Safety of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase I, Open-Label Study in Healthy Adult Volunteers.
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Issue Date
12/20/2022
Authors
Lodise, Thomas P
O'Donnell, J Nicholas
Raja, Shruti
Guptill, Jeffrey T
Zaharoff, Smitha
Schwager, Nyssa
Fowler, Vance G
Beresnev, Tatiana
Wall, Alison
Wiegand, Katherine
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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 ( = 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.
Citation
Lodise TP, O'Donnell JN, Raja S, Guptill JT, Zaharoff S, Schwager N, Fowler VG Jr, Beresnev T, Wall A, Wiegand K, Serti Chrisos E, Balevic S, Chambers HF; Antibacterial Resistance Leadership Group. Safety of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase I, Open-Label Study in Healthy Adult Volunteers. Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0093522. doi: 10.1128/aac.00935-22. Epub 2022 Nov 17. PMID: 36394316; PMCID: PMC9764989.
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UM1AI104681/HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)