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).
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.
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).
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.
Profile of the SeptiCyte™ LAB Gene Expression Assay to Diagnose Infection in Critically Ill Patients
Abstract. Sepsis is a severe and frequently occurring clinical syndrome, caused by the inflammatory response to infections. Recent studies on the huma...
Pharmacodynamic Modelling of β-lactam/β-lactamase Inhibitor Checkerboard Data: Illustration with Aztreonam–Avibactam
Abstract. Objectives. Checkerboard experiments followed by fractional inhibitory concentration (FIC) index determinations are commonly used to assess ...
Detection and Prevalence of Carbapenem-resistant Gram-negative Bacteria Among European Laboratories Part of the COMBACTE Network: A COMBACTE LAB-Net Survey
Abstract: Antimicrobial resistance (AMR) represents a global public health threat which jeopardizes the progress that modern medicine has made over th...