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.

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

“…Recently published PK data for ATM-AVI (REJUVENATE study) suggests that a maintenance dose of 1500–500 mg every 6 hours (3-hour infusion) with a 500–167 mg loading dose (30-minute infusion) displays >90% probability of target attainment at an MIC of 8 mg/L with a target of 60% f T>MIC. 72 With MIC 90 values ≤2 mg/L for most clinical isolates, ATM-AVI appears promising ( Table 2 ). Importantly, the ATM-AVI adverse events were comparable to those reported for ATM monotherapy.…”

Treatment of invasive IMP‐4Enterobacter cloacaeinfection in transplant recipients using ceftazidime/avibactam with aztreonam: A case series and literature review

“…One study of 70 MBL‐carrying isolates demonstrated that addition of avibactam to aztreonam could restore the in vitro susceptibility to aztreonam in 98.6% of isolates 11 . While ceftazidime/avibactam with aztreonam has been described in several case reports, 6,8,12‐15 the first Phase 2a pharmacokinetic evaluation of the combination has recently been published, highlighting a favorable adverse effect profile and the critical importance of drug dosing and drug exposure 16 . An aztreonam/avibactam combination product is in development and has progressed to Phase III clinical trials, 17,18 but transplant recipients are notably excluded from these initial trials.…”

In Vitro Activity of a Novel Siderophore-Cephalosporin LCB10-0200 (GT-1), and LCB10-0200/Avibactam, against Carbapenem-Resistant Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa Strains at a Tertiary Hospital in Korea

“…In addition, the combination of AVI with ATM also demonstrated good activity against Ambler class A/C and class B β-lactamase-coproducing strains [ 20 ]. This combination was studied in a phase IIa clinical trial for the treatment of cIAI [ 21 ]. Until now, the in vitro activity of a siderophore-cephalosporin and AVI combination has not been well studied.…”