Pharmacodynamics of Ceftazidime plus Avibactam against KPC-2-Bearing Isolates of Klebsiella pneumoniae in a Hollow Fiber Infection Model.

Abstract

Ceftazidime-avibactam (CAZ/AVI) combines ceftazidime with a diazabicyclooctane non-β-lactam β-lactamase inhibitor. This has potent inhibitory activity against KPC-type enzymes. We studied activity of clinically relevant regimens of CAZ/AVI against two KPC-2-bearing Klebsiella pneumoniae isolates (sequence type 258 recovered sequentially from the same patient) with and without ompK36 mutations in a hollow fiber infection model. The baseline total bacterial burden exceeded 109 CFU. For both isolates, there was early multi-log CFU/ml reductions in the bacterial burden for all regimens. Bacterial subpopulations with reduced susceptibilities to CAZ/AVI were isolated only from the no-treatment control arms. All CAZ/AVI regimens resulted in undetectable colony counts between days 6 and 8. At day 10, the total volume of each CAZ/AVI arm was plated, with no organisms recovered from any regimen, documenting complete eradication. A population model was fit to avibactam concentrations and total colony count outputs. The model fit was acceptable and demonstrated a large kill rate constant (Kkill = 6.29 h-1) and a relatively low avibactam concentration at which kill rate was half maximal (C50 = 2.19 mg/liter), concordant with the observed bacterial burden decline. A threshold analysis identified time > 4 mg/liter of avibactam as the index most closely linked to bacterial burden decline. Given the clinical outcomes seen with KPC-bearing organisms and the toxicities that occur when patients are treated with currently available polymyxins, drugs such as CAZ/AVI should have a prominent place in early therapy.

• Authors: G L Drusano, Ryan K Shields, Nino Mtchedlidze, M Hong Nguyen, Cornelius J Clancy, Michael Vicciarelli, Arnold Louie
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 63 Issue 8 (08 2019) ISSN: 1098-6596 [Electronic] United States
• PMID: 31160285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Society for Microbiology.

Chemical References

• Anti-Bacterial Agents
• Azabicyclo Compounds
• Bacterial Proteins
• Drug Combinations
• avibactam, ceftazidime drug combination
• avibactam
• Ceftazidime
• beta-lactamase KPC-2
• beta-Lactamases

Topics

• Anti-Bacterial Agents (pharmacology)
• Azabicyclo Compounds (pharmacology)
• Bacterial Proteins (metabolism)
• Carbapenem-Resistant Enterobacteriaceae (drug effects, metabolism)
• Ceftazidime (pharmacology)
• Drug Combinations
• Humans
• Klebsiella Infections (drug therapy, metabolism)
• Klebsiella pneumoniae (drug effects)
• Microbial Sensitivity Tests (methods)
• beta-Lactamases (metabolism)