Colistin Resistance Development Following Colistin-Meropenem Combination Therapy Versus Colistin Monotherapy in Patients With Infections Caused by Carbapenem-Resistant Organisms
Authors: Dickstein Yaakov , Lellouche Jonathan , Schwartz David , Nutman Amir , Rakovitsky Nadya , Dishon Benattar Yael , Altunin Sergey , Bernardo Mariano , Iossa Domenico , Durante-Mangoni Emanuele , Antoniadou Anastasia , Skiada Anna , Deliolanis Ioannis , Daikos George L , Daitch Vered , Yahav Dafna , Leibovici Leonard , Rognås Viktor , Friberg Lena E , Mouton Johan W , Paul Mical , Carmeli Yehuda ,   AIDA Study Group, Paul Mical , Dishon Benattar Yael , 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 , Deliolanis Ioannis , 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 , Clara Pafundi Pia , Mouton Johan , Friberg Lena , Kristoffersson Anders , Theuretzbacher Ursula 
Published: November 2019

Abstract

Background
We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms.

Methods
This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E).

Results
Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475–10.184; P = .006).

Conclusions
Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention.