Randomized, Placebo-Controlled Study to Assess the Impact on QT/QTc Interval of Supratherapeutic Doses of Ceftazidime-Avibactam or Ceftaroline Fosamil-Avibactam

Potential effects of supratherapeutic doses of intravenous (IV) ceftazidime-avibactam and ceftaroline fosamil-avibactam on cardiac repolarization were assessed in a thorough QT/QTc study. This was a double-blind, randomized, placebo-controlled, four-period crossover Phase I study (NCT01290900) in healthy males (n=51). Subjects received, in randomized order and separated by 3 days washout: single doses of IV ceftaroline fosamil 1,500mg with avibactam 2,000mg; IV ceftazidime 3,000mg with avibactam 2,000mg; oral moxifloxacin 400mg (open-label positive control); and IV placebo (saline). Least square mean and two-sided 90% confidence intervals (CI) for change from baseline in Fridericia-corrected QT interval (QTcF) for active treatments versus placebo were estimated at 10 time points over 24hours. The upper bound of the two-sided 90% CI for placebo-corrected QTcF did not exceed 10milliseconds at any time point over 24hours for ceftaroline fosamil-avibactam or ceftazidime-avibactam. The lower bound of the two-sided 90% CI for the difference between moxifloxacin and placebo in QTcF over 1-4hours was >5milliseconds, confirming assay sensitivity. Pharmacokinetics results confirmed achievement of supratherapeutic plasma concentrations. No safety concerns were raised. In conclusion, supratherapeutic doses of ceftaroline fosamil-avibactam or ceftazidime-avibactam were not associated with QT/QTc prolongation in this study population.