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

摘要

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. Background and rationale Colistin, discovered in 1947, has resurged in the past decade for the treatment of multidrug-resistant Gram-negative bacteria (GNB). As a polymyxin, it acts both by disrupting the cell membrane and by binding lipid polysaccharide and blocking the effects of endotoxin.1 ,2 Polymyxins are bactericidal by inducing rapid cell death mediated through hydroxyl radical production.3 Observational studies suggested higher mortality among patients treated with colistin or polymyxin B compared with patients given other antibiotics, mostly β-lactams.4 ,5 Despite the fact that most of these studies were limited by the probable underdosing of colistin, the pooled rates of nephrotoxicity were higher with colistin compared with other antibiotics.4 Rates of nephrotoxicity in recent studies designed to assess this outcome have ranged from 6–14% to 32–55%, with much of the difference due to different definitions of renal failure.6–15 The daily dose12 ,15 and the total cumulative dose10 ,11 ,16 have been associated with increased risk of nephrotoxicity. Additionally, colistin is associated with neurological toxicity that is more difficult to appreciate in critically ill patients.17 Studies currently focus on improving the efficacy and safety profile of colistin, combination therapy being one commonly adopted strategy. Ideally, a combination regimen should improve clinical success via improved reduction of the bacterial load, more rapid killing, killing or inhibition at lower drug concentrations, thus avoiding toxicity and minimising the risk of resistance selection. Carbapenems are commonly added to colistin in clinical practice for the treatment of infections due to carbapenem-resistant GNB (CR GNB). Several recent observational studies concluded that combination therapies including a carbapenem have a significant and important advantage over colistin monotherapy.18–23 These studies have been highly influential on clinical practice worldwide, leading to the view that colistin should not be used as monotherapy. The limitations of these studies include indication bias inherent to observational studies comparing treatment regimens, moderate to very small sample sizes, inclusion of multiple different regimens in the combination arm and inclusion of carbapenemase-producing carbapenem-susceptible bacteria together with CR bacteria.24 To formally appraise the potential benefit of polymyxin–carbapenem combination therapy, we conducted a systematic review and meta-analysis of their in vitro interactions.25 We found that in time-kill studies, carbapenem–polymyxin combination therapy showed synergy rates of 77% (95% CI 64% to 87%) for Acinetobacter baumannii, 44% (95% CI 23% to 51%) for Klebsiella pn