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.

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.

Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme.

Objectives: This analysis evaluated the clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates pooled from the adult Phase III clinical trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI) or nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP). Methods: Baseline isolates from five Phase III randomized controlled trials of ceftazidime/avibactam versus predominantly carbapenem comparators in patients with cIAI (RECLAIM 1 and 2; NCT01499290 and RECLAIM 3; NCT01726023), cUTI (RECAPTURE 1 and 2; NCT01595438 and NCT01599806), NP including VAP (REPROVE; NCT01808092) and cIAI or cUTI caused by ceftazidime-non-susceptible Gram-negative pathogens (REPRISE; NCT01644643) were tested for MDR status and susceptibility to ceftazidime/avibactam and carbapenem-based comparators using CLSI broth microdilution methodology. Microbiological and clinical responses for patients with ≥1 MDR Enterobacteriaceae or P. aeruginosa isolate were assessed at the test-of-cure (TOC) visit. Results: In the pooled microbiologically modified ITT population, 1051 patients with MDR Enterobacteriaceae and 95 patients with MDR P. aeruginosa isolates were identified. Favourable microbiological response rates at TOC for all MDR Enterobacteriaceae and MDR P. aeruginosa were 78.4% and 57.1%, respectively, for ceftazidime/avibactam and 71.6% and 53.8%, respectively, for comparators. The proportions of patients with ≥1 MDR isolate who were clinically cured at TOC were similar in the ceftazidime/avibactam (85.4%) and comparator (87.9%) arms. Conclusions: Ceftazidime/avibactam demonstrated similar clinical efficacy to predominantly carbapenem comparators against MDR Enterobacteriaceae and P. aeruginosa, and may be a suitable alternative to carbapenem-based therapies for cIAI, cUTI and NP/VAP caused by MDR Gram-negative pathogens.

In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a Phase 3 clinical trial programme for the treatment of complicated urinary tract infections.

Objectives: To evaluate the in vitro activity of ceftazidime/avibactam relative to comparator agents against Gram-negative isolates from a Phase 3 clinical trial programme for complicated urinary tract infections (RECAPTURE). Methods: The in vitro activity of ceftazidime/avibactam was evaluated against 840 Gram-negative pathogens isolated at baseline from 1033 randomized patients in two pivotal Phase 3 clinical trials for the treatment of complicated urinary tract infections. The trials were conducted in 160 institutions from 25 countries worldwide. Susceptibility testing was performed by broth microdilution at a central laboratory according to CLSI methodologies. Results: Overall, ceftazidime/avibactam showed significant activity against the Enterobacteriaceae and Pseudomonas aeruginosa with MIC 90 values of 0.5 and 8 mg/L, respectively. Against the most common Enterobacteriaceae, MIC 90 values were 0.25 mg/L for Escherichia coli , 1 mg/L for Klebsiella pneumoniae , 0.06 mg/L for Proteus mirabilis and 2 mg/L for Enterobacter cloacae . The ceftazidime/avibactam MIC 90 for 154 ceftazidime-non-susceptible isolates of Enterobacteriaceae was 1 mg/L and the ceftazidime/avibactam MIC 90 for 15 non-susceptible isolates of P. aeruginosa was 64 mg/L. There was a significant reduction in the ceftazidime/avibactam MIC relative to ceftazidime alone for most of the Enterobacteriaceae isolates. Conclusions: The ceftazidime/avibactam in vitro activity against these clinical urinary tract isolates demonstrates the potential utility of the drug in complicated urinary tract infections.