Safety of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase I, Open-Label Study in Healthy Adult Volunteers

Abstract

This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.

Keywords: aztreonam; ceftazidime-avibactam; clinical trials; safety.

FIG 1

Disposition of study subjects.

FIG 2

Individual alanine aminotransaminase (ALT) values by study product cohort. ALT (U/L) reference range for male: 17–63. Grade 1 AE was >63 to 105 U/L; grade 2 AE was 106 to 175 U/L; grade 2 was >175 U/L. ALT (U/L) reference range for female: 14–54. Grade 1 AE was >54 to 105 U/L; grade 2 AE was 106 to 175 U/L; grade 2 was >175 U/L. Blue lines represent males and red lines represent females.

FIG 3

Individual aspartate aminotransferase (AST) values by study product cohort. AST (U/L) reference range for all subjects: 15 to 41. Grade 1 AE was >42 to 105U/L; grade 2 AE was 106 to 175 U/L; grade 2 was >175 U/L. Blue lines represent males and red lines represent females.

FIG 4

Individual prothrombin values by study product cohort. Prothrombin time (PT, seconds) reference range for all subjects was 9.5 to 13.1 seconds. Grade 1 AE was >9.5 to 14.4 seconds; grade 2 was 14.5 to 15.7 seconds; grade 3 was >15.7 seconds. Blue lines represent males and red lines represent females.