Safety Profile of Ceftazidime-Avibactam: Pooled Data from the Adult Phase II and Phase III Clinical Trial Programme.

INTRODUCTION: Ceftazidime-avibactam combines the established anti-pseudomonal cephalosporin, ceftazidime, with the novel non-ß-lactam ß-lactamase inhibitor, avibactam. OBJECTIVES: The aim of this study was to evaluate the safety of ceftazidime-avibactam in adults using pooled data from two phase II (NCT00690378, NCT00752219) and five phase III (NCT01499290, NCT01726023, NCT01644643, NCT01808093 and NCT01595438/NCT01599806) clinical studies. METHODS: Safety data from seven multicentre, randomised, active-comparator studies were pooled by study group at the patient level for descriptive analyses, comprising patients with complicated urinary tract infection (cUTI), including pyelonephritis, complicated intra-abdominal infection (cIAI), or nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), treated with ceftazidime-avibactam ± metronidazole or comparator. RESULTS: In total, 4050 patients (ceftazidime-avibactam ± metronidazole, n = 2024; comparator, n = 2026) were included in the pooled analysis. Adverse events (AEs) up to the last study visit occurred in 996 (49.2%) and 965 (47.6%) patients treated with ceftazidime-avibactam ± metronidazole and comparator, respectively. The most common AEs across treatment groups were diarrhoea, nausea, headache, vomiting and pyrexia. There were few discontinuations due to AEs (2.5% and 1.7% for ceftazidime-avibactam ± metronidazole and comparators, respectively). Overall rates of serious AEs were 8.7% for ceftazidime-avibactam ± metronidazole and 7.2% for comparators; respective rates of AEs with an outcome of death were 2.0% and 1.8%. AEs considered causally related to the study drug or procedures occurred in 10.7% and 9.6% of patients treated with ceftazidime-avibactam ± metronidazole and comparators; the most common drug-related AEs in both groups were diarrhoea, headache, nausea and increased alanine aminotransferase. No impact to the safety profile of ceftazidime-avibactam ± metronidazole was found with regard to intrinsic factors, such as age or renal function at baseline, or extrinsic factors, such as geographical origin. Potentially clinically significant changes in laboratory parameters were infrequent with no trends or safety concerns identified. CONCLUSION: The observed safety profile of ceftazidime-avibactam across infection types is consistent with the established safety profile of ceftazidime monotherapy and no new safety findings were identified. This analysis supports the use of ceftazidime-avibactam as a treatment option in adults with cUTI, cIAI and NP, including VAP.

Ceftazidime-Avibactam Susceptibility Breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa.

Clinical susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa for the ceftazidime-avibactam dosage regimen of 2,000/500 mg every 8 h (q8h) by 2-h intravenous infusion (adjusted for renal function) have been established by the FDA, CLSI, and EUCAST as susceptible (MIC, ≤8 mg/liter) and resistant (MIC, >8 mg/liter). The key supportive data from pharmacokinetic/pharmacodynamic analyses, in vitro surveillance, including molecular understanding of relevant resistance mechanisms, and efficacy in regulatory clinical trials are collated and analyzed here.

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 Isolates in a Phase 3 Open-Label Clinical Trial for Complicated Intra-Abdominal and Urinary Tract Infections Caused by Ceftazidime-Nonsusceptible Gram-Negative Pathogens.

The in vitro activity of ceftazidime-avibactam was evaluated against 341 Gram-negative isolates from 333 patients in a randomized, phase 3 clinical trial of patients with complicated urinary tract or intra-abdominal infections caused by ceftazidime-nonsusceptible pathogens (NCT01644643). Ceftazidime-avibactam MIC90 values against Enterobacteriaceae and Pseudomonas aeruginosa (including several class B or D enzyme producers that avibactam does not inhibit) were 1 and 64 µg/ml, respectively. Overall, the ceftazidime-avibactam activity against ceftazidime-nonsusceptible isolates was comparable to the activity of ceftazidime-avibactam previously reported against ceftazidime-susceptible isolates. (This study has been registered at ClinicalTrials.gov under identifier NCT01644643.).

Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study.

BACKGROUND: Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens. METHODS: REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18-90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5-21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7-10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643. FINDINGS: Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6-94·7] of 154 patients) and best available therapy (135 [91%; 85·9-95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam. INTERPRETATION: These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa. FUNDING: AstraZeneca.