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

Ceftazidime-avibactam (CAZ/AVI) combines ceftazidime with a diazabicyclooctane non-beta-lactam beta-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 Kiebsiella pneurnoniae 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 10(9) 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.