Mical Paul1, George L Daikos2, Emanuele Durante-Mangoni3, Dafna Yahav4, Yehuda Carmeli5, Yael Dishon Benattar6, Anna Skiada2, Roberto Andini3, Noa Eliakim-Raz7, Amir Nutman5, Oren Zusman8, Anastasia Antoniadou9, Pia Clara Pafundi3, Amos Adler10, Yaakov Dickstein11, Ioannis Pavleas12, Rosa Zampino3, Vered Daitch8, Roni Bitterman11, Hiba Zayyad11, Fidi Koppel11, Inbar Levi13, Tanya Babich8, Lena E Friberg14, Johan W Mouton15, Ursula Theuretzbacher16, Leonard Leibovici8. 1. Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel; Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel. Electronic address: paulm@technion.ac.il. 2. First Department of Medicine, Laikon General Hospital, Athens, Greece; National and Kapodistrian University of Athens, Athens, Greece. 3. Internal Medicine, University of Campania 'L Vanvitelli', and AORN dei Colli-Monaldi Hospital, Napoli, Italy. 4. Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Israel. 5. Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Israel; Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel. 6. Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel; Cheryl Spencer Department of Nursing, University of Haifa, Haifa, Israel. 7. Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Israel. 8. Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Israel. 9. National and Kapodistrian University of Athens, Athens, Greece; Fourth Department of Medicine, Attikon University General Hospital, Athens, Greece. 10. Microbiology Laboratory, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel. 11. Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel. 12. Intensive Care Unit, Laikon General Hospital, Athens, Greece. 13. Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel. 14. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. 15. Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands. 16. Center for Anti-Infective Agents, Vienna, Austria.
Abstract
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.
RCT Entities:
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.
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