Avibactam Pharmacokinetic/Pharmacodynamic Targets

  • Wright W. Nichols, Paul Newell, Ian A. Critchley, Todd Riccobene, Shampa Das
  • Antimicrobial Agents and Chemotherapy, April 2018, ASM Journals
  • DOI: 10.1128/aac.02446-17

Understanding the pharmacodynamics of a clinically-used β-lactamase inhibitor, avibactam

What is it about?

The paper describes how quantitative PK/PD "targets" were deduced from preclinical experiments that enabled human pharmacokinetic simulations to predict the achievement of efficacious antibacterial activity in patients that would be yielded by different dosing regimes of 3 β-lactam/avibactam (a β-lactamase inhibitor) drug combinations: ceftazidime (a cephalosporin β-lactam)/avibactam, aztreonam (a monobactam β-lactam)/avibactam, and ceftaroline fosamil (a further cephalosporin β-lactam)/avibactam.

Why is it important?

The work was a key step in preparing for clinical trials of ceftazidime/avibactam, aztreonam/avibactam, and ceftaroline fosamil/avibactam. These drugs overcome many important β-lactamase-mediated resistances to ceftazidime, aztreonam, and ceftaroline fosamil in the Gram-negative bacteria, Pseudomonas aeruginosa and the Enterobacteriaceae.

Perspectives

Wright Nichols
Consultant Microbiologist

This drug combination, ceftazidime/avibactam, was the first drug to be licensed that included one of a new set of β-lactamase inhibitors. Since the previous clinical development of a β-lactamase inhibitor, antibacterial PK/PD has progressed a great deal. However the PK/PD of a β-lactam combined with a β-lactamase inhibitor had not been studied at all. Thus the work described in this paper was pioneering.

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http://dx.doi.org/10.1128/aac.02446-17

The following have contributed to this page: Wright Nichols