A single- and multiple-dose study to determine the safety, tolerability, and pharmacokinetics (PK) of ceftaroline fosamil plus avibactam (CXL) administered by intravenous (IV) infusion to healthy subjects

Purpose: Ceftaroline (CPT) fosamil (the prodrug of CPT) is a new broad-spectrum cephalosporin with activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus, as well as common gram-negative pathogens. Avibactam (AVI) is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A and class C enzymes. This study was conducted to determine the safety, tolerability, and PK of IV doses of CXL in healthy adults.

Methods: This study included 2 parts. In the open-label arm, 12 subjects received single IV infusions over 1 hr of 600 mg CPT fosamil, 600 mg AVI, and 600/600 mg CXL separated by a 5-d washout. In the double-blind arm, 9 active/3 placebo subjects per cohort received IV infusions of CXL 600/600 mg q12h, CXL 400/400 mg q8h, CXL 900/900 mg q12h, or CXL 600/600 mg q8h for 10 d. CPT and AVI in plasma and urine were measured. 

Results: Following single IV doses alone or coadministered with AVI, CPT fosamil was rapidly converted to CPT. There were no significant differences in systemic exposure of CPT or AVI administered alone or when coadministered. No appreciable accumulation occurred with multiple IV doses of CXL. Infusions of CPT fosamil, AVI, and CXL were well tolerated. All adverse events (AEs) were mild to moderate in severity; no serious AEs occurred. Infusion-site reactions were the most common AEs reported with multiple dosing. There were no discontinuations due to an AE in the single-dose arm and 2 (5.6%) on CXL in the multiple-dose arm.

Conclusion: There was no apparent PK interaction between CPT fosamil and AVI administered as a single dose. PK parameters for CPT and AVI were similar on Days 1 and 10 when coadministered for 10 days. Infusions of CPT fosamil, AVI, and CXL were safe and well tolerated at total daily doses up to 1800 mg.