Ceftazidime-Avibactam: a Novel Cephalosporin/β-lactamase Inhibitor Combination

• Published in: Drugs (New York, N.Y.) Vol. 73; no. 2; pp. 159 - 177
• Main Authors: Zhanel, George G., Lawson, Christopher D., Adam, Heather, Schweizer, Frank, Zelenitsky, Sheryl, Lagacé-Wiens, Philippe R. S., Denisuik, Andrew, Rubinstein, Ethan, Gin, Alfred S., Hoban, Daryl J., Lynch, Joseph P., Karlowsky, James A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing AG 01.02.2013; Adis International
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - pharmacology; Azabicyclo Compounds - therapeutic use; Bacterial Infections - drug therapy; beta-Lactamase Inhibitors; Biological and medical sciences; Ceftazidime - chemistry; Ceftazidime - pharmacology; Ceftazidime - therapeutic use; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Review Article; AmpC; Meropenem; Complicated Urinary Tract Infection; Ceftaroline; Ceftazidime; Human; Drug combination; Treatment resistance; Enzyme; Indication; Toxicity; β-Lactams; Treatment efficiency; Enzyme inhibitor; Avibactam; β-Lactamase; Review; Biological activity; Antibiotic; Chemistry; Cephalosporin derivatives; β-Lactamases inhibitor; Animal; Hydrolases; Clinical trial; Antibacterial agent; Mechanism of action; Pharmacokinetics
• ISSN: 0012-6667; 1179-1950; 1179-1950
• DOI: 10.1007/s40265-013-0013-7

Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa , the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis , Clostridium perfringens , Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C max ) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone. Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date. In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections.