Journal Article

Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial

De Pascale, Gennaro, Garnacho-Montero, José, Matthaiou, Dimitrios K., Jiménez-Jorge, Silvia, Rosso-Fernández, Clara María, Díaz-Miguel, Ramón Ortiz, Fernández-Hinojosa, Esteban, Estella, Angel, Cisneros, José M., Roca-Oporto, Cristina, Antonelli, Massimo, Ramírez, Paula, Dimopoulos, George

2019

Overview

Background 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. Trial registration ClinicalTrials.gov, NCT01292031 . Registered 9 February 2011.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Anti-Bacterial Agents - adverse effects / Anti-Bacterial Agents - standards / Anti-Bacterial Agents - therapeutic use / Antibacterial agents / Antibiotics / Antimicrobial agents / Carbapenem-resistant gram-negative bacilli / Care and treatment / Clinical trials / Colistin / Colistin - adverse effects / Colistin - standards / Colistin - therapeutic use / Comparative analysis / Critical care / Critical Care Medicine / Drug dosages / Drug resistance / Emergency Medicine / Equivalence Trials as Topic / Female / Humans / Intensive / Kidney failure / Labels / Male / Medicine / Medicine & Public Health / Meropenem / Meropenem - adverse effects / Meropenem - standards / Meropenem - therapeutic use / Microbiology / Middle Aged / Mortality / Multidrug-resistant bacteria / Nosocomial infections / Pathogenic microorganisms / Pathogens / Patients / Pneumonia / Pneumonia, Ventilator-Associated - drug therapy / Prospective Studies / Sample size / Spain / Staphylococcus infections / Treatment Outcome / Ventilator-associated pneumonia / Ventilators