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

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 &lt;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.

Carbapenem-Resistant Gram-Negative Bacterial Infections in Children

“…The safety profile in one phase I trial and two phase II trials including children from 3 months to 18 years of age was similar to that observed in the adult population (72)(73)(74). Based on the results from these trials, the Food and Drug Administration (FDA) has recently approved its use in pediatric patients Ͼ3 months of age with complicated intra-abdominal infections (cIAIs), in conjunction with an agent active against anaerobic organisms, and also those with urinary tract infections (UTIs).…”

Nicho terapéutico de ceftazidima-avibactam frente a bacterias gramnegativas resistentes a carbapenémicos en Colombia

“…Se observaron respuestas clínicas/microbiológicas favorables en el ≥90 % de los pacientes en ambos grupos de tratamiento al final de este. Como conclusión, la CAZ-AVI más metronidazol fue bien tolerada, con un perfil de seguridad similar a la ceftazidima sola, y pareció ser efectiva en pacientes pediátricos con infección por gramnegativos, incluidas cepas no susceptibles a ceftazidima (27).…”

The Strategies of Pathogen-Oriented Therapy on Circumventing Antimicrobial Resistance

“…Among the avibactam conjugates, ceftazidime-avibactam has been used in Europe and the United States for the treatment of adults with complicated urinary tract infections (e.g., pyelonephritis and hospital-acquired pneumonia). It is also approved recently by the European Drug Administration for adult patients infected with aerobic Gram-negative bacteria with limited treatment regimen [ 38 , 69 ]. Meropenem-vaborbactam is the first carbapenem/ β -lactamase inhibitor conjugate recently approved by the US Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections and acute pyelonephritis [ 39 , 40 ].…”