COMBINE: Phase 1 Safety Outcomes for Ceftazidime-Avibactam in Combination With Aztreonam

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A 2-hour intermittent infusion of ceftazidime-avibactam (CZA) with aztreonam (ATM) is safe, but clinicians should exercise caution when prescribing continuous infusion ATM and only consider using in combination when benefits to the patient outweigh the risks.

Results of the phase 1, open-label, single center COMBINE trial (NCT03978091), shared in a poster at IDWeek 2022, held October 19-23, 2022, in Washington, DC, detailed the safety of the optimal dosing of CZA-ATM using hollow fiber infection models of Metallo-β-lactamase (MBL)-producing Enterobacterales.

There exists a significant unmet need for antibiotics with activity against MBLs, a problematic resistance mechanism present in some Gram-negative bacteria. CZA-ATM is one of the antibiotic combinations commonly used for MBL-producing Gram-negative infections, with avibactam working to inhibit extended spectrum beta-lactamase (ESBL) and Klebsiella pneumoniae carbapenemase (KPC) beta-lactamases while ATM effectively binds to bacterial penicillin-binding proteins. The safety of the combination, however, has not been established in controlled trials.

The COMBINE trial assessed the safety and pharmacokinetics of 3 treatment regimens through 7 days: CZA combined with ATM, CZA alone, and ATM alone. Participants included 48 healthy adult male and female volunteers between the ages of 18 and 45 years who were subsequently assigned to 1 of 6 dosing cohorts:

• CZA 2.5 g intravenously (IV) as 2-hour infusion every 8 hours for 7 days
• CZA 2.5 g IV as 2-hour infusion x 1, then 0.32 g per hour IV daily as a continuous infusion (CI) (7.5 g/day) for 7 days
• ATM 2 g IV as 2-hour infusion every 6 hours for 7 days
• ATM 2 g IV as a 2-hour infusion x 1, then 0.33 g per hour IV daily as a CI (8 g/day) for 7 days
• CZA 2.5 g IV as 2-hour infusion every 8 hours for 7 days and ATM 1.5 g IV as 2-hour infusion every 6 hours for 7 days
• CZA 2.5 g IV as 2-hour infusion every 8 hours for 7 days and ATM 2 g IV as 2- hour infusion every 6 hours for 7 days

Of the 48 study subjects, 24 (50%) were female and 29 (60%) were Black, with a mean age of 33.5 (6.2) years and mean weight of 75.7 (12.1) kg.

Participants were admitted to the study unit for 7 days in order to receive the study regimens, with final follow-up visits on Day 11 (+3 days after Day 1 of receiving the study product).

Investigators monitored safety via daily assessments of adverse events (AEs), vital signs, and symptom-directed physical exams, recording type, incidence, relatedness, and severity of AEs and serious adverse events (SAEs) from the start of the infusion of the first dose through the final study visit.

Overall in the safety population, 46 subjects (96%) experienced at least 1 AE, with 6 individuals (13%) experiencing a Grade 3 AE, 19 subjects (40%) experiencing a Grade 2 AE, and 21 subjects (44%) experiencing a Grade 1 AE. The most common AE was alanine transaminase (ALT)/aspartate transaminase (AST) elevations (n = 19), and 89% of those who reported it received ATM or CZA-ATM. These subjects reported no symptoms.

Hematologic and coagulation AEs were the second most frequent AEs observed, and most were of mild to moderate severity. All other AEs were comparable across all dose cohorts.

Overall, clinicians determined that a 2-hour intermittent infusion of CZA-ATM is safe but a continuous infusion of ATM should be used with caution.

“If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters,” investigators concluded. “Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this Phase 1 study.”