Ceftaroline Fosamil Therapy in Patients With Acute Bacterial Skin and Skin Structure Infections With Systemic Inflammatory Signs: A Retrospective Dose Comparison Across Three Pivotal Trials

Abstract Background Post-hoc analysis compared pharmacokinetics and clinical outcomes of ceftaroline fosamil 600 mg every 12 (q12h) versus every 8 hours (q8h), in patients with acute bacterial skin and skin structure infections (ABSSSI) and signs of sepsis. Methods Clinical outcomes at test-of-cure in patients with ABSSSI and systemic inflammatory signs/systemic inflammatory response (SIRS), and ceftaroline minimum inhibitory concentrations (MICs) against baseline pathogens were compared between COVERS (ceftaroline fosamil 600 mg q8h, 2-h infusion) and the CANVAS 1 and 2 trials (ceftaroline fosamil 600 mg q12h, 1-h infusion). Ceftaroline exposures among patients in COVERS with or without markers of sepsis were compared using population pharmacokinetic (PK) modeling. Results In COVERS, 62% (312/506) and 41% (208/506) of ceftaroline fosamil-treated patients had ≥1 systemic sign or SIRS, respectively and 55% (378/693) and 22% (152/693), respectively in the CANVAS trials. Clinical cure rates for the modified intent-to-treat (MITT) population in COVERS and CANVAS were similar for ceftaroline fosamil-treated patients with ≥1 sign of sepsis (82% [255/312] and 85% [335/394]) and for those with SIRS (84% [168/199] and 85% [131/155]). Ceftaroline MIC distributions were similar across trials. Sepsis did not affect predicted individual steady-state ceftaroline exposures. Conclusions Clinical cure rates in patients with ≥1 systemic inflammatory sign or SIRS were comparable for both ceftaroline fosamil dosage regimens. Pathogen susceptibilities to ceftaroline were similar across trials. Ceftaroline exposures were not affected by disease severity. Ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most ABSSSI patients with sepsis. Trial Registry Information https://clinicaltrials.gov: (NCT01499277, NCT00424190, NCT00423657).