The β‐Lactams Strike Back: Ceftazidime‐Avibactam

Abstract

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-lactamase, 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 (cUTI) and complicated intraabdominal infections (cIAI). In a phase II trial of patients with cUTI, 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 United States 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.

Clinical and laboratory considerations for the rapid detection of carbapenem-resistant Enterobacteriaceae

“…70,71 KPC and some OXA-48 carbapenemases are inhibited by ceftazidime-avibactam, which may be a therapeutic option for strains expressing these enzymes. However, this drug does not have activity against the class B metallo-b-lactamases (such as NDM), 72 and resistance in at least one KPC-producing K. pneumoniae has been described. 73 A few publications propose potential algorithms for treatment of CRE infection based on molecular detection of specific carbapenemases 74 and carbapenem MIC.…”

“…81 Additionally, it is important that surveillance methods be able to distinguish CP-CRE from strains with other mechanisms of carbapenem resistance because more aggressive infection control interventions are recommended for patients colonized with CP-CRE. 72 In control of the Israeli outbreak, those with CP-CRE were isolated and cohorted together while those with non-CPproducing CRE were placed in contact isolation, but were not cohorted. The US.…”

“…CDC recognizes that facilities will vary in their CRE screening processes based on their regional CRE epidemiology, but has issued guidance that CRE screening be considered for patients who have had overnights stays in US facilities with high CRE prevalence, or in overseas healthcare facilities in the prior 6-12 months. 72 Despite this guidance, there remains great variability in CRE screening processes among US institutions. A survey of infectious disease providers and members of the Emerging Infections Network in 2014 found that only 18% of represented institutions performed active surveillance for CRE 82 Whether or not CRE screening is cost effective in settings with low CRE prevalence is unclear.…”

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

“…Unfortunately, TOL/TAZ is not effective against pathogens producing metallo-β-lactamases (MBLs) or Klebsiella pneumoniae carbapenemases (KPCs) [16]. On the contrary, besides its excellent activity against ESBL-producing strains (susceptibility rates over 90% in a series of more than 5000 isolates tested) [17], CAZ/AVI inhibits KPC-producing organisms, thereby broadening the spectrum of ceftazidime to many CRE and Pseudomonas strains [18]. Notwithstanding this difference, the activity spectra of the two new BLBLI combinations overlap [5].…”

Pharmacodynamic and pharmacokinetic considerations in the treatment of critically Ill patients infected with carbapenem-resistant Enterobacteriaceae

“…114 Monte Carlo simulations predict >98% probability of target attainment for ceftazidime-avibactam MICs 8 mg/ml using the standard dose of 2.5 g (2 g ceftazidime, 500 mg avibactam) infused over 2 hours every 8 hours. 111 In critically ill patients it would be expected, based on the hydrophilicity and PK profile, that ceftazidime-avibactam might have lower serum concentrations due to the larger Vd and/or altered renal clearance. 8 There is no data on whether more prolonged or extended infusions of ceftazidime-avibactam beyond the approved 2 hour infusion would improve the PK-PD profile or target attainment rate in this patient population.…”