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Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial.
Pediatr Infect Dis J. 2019 08; 38(8):816-824.PI

Abstract

BACKGROUND

Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI.

METHODS

Hospitalized children (≥3 months to <18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7-15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit.

RESULTS

Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits.

CONCLUSIONS

Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains.

Authors+Show Affiliations

From the Rady Children's Hospital/University of California San Diego School of Medicine, San Diego, CA.AstraZeneca, Alderley Park, Macclesfield, United Kingdom.Pfizer, Sandwich, Kent, United Kingdom.Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.AstraZeneca, Alderley Park, Macclesfield, United Kingdom.Thomayerova Nemocnice, Prague, Czech Republic.Pfizer, Groton, CT.Allergan plc, Madison, NJ.Pfizer, Groton, CT.Pfizer, New York, NY.AstraZeneca, Alderley Park, Macclesfield, United Kingdom.Smolensk State Medical University, Smolensk, Russia.Pfizer, Cambridge, MA.

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31306396

Citation

Bradley, John S., et al. "Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial." The Pediatric Infectious Disease Journal, vol. 38, no. 8, 2019, pp. 816-824.
Bradley JS, Broadhurst H, Cheng K, et al. Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial. Pediatr Infect Dis J. 2019;38(8):816-824.
Bradley, J. S., Broadhurst, H., Cheng, K., Mendez, M., Newell, P., Prchlik, M., Stone, G. G., Talley, A. K., Tawadrous, M., Wajsbrot, D., Yates, K., Zuzova, A., & Gardner, A. (2019). Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial. The Pediatric Infectious Disease Journal, 38(8), 816-824. https://doi.org/10.1097/INF.0000000000002392
Bradley JS, et al. Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial. Pediatr Infect Dis J. 2019;38(8):816-824. PubMed PMID: 31306396.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial. AU - Bradley,John S, AU - Broadhurst,Helen, AU - Cheng,Karen, AU - Mendez,Maria, AU - Newell,Paul, AU - Prchlik,Martin, AU - Stone,Gregory G, AU - Talley,Angela K, AU - Tawadrous,Margaret, AU - Wajsbrot,Dalia, AU - Yates,Katrina, AU - Zuzova,Antonina, AU - Gardner,Annie, PY - 2019/7/16/entrez PY - 2019/7/16/pubmed PY - 2020/4/28/medline SP - 816 EP - 824 JF - The Pediatric infectious disease journal JO - Pediatr Infect Dis J VL - 38 IS - 8 N2 - BACKGROUND: Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI. METHODS: Hospitalized children (≥3 months to <18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7-15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit. RESULTS: Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains. SN - 1532-0987 UR - https://www.unboundmedicine.com/medline/citation/31306396/Safety_and_Efficacy_of_Ceftazidime_Avibactam_Plus_Metronidazole_in_the_Treatment_of_Children_≥3_Months_to_<18_Years_With_Complicated_Intra_Abdominal_Infection:_Results_From_a_Phase_2_Randomized_Controlled_Trial_ DB - PRIME DP - Unbound Medicine ER -