@article{3103993,
    title = "Colistin plus meropenem for carbapenem-resistant Gram-negative infections: in vitro synergism is not associated with better clinical outcomes",
    author = "Nutman, A. and Lellouche, J. and Temkin, E. and Daikos, G. and Skiada, A. and Durante-Mangoni, E. and Dishon-Benattar, Y. and Bitterman, R. and Yahav, D. and Daitch, V. and Bernardo, M. and Iossa, D. and Zusman, O. and Friberg, L.E. and Mouton, J.W. and Theuretzbacher, U. and Leibovici, L. and Paul, M. and Carmeli, Y. and Benattar, Y.D. and Dickstein, Y. and Zayyad, H. and Koppel, F. and Zak-Doron, Y. and Altunin, S. and Andria, N. and Neuberger, A. and Stern, A. and Petersiel, N. and Raines, M. and Karban, A. and Eliakim-Raz, N. and Elbaz, M. and Atamna, H. and Babich, T. and Adler, A. and Levi, I. and Daikos, G.L. and Pavleas, I. and Antoniadou, A. and Kotsaki, A. and Andini, R. and Cavezza, G. and Bertolino, L. and Giuffre, G. and Giurazza, R. and Cuccurullo, S. and Galdo, M. and Murino, P. and Cristinziano, A. and Corcione, A. and Zampino, R. and Pafundi, P.C. and Mouton, J. and Friberg, L. and Kristoffersson, A. and AIDA Study Group",
    journal = "Clinical Microbiology and Infection",
    year = "2020",
    volume = "26",
    number = "9",
    pages = "1185-1191",
    publisher = "Elsevier B.V.",
    issn = "1198-743X",
    doi = "10.1016/j.cmi.2020.03.035",
    keywords = "colistin;  meropenem;  carbapenem derivative;  colistin;  meropenem, adult;  aged;  antibiotic therapy;  Article;  bacterium isolate;  bloodstream infection;  carbapenem resistance;  carbapenem resistant Acinetobacter baumannii;  carbapenem resistant Pseudomonas aeruginosa;  carbapenem-resistant Enterobacteriaceae;  clinical outcome;  combination drug therapy;  controlled study;  drug potentiation;  female;  Gram negative infection;  hospital acquired pneumonia;  human;  in vitro study;  major clinical study;  male;  monotherapy;  mortality;  priority journal;  secondary analysis;  urinary tract infection;  ventilator associated pneumonia;  antibiotic resistance;  bacterial pneumonia;  clinical trial;  cross infection;  drug effect;  Gram negative bacterium;  Gram negative infection;  microbial sensitivity test;  microbiology;  middle aged;  multicenter study;  randomized controlled trial;  treatment outcome;  very elderly, Aged;  Aged, 80 and over;  Carbapenems;  Colistin;  Cross Infection;  Drug Resistance, Bacterial;  Drug Synergism;  Female;  Gram-Negative Bacteria;  Gram-Negative Bacterial Infections;  Humans;  Male;  Meropenem;  Microbial Sensitivity Tests;  Middle Aged;  Pneumonia, Bacterial;  Treatment Outcome",
    abstract = "Objectives: In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. Methods: This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin–meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin–meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. Results: The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31–1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22–2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26–1.04) or 14-day mortality (aOR1.09, 95% CI 0.60–1.96). Discussion: In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit. © 2020 European Society of Clinical Microbiology and Infectious Diseases"
}