233. Safety of Ceftazidime-Avibactam (CZA) in Combination with Aztreonam (ATM) in a Phase I, Open-Label Study in Healthy Adult Subjects (COMBINE)
Authors: Lodise Thomas , Nicholas O’Donnell J , Raja Shruti , Balevic Stephen , Guptill Jeffrey , Schwager Nyssa , Zaharoff Smitha , Fowler Vance G , Ghazaryan Varduhi , Beresnev Tatiana , wall Alison , Wiegand Katherine , Chambers Henry 
Published: December 2022

Abstract

Background
The combination of CZA-ATM is frequently used to treat patients with metallo-β-lactamase (MBL)-producing Enterobacterales (EB) infections, but its safety has not been established in controlled trials. This phase 1 study evaluated the safety of the optimal CZA-ATM regimens identified in the hollow fiber infection model of MBL-producing EB (PMID: 32464664).

Methods
The phase I, open-label, single center study enrolled healthy adults aged 18-45 years (NCT03978091). Subjects were sequentially assigned to 1 of 6 Cohorts and administered investigational product(s) (IP) for 7 days (Table 1). Study safety was monitored by assessments of adverse events (AEs), vital signs, and clinical laboratory safety tests.

Results
Of 48 subjects enrolled, 50% were female and 60% were Black. The mean (SD) age was 33.5 (6.2) years and mean (SD) weight was 75.7 (12.1) kg. The number of subjects who had ≥ 1 AE and experienced ≥ 1 IP related AE was 46 (96%) and 41 (85%), respectively. Frequency of IP related AEs by MedDRA system organ class, severity, and Cohort are shown in Figure 1. The occurrence of IP related investigation AEs were more frequent in the combination vs single IP Cohorts (Table 2). The most common IP related investigation AEs were ALT/AST elevations (35%) with 94% occurring in subjects who received ATM alone or in combination. The incidence of ALT/AST elevation AEs in the combination Cohorts were comparable to the ATM alone Cohorts. In the ATM single IP Cohorts, 3 subjects experienced severe ALT/AST elevation AEs, which halted the study. All subjects who experienced ALT/AST elevations were asymptomatic, had no other clinical findings suggestive of liver injury, and all resolved without intervention. Most other IP related AEs were of mild severity and similar across Cohorts except prolonged prothrombin time (PT) AEs, which was more frequent in combination Cohorts.

Conclusion
Clinicians should only consider using CZA-ATM when the benefits outweigh the risks. If CZA-ATM is prescribed, clinicians are advised to monitor for hepatic injury. Close monitoring of coagulation parameters may also be prudent with CZA-ATM. Future comparator-controlled randomized clinical trials are required to better define the safety and efficacy of the CZA-ATM regimens.

Disclosures
Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant J Nicholas O'Donnell, Pharm.D., Merck & Co, Inc: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support Stephen Balevic, MD, Purdue Pharma: Grant/Research Support|UCB: Advisor/Consultant Jeffrey Guptill, MD, argenx: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds henry chambers, MD, Merck: DSMB member|Merck: Stocks/Bonds|Moderna: Stocks/Bonds.