Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial

Yaakov Dickstein; Jonathan Lellouche; Maayan Ben Dalak Amar; David Schwartz; Amir Nutman; Vered Daitch; Dafna Yahav; Leonard Leibovici; Anna Skiada; Anastasia Antoniadou; George L. Daikos; Roberto Andini; Rosa Zampino; Emanuele Durante-Mangoni; Johan W. Mouton; Lena E. Friberg; Yael Dishon Benattar; Roni Bitterman; Ami Neuberger; Yehuda Carmeli; Mical Paul; Hiba Zayyad; Fidi Koppel; Yael Zak-Doron; Sergey Altunin; Nizar Andria; Anat Stern; Neta Petersiel; Marina Raines; Amir Karban; Noa Eliakim-Raz; Oren Zusman; Michal Elbaz; Heyam Atamna; Tanya Babich; Amos Adler; Inbar Levi; Ioannis Pavleas; Antigoni Kotsaki; Domenico Iossa; Mariano Bernardo; Giusi Cavezza; Lorenzo Bertolino; Giuseppe Giuffre; Roberto Giurazza; Susanna Cuccurullo; Maria Galdo; Patrizia Murino; Adriano Cristinziano; Antonio Corcione; Pia Clara Pafundi

doi:10.1093/cid/ciy988

Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial

Yaakov Dickstein, Jonathan Lellouche, Maayan Ben Dalak Amar, David Schwartz, Amir Nutman, Vered Daitch, Dafna Yahav, Leonard Leibovici, Anna Skiada, Anastasia Antoniadou, George L. Daikos, Roberto Andini, Rosa Zampino, Emanuele Durante-Mangoni, Johan W. Mouton, Lena E. Friberg, Yael Dishon Benattar, Roni Bitterman, Ami Neuberger, Yehuda CarmeliMical Paul, Hiba Zayyad, Fidi Koppel, Yael Zak-Doron, Sergey Altunin, Nizar Andria, Anat Stern, Neta Petersiel, Marina Raines, Amir Karban, Noa Eliakim-Raz, Oren Zusman, Michal Elbaz, Heyam Atamna, Tanya Babich, Amos Adler, Inbar Levi, Ioannis Pavleas, Antigoni Kotsaki, Domenico Iossa, Mariano Bernardo, Giusi Cavezza, Lorenzo Bertolino, Giuseppe Giuffre, Roberto Giurazza, Susanna Cuccurullo, Maria Galdo, Patrizia Murino, Adriano Cristinziano, Antonio Corcione, Pia Clara Pafundi

Department of Nursing

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

Abstract

Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P =. 174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI},. 118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). Conclusions: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration: NCT01732250.

Original language	English
Article number	ciy988
Pages (from-to)	769-777
Number of pages	9
Journal	Clinical Infectious Diseases
Volume	69
Issue number	5
DOIs	https://doi.org/10.1093/cid/ciy988
State	Published - 16 Aug 2019

Bibliographical note

Funding Information:
Potential conflicts of interest. 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 report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Funding Information:
Financial support. This work was funded 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 number Health-F3-2011–278348).

Publisher Copyright:
© 2018 The Author(s) 2018.

Keywords

Acinetobacter
carbapenem-resistant
colistin
gram-negative bacteria
XDR-TB

ASJC Scopus subject areas

Microbiology (medical)
Infectious Diseases

UN SDGs

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

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10.1093/cid/ciy988

Cite this

Dickstein, Y., Lellouche, J., Ben Dalak Amar, M., Schwartz, D., Nutman, A., Daitch, V., Yahav, D., Leibovici, L., Skiada, A., Antoniadou, A., Daikos, G. L., Andini, R., Zampino, R., Durante-Mangoni, E., Mouton, J. W., Friberg, L. E., Dishon Benattar, Y., Bitterman, R., Neuberger, A., ... Clara Pafundi, P. (2019). Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial. Clinical Infectious Diseases, 69(5), 769-777. Article ciy988. https://doi.org/10.1093/cid/ciy988

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title = "Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial",

abstract = "Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P =. 174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI},. 118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). Conclusions: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration: NCT01732250.",

keywords = "Acinetobacter, carbapenem-resistant, colistin, gram-negative bacteria, XDR-TB",

author = "Yaakov Dickstein and Jonathan Lellouche and {Ben Dalak Amar}, Maayan and David Schwartz and Amir Nutman and Vered Daitch and Dafna Yahav and Leonard Leibovici and Anna Skiada and Anastasia Antoniadou and Daikos, {George L.} and Roberto Andini and Rosa Zampino and Emanuele Durante-Mangoni and Mouton, {Johan W.} and Friberg, {Lena E.} and {Dishon Benattar}, Yael and Roni Bitterman and Ami Neuberger and Yehuda Carmeli and Mical Paul and Hiba Zayyad and Fidi Koppel and Yael Zak-Doron and Sergey Altunin and Nizar Andria and Anat Stern and Neta Petersiel and Marina Raines and Amir Karban and Noa Eliakim-Raz and Oren Zusman and Michal Elbaz and Heyam Atamna and Tanya Babich and Amos Adler and Inbar Levi and Ioannis Pavleas and Antigoni Kotsaki and Domenico Iossa and Mariano Bernardo 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 and {Clara Pafundi}, Pia",

