Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol.
BACKGROUND
The emergence of antibiotic-resistant bacteria has driven renewed interest in older antibacterials, including colistin. Previous studies have shown that colistin is less effective and more toxic than modern antibiotics. In vitro synergy studies and clinical observational studies suggest a benefit of combining colistin with a carbapenem. A randomised controlled study is necessary for clarification.


METHODS
This is a multicentre, investigator-initiated, open-label, randomised controlled superiority 1:1 study comparing colistin monotherapy with colistin-meropenem combination therapy for infections caused by carbapenem-resistant Gram-negative bacteria. The study is being conducted in 6 centres in 3 countries (Italy, Greece and Israel). We include patients with hospital-associated and ventilator-associated pneumonia, bloodstream infections and urosepsis. The primary outcome is treatment success at day 14, defined as survival, haemodynamic stability, stable or improved respiratory status for patients with pneumonia, microbiological cure for patients with bacteraemia and stability or improvement of the Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes include 14-day and 28-day mortality as well as other clinical end points and safety outcomes. A sample size of 360 patients was calculated on the basis of an absolute improvement in clinical success of 15% with combination therapy. Outcomes will be assessed by intention to treat. Serum colistin samples are obtained from all patients to obtain population pharmacokinetic models. Microbiological sampling includes weekly surveillance samples with analysis of resistance mechanisms and synergy. An observational trial is evaluating patients who met eligibility requirements but were not randomised in order to assess generalisability of findings.


BACKGROUND
The study was approved by ethics committees at each centre and informed consent will be obtained for all patients. The trial is being performed under the auspices of an independent data and safety monitoring committee and is included in a broad dissemination strategy regarding revival of old antibiotics.


BACKGROUND
NCT01732250 and 2012-004819-31; Pre-results.
Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
Yaakov
Y
Dickstein
Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel.
Leonard
L
Leibovici
Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
Dafna
D
Yahav
Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
Noa
N
Eliakim-Raz
First Department of Medicine, University of Athens, Athens, Greece.
George L
GL
Daikos
First Department of Medicine, University of Athens, Athens, Greece.
Anna
A
Skiada
Fourth Department of Medicine, University of Athens, Athens, Greece.
Anastasia
A
Antoniadou
Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
Yehuda
Y
Carmeli
Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
Amir
A
Nutman
Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
Inbar
I
Levi
Microbiology Laboratory, Tel Aviv Sourasky Medical Centre, Tel-Aviv, Israel.
Amos
A
Adler
Internal Medicine, Second University of Naples, Monaldi Hospital-AORN dei Colli, Napoli, Italy.
Emanuele
E
Durante-Mangoni
Internal Medicine, Second University of Naples, Monaldi Hospital-AORN dei Colli, Napoli, Italy.
Roberto
R
Andini
Internal Medicine, Second University of Naples, Monaldi Hospital-AORN dei Colli, Napoli, Italy.
Giusi
G
Cavezza
Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands.
Johan W
JW
Mouton
Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands.
Rixt A
RA
Wijma
Center for Anti-Infective Agents, Vienna, Austria.
Ursula
U
Theuretzbacher
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Lena E
LE
Friberg
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Anders N
AN
Kristoffersson
Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel.
Oren
O
Zusman
Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
Fidi
F
Koppel
Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
Yael
Y
Dishon Benattar
Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
Sergey
S
Altunin
Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
Mical
M
Paul
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy*; D003091:Colistin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006115:Greece; D006801:Humans; D007557:Israel; D007558:Italy; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy*; D012107:Research Design; D013845:Thienamycins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000188:drug therapy*; D055815:Young Adult
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem; D003091:Colistin
carbapenem-resistant Gram negative bacteria; colistin; combination therapy; meropenem