Introduction

Isolates producing ESBLs, the most common β-lactamase enzymes, are a major cause of β-lactam resistance among gram-negative bacteria and have been on rise in healthcare settings. Carbapenems have been used as the first-line treatment for infections caused by β-lactamase-producing Enterobacterales. However, there has been an increase in the carbapenem-resistant Enterobacterales. Ceftazidime/avibactam, is a combination of cephalosporin and a non-β-lactam β-lactamase inhibitor. This combination has proven efficacy and safety against a wide range of serious infections, including those caused by multidrug resistant gram-negative pathogens.

Aim

To assess the clinical and microbiological outcomes and safety of ceftazidime/avibactam in patients with infections caused by β-lactamase-producing (including ESBLs, AmpC and serine carbapenemases) Gram-negative pathogens across five Phase 3, randomized, controlled, multicentre trials.

Method

Study Design

• Post-hoc exploratory subset analysis of 5 phase 3, randomized clinical trials.

Treatment Strategy

• Patient population included adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis and nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP)
• The trials recruited patients with cUTI/pyelonephritis (RECAPTURE 1 and 2), cIAI (RECLAIM 1, 2 and 3), cUTI/cIAI (REPRISE) and NP, including VAP (REPROVE).
• Patients were randomized 1:1 to IV ceftazidime/avibactam (plus metronidazole for patients with cIAI) or comparators (carbapenems in >97% patients) for 5-21 days
• Clinical and microbiological responses at the test-of-cure visit were evaluated for patients with ESBLs, and/or plasmidic and/or overexpression of chromosomal AmpC, and/or serine carbapenemases without MBLs identified in baseline Gram-negative isolates by phenotypic screening and molecular characterization in the pooled microbiological modified ITT (mMITT) population

  Endpoints

• Clinical cure defined as complete resolution or significant improvement in of signs and symptoms of the index infection without any need for further treatment
• Microbiological response at test-of-cure visit which included eradication and presumed eradication
• Rate of adverse events (AEs)

Results

• The pooled mMITT population comprised 2585 patients
• Of these, 809 patients had >1 β-lactamase-producing baseline pathogen (ceftazidime/avibactam, n = 389; comparator, n = 420)
• Out of these, 792 patients had non-MBL β-lactamase producing pathogens (ceftazidime/avibactam, n = 379; comparator, n = 413)
• Baseline demographics of patients with non-MBL β-lactamase producing pathogens were similar between the ceftazidime/avibactam and comparator arms
• The most frequent β-lactamase-producing pathogens across treatment groups were Escherichia coli (n = 381), Klebsiella pneumoniae (n = 261) and Pseudomonas aeruginosa (n = 53)
• Clinical cure rates at TOC in the pooled non-MBL β-lactamase-producing mMITT population were highest for patients with cUTI
• The clinical responses at TOC indication-wise and all combined infections are shown in Figure 1.

  Figure 1. Clinical responses at TOC in patients with β-lactamase-producing non-MBL gram-negative pathogens

  

• Favorable microbiological response rates were highest in patients with cIAI
• The microbiological responses at TOC indication-wise and all combined infections are shown in Figure 2.

  Figure 2. Microbiological responses at TOC in patients with β-lactamase-producing non-MBL gram-negative pathogens

  

• The incidence of AEs and serious AEs was comparable
• The most common AEs were diarrhea, nausea and headache

Conclusion

• Ceftazidime/avibactam is effective and safe in patients with complicated intra-abdominal infection, complicated urinary tract infection/pyelonephritis and nosocomial pneumonia, including ventilator-associated pneumonia infections caused by β-lactamase producing gram-negative pathogens.

J Antimicrob Chemother. 2023 Nov 6;78(11):2672-2682.