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

Abstract

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-spect...

Antimicrobial Activity of Ceftazidime-Avibactam against Gram-Negative Organisms Collected from U.S. Medical Centers in 2012

“…However, similar to other cephalosporins, ceftazidime can be hydrolyzed by some class A enzymes, including ESBLs and KPCs, and class C enzymes. Avibactam is a novel non-␤-lactam ␤-lactamase inhibitor that protects ␤-lactams from hydrolysis by Ambler class A and C ␤-lactamases and some class D (OXA) enzymes (8,24,25). The results of the present study clearly demonstrate that avibactam restores ceftazidime activity against Enterobacteriaceae producing the ␤-lactamases most commonly found in U.S. hospitals, including ESBLs and KPCs (13).…”

Assessment of the In Vitro Activity of Ceftazidime-Avibactam against Multidrug-Resistant Klebsiella spp. Collected in the INFORM Global Surveillance Study, 2012 to 2014

“…Avibactam is capable of protecting ␤-lactams from hydrolysis in Gram-negative bacteria that produce both ESBLs and carbapenemases, including Ambler class A and/or class C enzyme producers and some class D enzymes (9). In this analysis, ceftazidimeavibactam demonstrated potent in vitro activity against MDR Klebsiella spp.…”

“…Specifically, avibactam is capable of protecting ␤-lactams from hydrolysis by ESBLs and carbapenemases, including Ambler class A and/or class C enzyme producers and some class D enzymes (9)(10)(11). Avibactam has been evaluated in combination with ceftazidime to assess whether it enhances ceftazidime's spectrum of antibacterial activity to include Gram-negative bacteria that produce ESBLs and/or carbapenemases, including KPC-producing strains.…”

What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

“…Notwithstanding this difference, the activity spectra of the two new BLBLI combinations overlap [5]. CAZ/AVI combines an established third-generation cephalosporin (ceftazidime) and avibactam, a novel synthetic non-β-lactam/β-lactamase inhibitor that has very limited intrinsic antimicrobial activity but is endowed with a peculiar mechanism of β-lactamase inhibition [19] that makes the combination more effective against resistant GNB versus other BLBLIs [20]. The main pharmacokinetic features of TOL/TAZ are the following: rapid tissue distribution, low protein binding, nonclinically significant drug-drug interactions via the cytochrome P450 (CYP450) enzymes, lung penetration, and extensive renal excretion [21].…”