/s13054-019-2627-y1466-609XPMC6883535