Background: Infections caused by KPC-producing K. pneumoniae (KPC-Kp) result in unacceptably high rates of morbidity and mortality, highlighting the need for new active antimicrobial agents. Ceftazidime-avibactam (CAZ-AVI) is a promising option for these infections as KPC-Kp susceptibility rates to this agent are high, however data assessing the rate and extent of bactericidal activity of CAZ-AVI against clinical KPC-Kp isolates are limited.
Methods: Nine CAZ-AVI susceptible (MIC range: 0.125-1 mg/L) ST258 KPC-Kp bloodstream isolates (5 KPC-2 and 4 KPC-3), with varying carbapenem MICs, were investigated. In vitro 24h time-kill experiments were employed to assess the pharmacodynamic activity of CAZ-AVI at a 106 CFU/mL starting inoculum after 0, 1, 2, 4, 6, 8, and 24 hours incubation. The two-fold CAZ-AVI concentration array implemented for the time-kills (160-30, 80-15, 40-7.5, and 20-3.75 mg/L) was anchored around an approximate free maximum concentration (fCmax) of 80-15 mg/L attained in humans after a 2,000-500mg dose. Bactericidal activity was defined as a ≥3 log10CFU/mL reduction of bacterial counts and the log ratio area was calculated to evaluate cumulative pharmacodynamic activity.
Results: CAZ-AVI achieved rapid bactericidal activity against all KPC-Kp isolates after 2 to 6 hours at all tested concentrations, which was maintained through 24 hours. Specifically, for the fCmax CAZ-AVI concentration of 80-15 mg/L, bactericidal activity was achieved by 2 hours for 66.7% (6/9) of isolates, including one resistant to polymyxin B. Eradication was achieved at 24 hours for 77.8% (7/9) isolates. Maximal bacterial reductions ranged between -3.24 and -6.45 log10CFU/mL at 6 hours and -4.18 and -6.56 log10CFU/mL after 24 hours. When the log ratio areas were calculated for each strain, CAZ-AVI killing did not differ significantly (p>0.05) between KPC-2 (mean: -4.24) and KPC-3 (mean: -4.34).
Conclusion: Despite an 8-fold range on the CAZ-AVI concentrations, nearly indistinguishable bacterial killing profiles were observed for all strains even with varying MICs and coproduction of different β-lactamases. Ceftazidime-avibactam displayed highly efficient pharmacodynamic activity against KPC-2 and KPC-3 bloodstream isolates.
B. N. Kreiswirth, None
L. Chen, None
J. Lenhard, None
N. Smith, None
P. Holden, None
B. T. Tsuji, None
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