BACKGROUND: Drug-resistant Gram-negative bacteria are a growing threat to children; thus new antibiotics are needed to treat infections caused by these pathogens. Ceftolozane/tazobactam is active against many Gram-negative pathogens and is approved for treatment of complicated intra-abdominal and urinary tract infections in adults, but has not been evaluated in children. METHODS: This phase 1, noncomparative, open-label, multicenter study characterized the pharmacokinetics (by noncompartmental analysis), safety, and tolerability of single intravenous doses of ceftolozane/tazobactam in pediatric patients (birth [7 days postnatal] to < 18 years of age) with proven/suspected Gram-negative infection or receiving perioperative prophylaxis (clinicaltrials.gov NCT02266706). Patients were enrolled into 1 of 6 age groups to receive a single, age-based ceftolozane/tazobactam dose, with timed blood sample collection for determining plasma concentrations of ceftolozane and tazobactam. Safety and tolerability were also evaluated. RESULTS: Thirty-seven patients received study drug; 34 were included in the pharmacokinetic population. Ceftolozane and tazobactam pharmacokinetic parameters were generally comparable for patients 3 months to < 18 years of age. Patients from birth (7 days postnatal) to < 3 months of age had lower clearance than older children, likely due to the immature renal function of these young infants. No deaths, study drug-related serious adverse events, or clinically significant laboratory abnormalities were observed after administration of ceftolozane/tazobactam. CONCLUSIONS: The doses evaluated in this study yielded ceftolozane/tazobactam exposure levels generally comparable with those in adults. Single doses of ceftolozane/tazobactam were well-tolerated, and no safety concerns were identified. These data informed pharmacokinetic/pharmacodynamic models to derive pediatric dose recommendations for phase 2 ceftolozane/tazobactam clinical trials.
BACKGROUND: Drug-resistant Gram-negative bacteria are a growing threat to children; thus new antibiotics are needed to treat infections caused by these pathogens. Ceftolozane/tazobactam is active against many Gram-negative pathogens and is approved for treatment of complicated intra-abdominal and urinary tract infections in adults, but has not been evaluated in children. METHODS: This phase 1, noncomparative, open-label, multicenter study characterized the pharmacokinetics (by noncompartmental analysis), safety, and tolerability of single intravenous doses of ceftolozane/tazobactam in pediatric patients (birth [7 days postnatal] to < 18 years of age) with proven/suspected Gram-negative infection or receiving perioperative prophylaxis (clinicaltrials.gov NCT02266706). Patients were enrolled into 1 of 6 age groups to receive a single, age-based ceftolozane/tazobactam dose, with timed blood sample collection for determining plasma concentrations of ceftolozane and tazobactam. Safety and tolerability were also evaluated. RESULTS: Thirty-seven patients received study drug; 34 were included in the pharmacokinetic population. Ceftolozane and tazobactam pharmacokinetic parameters were generally comparable for patients 3 months to < 18 years of age. Patients from birth (7 days postnatal) to < 3 months of age had lower clearance than older children, likely due to the immature renal function of these young infants. No deaths, study drug-related serious adverse events, or clinically significant laboratory abnormalities were observed after administration of ceftolozane/tazobactam. CONCLUSIONS: The doses evaluated in this study yielded ceftolozane/tazobactam exposure levels generally comparable with those in adults. Single doses of ceftolozane/tazobactam were well-tolerated, and no safety concerns were identified. These data informed pharmacokinetic/pharmacodynamic models to derive pediatric dose recommendations for phase 2 ceftolozane/tazobactam clinical trials.
Authors: Kajal B Larson; Yogesh T Patel; Susan Willavize; John S Bradley; Elizabeth G Rhee; Luzelena Caro; Matthew L Rizk Journal: Antimicrob Agents Chemother Date: 2019-05-24 Impact factor: 5.191
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
Authors: Samuel Dubinsky; Kevin Watt; Steven Saleeb; Bilal Ahmed; Caitlin Carter; Cindy H T Yeung; Andrea Edginton Journal: Clin Pharmacokinet Date: 2021-11-30 Impact factor: 6.447
Authors: Laura Butragueño-Laiseca; Iñaki F Troconiz; Santiago Grau; Nuria Campillo; Xandra García; Belén Padilla; Sarah N Fernández; María José Santiago Journal: Antibiotics (Basel) Date: 2020-12-10
Authors: Elio Castagnola; Francesca Bagnasco; Alessio Mesini; Philipp K A Agyeman; Roland A Ammann; Fabianne Carlesse; Maria Elena Santolaya de Pablo; Andreas H Groll; Gabrielle M Haeusler; Thomas Lehrnbecher; Arne Simon; Maria Rosaria D'Amico; Austin Duong; Evgeny A Idelevich; Marie Luckowitsch; Mariaclaudia Meli; Giuseppe Menna; Sasha Palmert; Giovanna Russo; Marco Sarno; Galina Solopova; Annalisa Tondo; Yona Traubici; Lillian Sung Journal: Antibiotics (Basel) Date: 2021-03-05