Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study
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- Oliver A Cornely
- University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical Trials Centre Cologne (CTC Cologne), Faculty of Medicine, University Hospital Cologne, Department I of Internal Medicine, German Centre for Infection Research (DZIF) partner site Cologne, Cologne, Germany
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- José M Cisneros
- Hospital Universitario Virgen del Rocío, Seville, Spain
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- Julian Torre-Cisneros
- Reina Sofia University Hospital-IMIBIC-UCO, Córdoba, Spain
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- María Jesús Rodríguez-Hernández
- Hospital Universitario Virgen del Rocío, Seville, Spain
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- Luis Tallón-Aguilar
- Hospital Universitario Virgen Macarena, Seville, Spain
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- Esther Calbo
- Hospital Universitario Mútua de Tarrasa and Universitat Internacional de Catalunya, Barcelona, Spain
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- Juan P Horcajada
- Hospital del Mar, IMIM, UAB, Barcelona, Spain
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- Christian Queckenberg
- University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical Trials Centre Cologne (CTC Cologne), Faculty of Medicine, University Hospital Cologne, Department I of Internal Medicine, German Centre for Infection Research (DZIF) partner site Cologne, Cologne, Germany
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- Ulrike Zettelmeyer
- University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical Trials Centre Cologne (CTC Cologne), Faculty of Medicine, University Hospital Cologne, Department I of Internal Medicine, German Centre for Infection Research (DZIF) partner site Cologne, Cologne, Germany
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- Dorothee Arenz
- University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical Trials Centre Cologne (CTC Cologne), Faculty of Medicine, University Hospital Cologne, Department I of Internal Medicine, German Centre for Infection Research (DZIF) partner site Cologne, Cologne, Germany
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- Clara M Rosso-Fernández
- Hospital Universitario Virgen del Rocío, Seville, Spain
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- Silvia Jiménez-Jorge
- Hospital Universitario Virgen del Rocío, Seville, Spain
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- Guy Turner
- Pfizer, New York, NY, USA
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- Susan Raber
- Pfizer, La Jolla, CA, USA
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- Seamus O’Brien
- Pfizer, New York, NY, USA
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- Alison Luckey
- Pfizer, New York, NY, USA
抄録
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Objectives</jats:title> <jats:p>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).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>
収録刊行物
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- Journal of Antimicrobial Chemotherapy
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Journal of Antimicrobial Chemotherapy 75 (3), 618-627, 2019-12-12
Oxford University Press (OUP)