note = "Funding Information: Potential conflicts of interest. 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, bioM{\'e}rieux SA, Rempex Pharmaceuticals, Nariva, Achoagen, Roche, Pfizer, and Shionogi. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Funding Information: Financial support. This work was funded 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 number Health-F3-2011–278348). Publisher Copyright: {\textcopyright} 2018 The Author(s) 2018.",

year = "2019",

month = aug,

day = "16",

doi = "10.1093/cid/ciy988",

language = "English",

volume = "69",

pages = "769--777",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

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Dickstein, Y, Lellouche, J, Ben Dalak Amar, M, Schwartz, D, Nutman, A, Daitch, V, Yahav, D, Leibovici, L, Skiada, A, Antoniadou, A, Daikos, GL, Andini, R, Zampino, R, Durante-Mangoni, E, Mouton, JW, Friberg, LE, Dishon Benattar, Y, Bitterman, R, Neuberger, A, Carmeli, Y, Paul, M, Zayyad, H, Koppel, F, Zak-Doron, Y, Altunin, S, Andria, N, Stern, A, Petersiel, N, Raines, M, Karban, A, Eliakim-Raz, N, Zusman, O, Elbaz, M, Atamna, H, Babich, T, Adler, A, Levi, I, Pavleas, I, Kotsaki, A, Iossa, D, Bernardo, M, Cavezza, G, Bertolino, L, Giuffre, G, Giurazza, R, Cuccurullo, S, Galdo, M, Murino, P, Cristinziano, A, Corcione, A & Clara Pafundi, P 2019, 'Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial', Clinical Infectious Diseases, vol. 69, no. 5, ciy988, pp. 769-777. https://doi.org/10.1093/cid/ciy988

Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial. / Dickstein, Yaakov; Lellouche, Jonathan; Ben Dalak Amar, Maayan et al.
In: Clinical Infectious Diseases, Vol. 69, No. 5, ciy988, 16.08.2019, p. 769-777.

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

TY - JOUR

T1 - Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections

T2 - An Exploratory Subgroup Analysis of a Randomized Clinical Trial

AU - Dickstein, Yaakov

AU - Lellouche, Jonathan

AU - Ben Dalak Amar, Maayan

AU - Schwartz, David

AU - Nutman, Amir

AU - Daitch, Vered

AU - Yahav, Dafna

AU - Leibovici, Leonard

AU - Skiada, Anna

AU - Antoniadou, Anastasia

AU - Daikos, George L.

AU - Andini, Roberto

AU - Zampino, Rosa

AU - Durante-Mangoni, Emanuele

AU - Mouton, Johan W.

AU - Friberg, Lena E.

AU - Dishon Benattar, Yael

AU - Bitterman, Roni

AU - Neuberger, Ami

AU - Carmeli, Yehuda

AU - Paul, Mical

AU - Zayyad, Hiba

AU - Koppel, Fidi

AU - Zak-Doron, Yael

AU - Altunin, Sergey

AU - Andria, Nizar

AU - Stern, Anat

AU - Petersiel, Neta

AU - Raines, Marina

AU - Karban, Amir

AU - Eliakim-Raz, Noa

AU - Zusman, Oren

AU - Elbaz, Michal

AU - Atamna, Heyam

AU - Babich, Tanya

AU - Adler, Amos

AU - Levi, Inbar

AU - Pavleas, Ioannis

AU - Kotsaki, Antigoni

AU - Iossa, Domenico

AU - Bernardo, Mariano

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

AU - Clara Pafundi, Pia

N1 - Funding Information: Potential conflicts of interest. 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 report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Funding Information: Financial support. This work was funded 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 number Health-F3-2011–278348). Publisher Copyright: © 2018 The Author(s) 2018.

PY - 2019/8/16

Y1 - 2019/8/16

N2 - Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P =. 174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI},. 118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). Conclusions: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration: NCT01732250.

AB - Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P =. 174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI},. 118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). Conclusions: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration: NCT01732250.

KW - Acinetobacter

KW - carbapenem-resistant

KW - colistin

KW - gram-negative bacteria

KW - XDR-TB

UR - http://www.scopus.com/inward/record.url?scp=85071146817&partnerID=8YFLogxK

U2 - 10.1093/cid/ciy988

DO - 10.1093/cid/ciy988

M3 - Article

C2 - 30462182

AN - SCOPUS:85071146817

SN - 1058-4838

VL - 69

SP - 769

EP - 777

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 5

M1 - ciy988

ER -

Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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