Τίτλος:
Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background: Colistin–carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. Methods: A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual. Findings: Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference −5·7%, 95% CI −13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83–1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87–1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury). Interpretation: Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria. Funding: EU AIDA grant Health-F3-2011-278348. © 2018 Elsevier Ltd
Συγγραφείς:
Paul, M.
Daikos, G.L.
Durante-Mangoni, E.
Yahav, D.
Carmeli, Y.
Benattar, Y.D.
Skiada, A.
Andini, R.
Eliakim-Raz, N.
Nutman, A.
Zusman, O.
Antoniadou, A.
Pafundi, P.C.
Adler, A.
Dickstein, Y.
Pavleas, I.
Zampino, R.
Daitch, V.
Bitterman, R.
Zayyad, H.
Koppel, F.
Levi, I.
Babich, T.
Friberg, L.E.
Mouton, J.W.
Theuretzbacher, U.
Leibovici, L.
Περιοδικό:
The Lancet Infectious Diseases
Εκδότης:
The Lancet Publishing Group
Λέξεις-κλειδιά:
colistimethate; creatinine; meropenem; antiinfective agent; colistin; meropenem, Acinetobacter baumannii; Acinetobacter infection; aged; antibiotic therapy; arterial oxygen tension; Article; bacteremia; carbapenem-resistant Enterobacteriaceae; Clostridium difficile infection; combination drug therapy; controlled study; diarrhea; drug treatment failure; drug withdrawal; end stage renal disease; Enterobacteriaceae infection; female; Greece; hospital acquired pneumonia; human; intensive care unit; Israel; Italy; kidney failure; Klebsiella pneumoniae infection; loading drug dose; maintenance drug dose; major clinical study; male; mild renal impairment; monotherapy; open study; outcome assessment; parallel design; pneumonia; priority journal; Pseudomonas infection; randomized controlled trial; seizure; Sequential Organ Failure Assessment Score; superiority trial; urosepsis; ventilator associated pneumonia; adult; beta-lactam resistance; classification; clinical trial; combination drug therapy; comparative study; drug effect; Gram negative bacterium; Gram negative infection; isolation and purification; microbiology; middle aged; multicenter study; procedures; single blind procedure; treatment outcome; very elderly, Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactam Resistance; Colistin; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Greece; Humans; Israel; Italy; Male; Meropenem; Middle Aged; Single-Blind Method; Treatment Outcome
DOI:
10.1016/S1473-3099(18)30099-9
