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

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, Ana Cristina Padial Aguado, Miguel Montejo Baranda, Carlos García Bernedo, Marc Bludau, Lucía Boix-Palop, Karen Cheng, Boudewijn de Jonge, Francisco Javier González de Molina, Pilar Retamar Gentil, Julia Guzmán-Puche, Virginia Palomo Jiménez, José A López-Ruiz, Enrique Montero Mateos, Cristina Roca Oporto, Guillaume Piessen, Deborah Postil, Rosa M Jiménez Rodríguez, Javier Padillo Ruiz, Jan Rupp, Rafael Morales Soriano, Michele Wible, Ángela Cano Yuste, Silvia Gómez-Zorrilla, 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, Ana Cristina Padial Aguado, Miguel Montejo Baranda, Carlos García Bernedo, Marc Bludau, Lucía Boix-Palop, Karen Cheng, Boudewijn de Jonge, Francisco Javier González de Molina, Pilar Retamar Gentil, Julia Guzmán-Puche, Virginia Palomo Jiménez, José A López-Ruiz, Enrique Montero Mateos, Cristina Roca Oporto, Guillaume Piessen, Deborah Postil, Rosa M Jiménez Rodríguez, Javier Padillo Ruiz, Jan Rupp, Rafael Morales Soriano, Michele Wible, Ángela Cano Yuste, Silvia Gómez-Zorrilla

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.

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Figures

Figure 1.
Figure 1.
Patient flow diagram.
Figure 2.
Figure 2.
Mean (±SD) plasma concentration–time curves for aztreonam (a) and avibactam (b) following 3 h IV infusion of aztreonam/avibactam on Day 4, intensive PK sampling.

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