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

• Published in: The Pediatric infectious disease journal Vol. 38; no. 8; p. 816
• Main Authors: Bradley, John S, Broadhurst, Helen, Cheng, Karen, Mendez, Maria, Newell, Paul, Prchlik, Martin, Stone, Gregory G, Talley, Angela K, Tawadrous, Margaret, Wajsbrot, Dalia, Yates, Katrina, Zuzova, Antonina, Gardner, Annie
• Format: Journal Article
• Language: English
• Published: United States 01.08.2019
• Subjects: Adolescent; Age Factors; Anti-Bacterial Agents - therapeutic use; Azabicyclo Compounds - administration & dosage; Azabicyclo Compounds - adverse effects; Azabicyclo Compounds - pharmacokinetics; Azabicyclo Compounds - therapeutic use; Ceftazidime - administration & dosage; Ceftazidime - adverse effects; Ceftazidime - pharmacokinetics; Ceftazidime - therapeutic use; Child; Child, Preschool; Combined Modality Therapy; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Infant; Intraabdominal Infections - diagnosis; Intraabdominal Infections - drug therapy; Intraabdominal Infections - microbiology; Male; Metronidazole - administration & dosage; Metronidazole - adverse effects; Metronidazole - pharmacokinetics; Metronidazole - therapeutic use; Microbial Sensitivity Tests; Postoperative Complications; Treatment Outcome
• ISSN: 1532-0987
• DOI: 10.1097/INF.0000000000002392

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. 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. 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. 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.