Ravina Kullar1, Florian M Wagenlehner2, Myra W Popejoy1, Jianmin Long1, Brian Yu1, Ellie J C Goldstein3,4. 1. Merck Research Laboratories, Merck & Co, Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. 2. Department of Urology, Pediatric Urology and Andrology, Justus Liebig University Gießen, Rudolf-Buchheim Str. 7, 35392 Gießen, Germany. 3. David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA. 4. R. M. Alden Research Laboratory, 6133 Bristol Pkway #175, Santa Monica, CA 90230, USA.
Abstract
Objectives: For reasons not well understood, antibacterials can yield lower cure rates in renally impaired patients. We explored this subject for the novel antibacterial ceftolozane/tazobactam. Methods: ASPECT-complicated intra-abdominal infections (cIAIs) and ASPECT-complicated urinary tract infections (cUTIs) were randomized, double-blinded clinical trials. Analyses in moderate [creatinine clearance (CL CR ) 30-50 mL/min] and mild/no (CL CR > 50 mL/min) renal impairment (RI) patients were pre-specified as exploratory endpoints in the statistical analysis plans. We also explored variables potentially impacting outcomes in these subgroups. Clinicaltrials.gov NCT01445665/NCT01445678 and NCT01345929/NCT01345955. Results: At baseline, 4.5% (36/806) of cIAI patients and 7.3% (58/795) of cUTI patients had moderate RI. Moderate RI patients were older, had more comorbid conditions and had higher APACHE-II scores. In the cIAI microbiological intent-to-treat population, response rates were 48% and 69% in moderate RI patients receiving ceftolozane/tazobactam and meropenem, respectively; among moderate RI cIAI patients considered treatment failures, indeterminate responses were more frequent with ceftolozane/tazobactam (39%; 9/23) than meropenem (8%; 1/13). In the cUTI microbiological modified intent-to-treat population, response rates were 81% and 78% in moderate RI patients receiving ceftolozane/tazobactam and levofloxacin, respectively. In both studies, response rates in moderate RI patients were similar between treatment arms in microbiologically evaluable populations, which excluded indeterminate responses due to missing data/protocol deviations (cIAI: 72.7% ceftolozane/tazobactam versus 71.4% meropenem; cUTI: 87% ceftolozane/tazobactam versus 80% levofloxacin). Conclusions: Regardless of treatment, clinical cure rates in cIAI and cUTI were lower in moderate versus mild/no RI patients. In moderate RI cIAI patients, numerical differences in response rates between treatments were attributable to imbalances in the numerical patients deemed indeterminate.
RCT Entities:
Objectives: For reasons not well understood, antibacterials can yield lower cure rates in renally impaired patients. We explored this subject for the novel antibacterial ceftolozane/tazobactam. Methods: ASPECT-complicated intra-abdominal infections (cIAIs) and ASPECT-complicated urinary tract infections (cUTIs) were randomized, double-blinded clinical trials. Analyses in moderate [creatinine clearance (CL CR ) 30-50 mL/min] and mild/no (CL CR > 50 mL/min) renal impairment (RI) patients were pre-specified as exploratory endpoints in the statistical analysis plans. We also explored variables potentially impacting outcomes in these subgroups. Clinicaltrials.gov NCT01445665/NCT01445678 and NCT01345929/NCT01345955. Results: At baseline, 4.5% (36/806) of cIAI patients and 7.3% (58/795) of cUTI patients had moderate RI. Moderate RIpatients were older, had more comorbid conditions and had higher APACHE-II scores. In the cIAI microbiological intent-to-treat population, response rates were 48% and 69% in moderate RIpatients receiving ceftolozane/tazobactam and meropenem, respectively; among moderate RI cIAI patients considered treatment failures, indeterminate responses were more frequent with ceftolozane/tazobactam (39%; 9/23) than meropenem (8%; 1/13). In the cUTI microbiological modified intent-to-treat population, response rates were 81% and 78% in moderate RIpatients receiving ceftolozane/tazobactam and levofloxacin, respectively. In both studies, response rates in moderate RIpatients were similar between treatment arms in microbiologically evaluable populations, which excluded indeterminate responses due to missing data/protocol deviations (cIAI: 72.7% ceftolozane/tazobactam versus 71.4% meropenem; cUTI: 87% ceftolozane/tazobactam versus 80% levofloxacin). Conclusions: Regardless of treatment, clinical cure rates in cIAI and cUTI were lower in moderate versus mild/no RIpatients. In moderate RI cIAI patients, numerical differences in response rates between treatments were attributable to imbalances in the numerical patients deemed indeterminate.
Authors: A R Buonomo; A E Maraolo; R Scotto; M Foggia; E Zappulo; P Congera; S Parente; I Gentile Journal: Infection Date: 2020-01-24 Impact factor: 3.553
Authors: Dafna Yahav; Christian G Giske; Alise Grāmatniece; Henrietta Abodakpi; Vincent H Tam; Leonard Leibovici Journal: Clin Microbiol Rev Date: 2020-11-11 Impact factor: 26.132