Universität zu Köln

Cornely, Oliver A., Cisneros, Jose M., Torre-Cisneros, Julian, Jesus Rodriguez-Hernandez, Maria, Tallon-Aguilar, Luis, Calbo, Esther, Horcajada, Juan P., Queckenberg, Christian, Zettelmeyer, Ulrike, Arenz, Dorothee, Rosso-Fernandez, Clara M., Jimenez-Jorge, Silvia ORCID: 0000-0003-2944-6711, Turner, Guy, Raber, Susan, O'Brien, Seamus and Luckey, Alison (2020). Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study. J. Antimicrob. Chemother., 75 (3). S. 618 - 628. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2091

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Abstract

Objectives: To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/beta-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 500/167mg (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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Cornely, Oliver A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cisneros, Jose M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Torre-Cisneros, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Jesus Rodriguez-Hernandez, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Tallon-Aguilar, Luis UNSPECIFIED UNSPECIFIED UNSPECIFIED Calbo, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Horcajada, Juan P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Queckenberg, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Zettelmeyer, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Arenz, Dorothee UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosso-Fernandez, Clara M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jimenez-Jorge, Silvia UNSPECIFIED orcid.org/0000-0003-2944-6711 UNSPECIFIED Turner, Guy UNSPECIFIED UNSPECIFIED UNSPECIFIED Raber, Susan UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Brien, Seamus UNSPECIFIED UNSPECIFIED UNSPECIFIED Luckey, Alison UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-343313
DOI:	10.1093/jac/dkz497
Journal or Publication Title:	J. Antimicrob. Chemother.
Volume:	75
Number:	3
Page Range:	S. 618 - 628
Date:	2020
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2091
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GRAM-NEGATIVE PATHOGENS; ANTIMICROBIAL RESISTANCE; AZTREONAM-AVIBACTAM; DISSEMINATION; CEFTAZIDIME Multiple languages Infectious Diseases; Microbiology; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34331