Ceftazidime-Avibactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination for the Treatment of Resistant Gram-negative Organisms

Purpose: Multidrug-resistant gram-negative bacterial infections have emerged as a major threat in hospitalized patients. Treatment options are often inadequate and, as a result, these infections are associated with high mortality. A cephalosporin and a novel synthetic non-β-lactam, β-lactamase inhibitor, ceftazidime-avibactam, is approved for the treatment of serious infections caused by resistant gram-negative bacteria. This article reviews the spectrum of activity, clinical pharmacology, pharmacodynamic and pharmacokinetic properties, clinical efficacy and tolerability, and dosing and administration of ceftazidime-avibactam.

Methods: Searches of MEDLINE and International Pharmaceutical Abstracts from 1980 to September 2015 were conducted by using the search terms ceftazidime, avibactam, and ceftazidime-avibactam. Abstracts from Infectious Disease Week (2014-2015), the Interscience Conference on Antimicrobial Agents and Chemotherapy (2014-2015), and the European Congress of Clinical Microbiology and Infectious Diseases were also searched.

Findings: Ceftazidime, a third-generation cephalosporin, when combined with avibactam has a significant improvement in its activity against β-lactamase-producing gram-negative pathogens, including extended-spectrum β-lactamases, AmpC β-lactamases, Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Data from 2 Phase II and 1 Phase III clinical trial are available. In the Phase II trial of patients with complicated intra-abdominal infections, ceftazidime-avibactam produced clinical cure rates comparable to meropenem (91.2% vs 93.4%). Similarly, patients receiving ceftazidime-avibactam in a Phase II study of complicated urinary tract infections had clinical and microbiologic response rates similar to those receiving imipenem-cilastatin (70.4% and 71.4% microbiologic success rates, respectively). A Phase III trial compared ceftazidime-avibactam to best available therapy for the treatment of ceftazidime-resistant organisms. Clinical response and microbiological response for ceftazidime-avibactam versus best available therapy was comparable (90.9% and 91.2% clinical response, respectively); (81.8% and 63.5% microbiological response, respectively).

Implications: Currently, ceftazidime-avibactam is approved for the indications of complicated intra-abdominal infections (with metronidazole) and complicated urinary tract infections. Clinical trials published to date on this antimicrobial agent have shown its excellent safety and tolerability. This new combination agent has a role, but its use should be limited to patients without other treatment options in the empiric and documented treatment of multidrug-resistant gram-negative organisms. Further investigation is needed in patients with carbapenemase-producing Enterobacteriaceae and multidrug-resistant P aeruginosa who have bacteremia or nosocomial or ventilator-associated pneumonia. It is imperative that ceftazidime-avibactam be used in a responsible manner so that its effectiveness can be retained.