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Avibactam is a non-β-lactam β-lactamase inhibitor intended for use as a fixed-dose combination with ceftazidime for the treatment of certain serious Gram-negative infections. As avibactam is primarily excreted unchanged in the urine, renal impairment may affect its pharmacokinetics. This phase 1 study investigated the effect of renal impairment and hemodialysis on avibactam pharmacokinetics and safety. Healthy controls and subjects with increasing degrees of renal impairment received a single 30-minute intravenous (IV) infusion of avibactam (100 mg). Anuric subjects requiring hemodialysis received the same infusion pre- and posthemodialysis, separated by a 7- to 14-day washout. Blood and urine samples were collected, and pharmacokinetics were analyzed using noncompartmental methods. The relationships between avibactam total plasma clearance (CL) or renal clearance (CLR ) and creatinine clearance (CrCL) were evaluated by linear correlation analysis. Safety was also monitored. Increasing severity of renal impairment was associated with decreasing CL and CLR and increasing exposure and terminal half-life (t1/2 ). Avibactam CL and CLR demonstrated an approximately linear relationship with CrCL comparable to that previously observed for ceftazidime. In patients requiring hemodialysis, >50% of the administered avibactam was removed during a 4-hour hemodialysis session, demonstrating that avibactam should be administered after hemodialysis. No new safety findings were reported. To conclude, avibactam dose adjustment is warranted in patients with renal impairment based on the severity of impairment. Because the slope of the linear relationship between avibactam total plasma CL and CrCL is similar to that of ceftazidime, renal impairment dose adjustments should maintain the currently advised 4:1 ratio of ceftazidime:avibactam.

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to 90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to

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 1,500 mg with avibactam 2,000 mg; IV ceftazidime 3,000 mg with avibactam 2,000 mg; oral moxifloxacin 400 mg (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 (ΔQTcF) for active treatments versus placebo were estimated at 10 time points over 24 hours. The upper bound of the two-sided 90% CI for placebo-corrected ΔQTcF did not exceed 10 milliseconds at any time point over 24 hours for ceftaroline fosamil-avibactam or ceftazidime-avibactam. The lower bound of the two-sided 90% CI for the difference between moxifloxacin and placebo in ΔQTcF over 1-4 hours was >5 milliseconds, 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.