Colistin plus meropenem for carbapenem-resistant Gram-negative infections: in vitro synergism is not associated with better clinical outcomes. (September 2020)

• Record Type: Journal Article
• Authors: Nutman, Amir; Lellouche, Jonathan; Temkin, Elizabeth; Daikos, George; Skiada, Anna; Durante-Mangoni, Emanuele; Dishon-Benattar, Yael; Bitterman, Roni; Yahav, Dafna; Daitch, Vered; Bernardo, Mariano; Iossa, Domenico; Zusman, Oren; Friberg, Lena E.; Mouton, Johan W.; Theuretzbacher, Ursula; Leibovici, Leonard; Paul, Mical; Carmeli, Yehuda; Paul, Mical; Benattar, Yael Dishon; Dickstein, Yaakov; Bitterman, Roni; Zayyad, Hiba; Koppel, Fidi; Zak-Doron, Yael; Altunin, Sergey; Andria, Nizar; Neuberger, Ami; Stern, Anat; Petersiel, Neta; Raines, Marina; Karban, Amir; Leibovici, Leonard; Yahav, Dafna; Eliakim-Raz, Noa; Zusman, Oren; Elbaz, Michal; Atamna, Heyam; Daitch, Vered; Babich, Tanya; Carmeli, Yehuda; Nutman, Amir; Adler, Amos; Levi, Inbar; Daikos, George L.; Skiada, Anna; Pavleas, Ioannis; Antoniadou, Anastasia; Kotsaki, Antigoni; Durante-Mangoni, Emanuele; Andini, Roberto; Iossa, Domenico; Bernardo, Mariano; Cavezza, Giusi; Bertolino, Lorenzo; Giuffre, Giuseppe; Giurazza, Roberto; Cuccurullo, Susanna; Galdo, Maria; Murino, Patrizia; Cristinziano, Adriano; Corcione, Antonio; Zampino, Rosa; Pafundi, Pia Clara; Mouton, Johan; Friberg, Lena; Kristoffersson, Anders; Theuretzbacher, Ursula;
• Is Part Of: Clinical microbiology and infection. Volume 26:Number 9(2020)
• Page Start: 1185
• Page End: 1191
• Publication Date: 2020-09
• Subjects: Carbapenem resistance -- Checkerboard assay -- Colistin -- Combination treatment -- Gram-negative infections synergism; Medical microbiology -- Periodicals; Diagnostic microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.01
• DOI: 10.1016/j.cmi.2020.03.035
• Languages: English
• ISSNs: 1198-743X

Abstract

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.