PMID- 36394316 OWN - NLM STAT- MEDLINE DCOM- 20221222 LR - 20230906 IS - 1098-6596 (Electronic) IS - 0066-4804 (Print) IS - 0066-4804 (Linking) VI - 66 IP - 12 DP - 2022 Dec 20 TI - Safety of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase I, Open-Label Study in Healthy Adult Volunteers. PG - e0093522 LID - 10.1128/aac.00935-22 [doi] LID - e00935-22 AB - 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. FAU - Lodise, Thomas P AU - Lodise TP AUID- ORCID: 0000-0002-4730-0655 AD - Albany College of Pharmacy and Health Sciencesgrid.413555.3, Albany, New York, USA. FAU - O'Donnell, J Nicholas AU - O'Donnell JN AUID- ORCID: 0000-0001-5184-1385 AD - Albany College of Pharmacy and Health Sciencesgrid.413555.3, Albany, New York, USA. FAU - Raja, Shruti AU - Raja S AUID- ORCID: 0000-0003-0216-1564 AD - Duke Early Phase Clinical Research Unit, Duke Universitygrid.26009.3d School of Medicine, Durham, North Carolina, USA. FAU - Guptill, Jeffrey T AU - Guptill JT AD - Duke Early Phase Clinical Research Unit, Duke Universitygrid.26009.3d School of Medicine, Durham, North Carolina, USA. FAU - Zaharoff, Smitha AU - Zaharoff S AD - Duke Clinical Research Institute, Duke Universitygrid.26009.3d School of Medicine, Durham, North Carolina, USA. FAU - Schwager, Nyssa AU - Schwager N AD - Duke Clinical Research Institute, Duke Universitygrid.26009.3d School of Medicine, Durham, North Carolina, USA. FAU - Fowler, Vance G Jr AU - Fowler VG Jr AUID- ORCID: 0000-0002-8048-0897 AD - Duke Clinical Research Institute, Duke Universitygrid.26009.3d School of Medicine, Durham, North Carolina, USA. FAU - Beresnev, Tatiana AU - Beresnev T AUID- ORCID: 0000-0001-9543-0107 AD - Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA. FAU - Wall, Alison AU - Wall A AUID- ORCID: 0000-0002-6720-0977 AD - The Emmes Company, Rockville, Maryland, USA. FAU - Wiegand, Katherine AU - Wiegand K AD - The Emmes Company, Rockville, Maryland, USA. FAU - Serti Chrisos, Elisavet AU - Serti Chrisos E AUID- ORCID: 0000-0003-4129-0254 AD - The Emmes Company, Rockville, Maryland, USA. FAU - Balevic, Stephen AU - Balevic S AD - Duke Clinical Research Institute, Duke Universitygrid.26009.3d School of Medicine, Durham, North Carolina, USA. FAU - Chambers, Henry F AU - Chambers HF AUID- ORCID: 0000-0001-5317-4491 AD - University of California, San Francisco, and San Francisco General Hospital, San Francisco, California, USA. CN - Antibacterial Resistance Leadership Group LA - eng GR - UM1 AI104681/AI/NIAID NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20221117 PL - United States TA - Antimicrob Agents Chemother JT - Antimicrobial agents and chemotherapy JID - 0315061 RN - 0 (avibactam, ceftazidime drug combination) RN - G2B4VE5GH8 (Aztreonam) RN - 0 (Anti-Bacterial Agents) RN - 9M416Z9QNR (Ceftazidime) RN - 0 (Azabicyclo Compounds) RN - 0 (Drug Combinations) RN - EC 3.5.2.6 (beta-Lactamases) SB - IM MH - Humans MH - Adult MH - *Aztreonam/adverse effects MH - *Anti-Bacterial Agents/adverse effects MH - Healthy Volunteers MH - Ceftazidime/adverse effects MH - Azabicyclo Compounds/adverse effects MH - Drug Combinations MH - Volunteers MH - Microbial Sensitivity Tests MH - beta-Lactamases PMC - PMC9764989 OTO - NOTNLM OT - aztreonam OT - ceftazidime-avibactam OT - clinical trials OT - safety COIS- The authors declare a conflict of interest. Research reported herein was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1AI104681. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. EDAT- 2022/11/18 06:00 MHDA- 2022/12/23 06:00 PMCR- 2023/05/17 CRDT- 2022/11/17 13:35 PHST- 2022/11/18 06:00 [pubmed] PHST- 2022/12/23 06:00 [medline] PHST- 2022/11/17 13:35 [entrez] PHST- 2023/05/17 00:00 [pmc-release] AID - 00935-22 [pii] AID - aac.00935-22 [pii] AID - 10.1128/aac.00935-22 [doi] PST - ppublish SO - Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0093522. doi: 10.1128/aac.00935-22. Epub 2022 Nov 17.