1960. Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of Short Infusion Ceftazidime/Avibactam (CAZ/AVI) in Patients with Renal Impairment (RI)
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall

Background: CAZ/AVI is a cephalosporin/beta-lactamase inhibitor approved for treatment of resistant gram negative infections. While divided daily dosing with 2-hour extended infusion (EI) is used in patients with moderate RI (modRI, creatinine clearance [ClCr] 30-50 mL/min) & severe RI (sevRI, ClCr 15-30 or 6-15 mL/min], short infusion times would be preferred for convenience and could potentially be used in patients with RI and reduced drug clearance. The study objective was to evaluate PK/PD performance of shorter infusions versus labeled EI in patients with RI.

Methods: CAZ/AVI regimens of 1g CAZ/0.25g AVI Q8H in modRI, and 0.75g/0.19g Q12H or Q24H (depending on ClCr) in sevRI, were evaluated against ESBL & KPC-producing Enterobacteriaceae, multidrug resistant (MDR) & extremely drug resistant (XDR) P. aeruginosa (PsA), and at the approved susceptibility breakpoint using Monte Carlo Simulation (MCS) methods (Oracle Crystal Ball®, 5,000 simulated patients). Regimens were evaluated with infusion times of 2 and 0.5 hrs. PK parameters & MICs for MCS were obtained from the literature. The desired PD target for CAZ was % time above MIC of unbound drug (%fT>MIC) ≥50%, and for AVI was % time above the minimum effective concentration (MEC) of 1 ≥50%, with goal probability of target attainment (PTA) ≥90% for both compounds.

Results: PTAs for CAZ are listed below; PTA for AVI was 100% with all simulated regimens. Regimens administered over 0.5 hr achieved PTAs comparable to EI regimens in patients with modRI & sevRI against all organisms. In patients with sevRI (CLcr 15-30 mL/min), administering the total daily dose as a single dose given over 2 hrs (1.5g/0.38g Q24H) achieved PTA similar to divided-dose regimens at the breakpoint (98% and 100%, respectively); these results were also maintained with 0.5 hr infusions (PTA 96%).

Conclusion: In patients with modRI & sevRI, reduced infusion time of CAZ/AVI achieves PK/PD performance equivalent to standard EI regimens & improves clinical convenience.

 modRI (%)

sevRI (%)

15-30 mL/min

6-15 mL/min

CAZ Dose

Infusion Time (hrs)

1g Q8H

2

1.5g Q8H

0.5

0.75g Q12H

2

0.75 g Q12H

0.5

0.75g Q24H

2

0.75g Q24H

0.5

ESBL producers

≥99

≥99

≥99

≥99

≥99

≥99

KPC producers

98

98

98

97

98

98

MDR PsA

92

91

92

90

80

80

XDR PsA

87

87

86

86

74

72

Breakpoint

100

100

100

100

93

89

Andrea Boyce, PharmD1, Alexander Novin, PharmD, BCPS2, Matthew Miller, PharmD, BCPS1, Gerard Barber, RPh, MPH1 and Douglas N. Fish, PharmD2, (1)University of Colorado Hospital, Aurora, CO, (2)University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO

Disclosures:

A. Boyce, None

A. Novin, None

M. Miller, Actavis: Speaker's Bureau , Speaker honorarium

G. Barber, Merck: Speaker's Bureau , Speaker honorarium

D. N. Fish, None

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