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Pharmacodynamics of Ceftazidime plus Avibactam against KPC-2-Bearing Isolates of Klebsiella pneumoniae in a Hollow Fiber Infection Model.
Antimicrob Agents Chemother. 2019 08; 63(8)AA

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 (K kill = 6.29 h-1) and a relatively low avibactam concentration at which kill rate was half maximal (C 50 = 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+Show Affiliations

Institute for Therapeutic Innovation, University of Florida, Gainesville, Florida, USA gdrusano@ufl.edu.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Institute for Therapeutic Innovation, University of Florida, Gainesville, Florida, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Institute for Therapeutic Innovation, University of Florida, Gainesville, Florida, USA.Institute for Therapeutic Innovation, University of Florida, Gainesville, Florida, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31160285

Citation

Drusano, G L., et al. "Pharmacodynamics of Ceftazidime Plus Avibactam Against KPC-2-Bearing Isolates of Klebsiella Pneumoniae in a Hollow Fiber Infection Model." Antimicrobial Agents and Chemotherapy, vol. 63, no. 8, 2019.
Drusano GL, Shields RK, Mtchedlidze N, et al. Pharmacodynamics of Ceftazidime plus Avibactam against KPC-2-Bearing Isolates of Klebsiella pneumoniae in a Hollow Fiber Infection Model. Antimicrob Agents Chemother. 2019;63(8).
Drusano, G. L., Shields, R. K., Mtchedlidze, N., Nguyen, M. H., Clancy, C. J., Vicciarelli, M., & Louie, A. (2019). Pharmacodynamics of Ceftazidime plus Avibactam against KPC-2-Bearing Isolates of Klebsiella pneumoniae in a Hollow Fiber Infection Model. Antimicrobial Agents and Chemotherapy, 63(8). https://doi.org/10.1128/AAC.00462-19
Drusano GL, et al. Pharmacodynamics of Ceftazidime Plus Avibactam Against KPC-2-Bearing Isolates of Klebsiella Pneumoniae in a Hollow Fiber Infection Model. Antimicrob Agents Chemother. 2019;63(8) PubMed PMID: 31160285.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacodynamics of Ceftazidime plus Avibactam against KPC-2-Bearing Isolates of Klebsiella pneumoniae in a Hollow Fiber Infection Model. AU - Drusano,G L, AU - Shields,Ryan K, AU - Mtchedlidze,Nino, AU - Nguyen,M Hong, AU - Clancy,Cornelius J, AU - Vicciarelli,Michael, AU - Louie,Arnold, Y1 - 2019/07/25/ PY - 2019/03/01/received PY - 2019/05/24/accepted PY - 2019/6/5/pubmed PY - 2020/5/21/medline PY - 2019/6/5/entrez KW - KPC beta-lactamase KW - hollow fiber infection model KW - pharmacodynamics JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 63 IS - 8 N2 - 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 (K kill = 6.29 h-1) and a relatively low avibactam concentration at which kill rate was half maximal (C 50 = 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/31160285/Pharmacodynamics_of_Ceftazidime_plus_Avibactam_against_KPC_2_Bearing_Isolates_of_Klebsiella_pneumoniae_in_a_Hollow_Fiber_Infection_Model_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=31160285 DB - PRIME DP - Unbound Medicine ER -