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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
  1. Yaakov Dickstein1,
  2. Leonard Leibovici2,3,
  3. Dafna Yahav3,4,
  4. Noa Eliakim-Raz3,4,
  5. George L Daikos5,
  6. Anna Skiada5,
  7. Anastasia Antoniadou6,
  8. Yehuda Carmeli7,
  9. Amir Nutman3,7,
  10. Inbar Levi7,
  11. Amos Adler8,
  12. Emanuele Durante-Mangoni9,
  13. Roberto Andini9,
  14. Giusi Cavezza9,
  15. Johan W Mouton10,11,
  16. Rixt A Wijma10,
  17. Ursula Theuretzbacher12,
  18. Lena E Friberg13,
  19. Anders N Kristoffersson13,
  20. Oren Zusman2,3,
  21. Fidi Koppel1,
  22. Yael Dishon Benattar1,
  23. Sergey Altunin14†,
  24. Mical Paul1,14
  25. the AIDA consortium
  1. 1Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel
  2. 2Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
  3. 3Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel
  4. 4Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
  5. 5First Department of Medicine, University of Athens, Athens, Greece
  6. 6Fourth Department of Medicine, University of Athens, Athens, Greece
  7. 7Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel
  8. 8Microbiology Laboratory, Tel Aviv Sourasky Medical Centre, Tel-Aviv, Israel
  9. 9Internal Medicine, Second University of Naples, Monaldi Hospital-AORN dei Colli, Napoli, Italy
  10. 10Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands
  11. 11Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands
  12. 12Center for Anti-Infective Agents, Vienna, Austria
  13. 13Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
  14. 14Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
  1. Correspondence to Professor Mical Paul; paulm{at}post.tau.ac.il

Abstract

Introduction 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 and analysis 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.

Ethics and dissemination 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.

Trial registration number NCT01732250 and 2012-004819-31; Pre-results.

  • colistin
  • combination therapy
  • meropenem
  • carbapenem-resistant Gram negative bacteria

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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