The β-Lactams Strike Back: Ceftazidime-Avibactam.
Gram-negative resistance has reached a crucial point, with emergence of pathogens resistant to most or all available antibiotics. Ceftazidime-avibactam is a newly approved agent combining ceftazidime and a novel β-lactamase inhibitor with activity against multidrug-resistant gram-negative bacteria. Avibactam has increased potency and expanded spectrum of inhibition of class A and C β-lactamases relative to available β-lactamase inhibitors, including extended-spectrum β-lactamases, AmpC, and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Avibactam expands ceftazidime's spectrum of activity to include many ceftazidime- and carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. Early clinical data indicate that ceftazidime-avibactam is effective and well tolerated in patients with complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAI). In a phase II trial of patients with cUTIs, ceftazidime-avibactam produced similar rates of clinical and microbiologic success compared with imipenem-cilastatin (70.5% and 71.4% microbiologic success rates, respectively). Likewise, patients receiving ceftazidime-avibactam plus metronidazole in a phase II study of patients with cIAI had similar response rates to those receiving meropenem (91.2% and 93.4% clinical success rates, respectively). Based on available in vitro, in vivo, and phase II trial data, as well as preliminary phase III trial results in ceftazidime-resistant, gram-negative cUTI and cIAI, ceftazidime-avibactam received U.S. Food and Drug Administration approval for treatment of cUTI, including pyelonephritis, and cIAI, in combination with metronidazole, in adult patients with limited or no alternative treatment options. The approved dosage, ceftazidime 2 g-avibactam 0.5 g administered as a 2-hour infusion every 8 hours, was selected based on pharmacodynamic analysis and available clinical data. This dosage is under further investigation in patients with cUTI, cIAI, and nosocomial or ventilator-associated pneumonia. The current body of evidence suggests that ceftazidime-avibactam is a promising addition to our therapeutic armamentarium with potential to answer an urgent unmet medical need. Further data in highly resistant gram-negative infections, particularly those caused by KPC-producing Enterobacteriaceae, are needed. As it is introduced into clinical use, careful stewardship and rational use are essential to preserve ceftazidime-avibactam's potential utility.
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.
Evan J
EJ
Zasowski
Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee, Memphis, Tennessee.
Jeffrey M
JM
Rybak
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.|Department of Medicine, Division of Infectious Diseases, School of Medicine, Wayne State University, Detroit, Michigan.|Department of Pharmacy Services, Detroit Medical Center, Detroit, Michigan.
Michael J
MJ
Rybak
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D065093:beta-Lactamase Inhibitors / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D065093:beta-Lactamase Inhibitors; D002442:Ceftazidime
Enterobacteriaceae; Escherichia; Klebsiella; Klebsiella pneumoniae carbapenemase; Pseudomonas; carbapenemase; ceftazidime-avibactam; extended-spectrum β-lactamase; gram-negative; resistance; β-lactamase