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

AIDA Study Group

doi:10.1016/j.cmi.2020.03.035

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

AIDA Study Group

Bar-Ilan University - Azrieli Faculty of Medicine

Tel Aviv Sourasky Medical Center
Tel Aviv University
Laiko Hospital
National and Kapodistrian University of Athens
University of Campania Luigi Vanvitelli
Ospedale V. Monaldi
Rambam Health Care Campus Israel
University of Haifa
Rabin Medical Center Israel
Uppsala University
Erasmus University Rotterdam
Centre for Anti-Infective Agents
Technion-Israel Institute of Technology

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

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.

Original language	English
Pages (from-to)	1185-1191
Number of pages	7
Journal	Clinical Microbiology and Infection
Volume	26
Issue number	9
DOIs	https://doi.org/10.1016/j.cmi.2020.03.035
State	Published - Sep 2020

Bibliographical note

Publisher Copyright:
© 2020 European Society of Clinical Microbiology and Infectious Diseases

Funding

This work was supported by the European Commission FP7 AIDA project (preserving old antibiotics for the future: assessment of clinical efficacy by a pharmacokinetic/pharmacodynamic approach to optimize effectiveness and reduce resistance for off-patent antibiotics), Grant Health-F3-2011-278348. G. L. D. has received research funding from Pfizer , Achaogen , Rempex , MSD , and Gilead . E. D. -M. has received research funding from MSD and Pfizer . L. E. F. has received research funding from Genentech and Pharmetheus . Y. C. has received research funding from MSD , AstraZeneca , Allecra Therapeutics , DaVoltera , Intercell AG , bioMérieux SA , Rempex Pharmaceuticals , Nariva , Achoagen , Roche , Pfizer , and Shionogi . All other authors declare no competing interests.

Funders	Funder number
Allecra Therapeutics
Genentech and Pharmetheus
Rempex Pharmaceuticals
bioMérieux SA
Pfizer
AstraZeneca
Roche
Gilead Sciences
Meso Scale Diagnostics
European Commission	Health-F3-2011-278348
Shionogi

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Carbapenem resistance
Checkerboard assay
Colistin
Combination treatment
Gram-negative infections synergism

Access to Document

10.1016/j.cmi.2020.03.035

Cite this

@article{e5a13f85c9044221bfa91be9bc9930c2,

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

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.",

keywords = "Carbapenem resistance, Checkerboard assay, Colistin, Combination treatment, Gram-negative infections synergism",

author = "\{AIDA Study Group\} and Amir Nutman and Jonathan Lellouche and Elizabeth Temkin and George Daikos and Anna Skiada and Emanuele Durante-Mangoni and Yael Dishon-Benattar and Roni Bitterman and Dafna Yahav and Vered Daitch and Mariano Bernardo and Domenico Iossa and Oren Zusman and Friberg, \{Lena E.\} and Mouton, \{Johan W.\} and Ursula Theuretzbacher and Leonard Leibovici and Mical Paul and Yehuda Carmeli and Yaakov Dickstein and Hiba Zayyad and Fidi Koppel and Yael Zak-Doron and Sergey Altunin and Nizar Andria and Ami Neuberger and Anat Stern and Neta Petersiel and Marina Raines and Amir Karban and Noa Eliakim-Raz and Michal Elbaz and Heyam Atamna and Tanya Babich and Amos Adler and Inbar Levi and Daikos, \{George L.\} and Ioannis Pavleas and Anastasia Antoniadou and Antigoni Kotsaki and Roberto Andini and Giusi Cavezza and Lorenzo Bertolino and Giuseppe Giuffre and Roberto Giurazza and Susanna Cuccurullo and Maria Galdo and Patrizia Murino and Adriano Cristinziano and Antonio Corcione",

note = "Publisher Copyright: {\textcopyright} 2020 European Society of Clinical Microbiology and Infectious Diseases",

year = "2020",

month = sep,

doi = "10.1016/j.cmi.2020.03.035",

language = "אנגלית",

volume = "26",

pages = "1185--1191",

journal = "Clinical Microbiology and Infection",

issn = "1198-743X",

publisher = "Elsevier B.V.",

number = "9",

}

TY - JOUR

T1 - Colistin plus meropenem for carbapenem-resistant Gram-negative infections

T2 - in vitro synergism is not associated with better clinical outcomes

AU - AIDA Study Group

AU - Nutman, Amir

AU - Lellouche, Jonathan

AU - Temkin, Elizabeth

AU - Daikos, George

AU - Skiada, Anna

AU - Durante-Mangoni, Emanuele

AU - Dishon-Benattar, Yael

AU - Bitterman, Roni

AU - Yahav, Dafna

AU - Daitch, Vered

AU - Bernardo, Mariano

AU - Iossa, Domenico

AU - Zusman, Oren

AU - Friberg, Lena E.

AU - Mouton, Johan W.

AU - Theuretzbacher, Ursula

AU - Leibovici, Leonard

AU - Paul, Mical

AU - Carmeli, Yehuda

AU - Dickstein, Yaakov

AU - Zayyad, Hiba

AU - Koppel, Fidi

AU - Zak-Doron, Yael

AU - Altunin, Sergey

AU - Andria, Nizar

AU - Neuberger, Ami

AU - Stern, Anat

AU - Petersiel, Neta

AU - Raines, Marina

AU - Karban, Amir

AU - Eliakim-Raz, Noa

AU - Elbaz, Michal

AU - Atamna, Heyam

AU - Babich, Tanya

AU - Adler, Amos

AU - Levi, Inbar

AU - Daikos, George L.

AU - Pavleas, Ioannis

AU - Antoniadou, Anastasia

AU - Kotsaki, Antigoni

AU - Andini, Roberto

AU - Cavezza, Giusi

AU - Bertolino, Lorenzo

AU - Giuffre, Giuseppe

AU - Giurazza, Roberto

AU - Cuccurullo, Susanna

AU - Galdo, Maria

AU - Murino, Patrizia

AU - Cristinziano, Adriano

AU - Corcione, Antonio

PY - 2020/9

Y1 - 2020/9

N2 - 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.

AB - 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.

KW - Carbapenem resistance

KW - Checkerboard assay

KW - Colistin

KW - Combination treatment

KW - Gram-negative infections synergism

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U2 - 10.1016/j.cmi.2020.03.035

DO - 10.1016/j.cmi.2020.03.035

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C2 - 32251844

AN - SCOPUS:85084199137

SN - 1198-743X

VL - 26

SP - 1185

EP - 1191

JO - Clinical Microbiology and Infection

JF - Clinical Microbiology and Infection

IS - 9

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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