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

BMJ Open - Tập 6 Số 4 - Trang e009956 - 2016
Yaakov Dickstein1, Leonard Leibovici2,3, Dafna Yahav2,3, Noa Eliakim‐Raz2,3, George L. Daikos4, Anna Skiada4, Anastasia Antoniadou4, Yehuda Carmeli5, Amir Nutman5,3, Inbar Levi5, Amos Adler5, Emanuele Durante‐Mangoni6, Roberto Andini6, Giusi Cavezza6, Johan W. Mouton7,8, Rixt A. Wijma7, Ursula Theuretzbacher9, Lena E. Friberg10, Anders Kristoffersson10, Oren Zusman2,3, Fidi Koppel1, Yael Dishon Benattar1, Sergey Altunin11, Mical Paul11,1
1Rambam Health Care Campus
2Rabin Medical Center, Beilinson Hospital
3Tel-Aviv University
4University of Athens
5Tel Aviv Sourasky Medical Centre
6Second University of Naples, Monaldi Hospital-AORN dei Colli
7Erasmus Mc
8Radboudumc
9Center for Anti-Infective Agents
10 Uppsala University
11Israel Institute of Technology

Tóm tắt

IntroductionThe 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 analysisThis 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 disseminationThe 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 numberNCT01732250 and 2012-004819-31; Pre-results.

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BMJ Open

Tập 6 Số 4

e009956

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