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Crit Care. 2019 Nov 28;23(1):383. doi: 10.1186/s13054-019-2627-y.

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

Author information

1
Department of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocio CSIC, University of Seville, Avenida Manuel Siurot s/n, 41013, Seville, Spain. jmcisnerosh@gmail.com.
2
Clinical Trial Unit, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, 41013, Seville, Spain.
3
Department of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocio CSIC, University of Seville, Avenida Manuel Siurot s/n, 41013, Seville, Spain.
4
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
5
Intensive Care Clinical Unit, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, 41013, Seville, Spain.
6
Department of Critical Care, University Hospital ATTIKON, National and Kapodistrian University of Athens, Athens, Greece.
7
Intensive Medicine Unit, Hospital Universitario y Politécnico La Fe, Avinguda de Fernando Abril Martorell, 106, 46026, Valencia, Spain.
8
Intensive Medicine Unit, Hospital General Universitario de Ciudad Real, Calle Obispo Rafael Torija s/n, 13005, Ciudad Real, Spain.
9
Intensive Care Unit, Hospital Universitario de Jerez, Carretera Nacional IV s/n, 11407, Jerez de la Frontera, Cádiz, Spain.
10
Università Cattolica del Sacro Cuore, Rome, Italy.
11
Intensive Care Clinical Unit, Hospital Universitario Virgen Macarena, Calle Dr. Fedriani, 3, 41009, Seville, Spain.

Abstract

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.

KEYWORDS:

Carbapenem-resistant gram-negative bacilli; Colistin; Multidrug-resistant bacteria; Ventilator-associated pneumonia

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