Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study.

Abstract

OBJECTIVES:

To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/β-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI).

METHODS:

This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed.

RESULTS:

Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population).

CONCLUSIONS:

Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

• Authors: Oliver A Cornely, José M Cisneros, Julian Torre-Cisneros, María Jesús Rodríguez-Hernández, Luis Tallón-Aguilar, Esther Calbo, Juan P Horcajada, Christian Queckenberg, Ulrike Zettelmeyer, Dorothee Arenz, Clara M Rosso-Fernández, Silvia Jiménez-Jorge, Guy Turner, Susan Raber, Seamus O'Brien, Alison Luckey, COMBACTE-CARE consortium/REJUVENATE Study Group
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 75 Issue 3 Pg. 618-627 (03 01 2020) ISSN: 1460-2091 [Electronic] England
• PMID: 31828337 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Chemical References

• Anti-Bacterial Agents
• Azabicyclo Compounds
• Drug Combinations
• avibactam
• Ceftazidime
• Aztreonam

Topics

• Adult
• Anti-Bacterial Agents (adverse effects)
• Azabicyclo Compounds (adverse effects)
• Aztreonam (adverse effects)
• Ceftazidime
• Drug Combinations
• Humans
• Intraabdominal Infections (drug therapy)