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

• DOI: 10.1016/j.cmi.2020.03.035
• Publication Date: 2020-04-04T00:42:15Z
• Authors: Amir Nutman; Jonathan Lellouche; Elizabeth Temkin; George Daikos; Anna Skiada; Emanuele Durante-...; Yael Dishon-Benattar; Roni Bitterman; Dafna Yahav; Vered Daitch; Mariano Bernardo; Domenico Iossa; Oren Zusman; Lena E. Friberg; Johan W. Mouton; Ursula Theuretzba...; Leonard Leibovici; Mical Paul; Yehuda Carmeli; Mical Paul; Yael Dishon Benattar; Yaakov Dickstein; Roni Bitterman; Hiba Zayyad; Fidi Koppel; Yael Zak-Doron; Sergey Altunin; Nizar Andria; Ami Neuberger; Anat Stern; Neta Petersiel; Marina Raines; Amir Karban; Leonard Leibovici; Dafna Yahav; Noa Eliakim-Raz; Oren Zusman; Michal Elbaz; Heyam Atamna; Vered Daitch; Tanya Babich; Yehuda Carmeli; Amir Nutman; Amos Adler; Inbar Levi; George L. Daikos; Anna Skiada; Ioannis Pavleas; Anastasia Antoniadou; Antigoni Kotsaki; Emanuele Durante-...; Roberto Andini; Domenico Iossa; Mariano Bernardo; Giusi Cavezza; Lorenzo Bertolino; Giuseppe Giuffre; Roberto Giurazza; Susanna Cuccurullo; Maria Galdo; Patrizia Murino; Adriano Cristinziano; Antonio Corcione; Rosa Zampino; Pia Clara Pafundi; Johan Mouton; Lena Friberg; Anders Kristoffer...; Ursula Theuretzba...
• Keywords: Male; 0301 basic medicine; Infectious Medicine; Carbapenem resistance; EMC OR-01; Infektionsmedicin; Microbial Sensitivity Tests; 03 medical and health sciences; Checkerboard assay; Drug Resistance, Bacterial; Gram-Negative Bacteria; Pneumonia, Bacterial; Humans; Carbapenem resistance; Checkerboard assay; Colistin; Combination treatment; Gram-negative infections synergism; Aged; Aged, 80 and over; Cross Infection; Colistin; Drug Synergism; Meropenem; Middle Aged; EMC MM-04-28-01; 3. Good health; Gram-negative infections synergism; Treatment Outcome; Carbapenems; Combination treatment; Female; Gram-Negative Bacterial Infections

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.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.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).In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.