1986. Ceftazidime-Avibactam Combats KPC-2 and KPC-3-Producing Klebsiella pneumoniae ST258: New Pharmacodynamic Insights into the Next Generation of β-lactam/β-lactamase Inhibitors
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall

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.

 

 

 

 

 

 

 

 

 

 

Zackery Bulman, Pharm.D.1, Michael Satlin, MD2, Barry N. Kreiswirth, PhD3, Liang Chen, PhD4, Justin Lenhard, Pharm.D.1, Nicholas Smith, Pharm.D.1, Patricia Holden, B.S.1 and Brian T. Tsuji, Pharm.D.1, (1)University at Buffalo, SUNY, Buffalo, NY, (2)New York-Presbyterian, New York, NY, (3)Public Health Research Institute, Rutgers New Jersey Medical School, Newark, NJ, (4)Public Health Research Institute, Rutgers University, Newark, NJ

Disclosures:

Z. Bulman, None

M. Satlin, Allergan: Grant Investigator , Grant recipient

B. N. Kreiswirth, None

L. Chen, None

J. Lenhard, None

N. Smith, None

P. Holden, None

B. T. Tsuji, None

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