P-1249. Effect of Starting Inoculum and β-lactamase Retention on the Activity of Imipenem/Relebactam (I/R) and Aztreonam (ATM) plus I/R in Hollow Fiber Infection (HFIM) Studies of P. aeruginosa (PSA)

TL;DR

This study compares how different infection model cartridges affect antibiotic effectiveness against P. aeruginosa, focusing on imipenem/relebactam and aztreonam combinations.

Contribution

The study reveals how cartridge pore size influences β-lactamase retention and antibiotic efficacy in pre-clinical models.

Findings

C7011 cartridges showed better bacterial killing for CL 5701 at standard inocula compared to C2011.

High inocula reduced differences in killing between cartridge types for both isolates.

C2011 showed better short-term killing for MB 10480 at high inocula, but C7011 had better long-term results.

Abstract

HFIMs are the gold standard pre-clinical PK/PD model for studying humanized antibiotic exposure-response relationships. Standard HFIM cartridges (Fibercell C2011) use 20 kD MWCO fibers, which retain β-lactamases from lysed bacteria. Newer cartridges (Fibercell C7011) have larger 0.03 µm pores and are less prone to β-lactamase retention. We evaluated whether bacterial killing differs between I/R and I/R + ATM in PSA HFIM studies using C2011 vs. C7011 cartridges.Figure 1.Hollow fiber infection models evaluating bacterial killing against P. aeruginosa CL 5701 at standard (a) and high (b) starting inoculaI/R, imipenem/relebactamFigure 2.Hollow fiber infection models evaluating bacterial killing against P. aeruginosa MB 10480 at standard (a) and high (b) starting inoculaATM, aztreonam; I/R, imipenem/relebactam

Hollow fiber infection models evaluating bacterial killing against P. aeruginosa CL 5701 at standard (a) and high (b) starting inocula

I/R, imipenem/relebactam

Hollow fiber infection models evaluating bacterial killing against P. aeruginosa MB 10480 at standard (a) and high (b) starting inocula

ATM, aztreonam; I/R, imipenem/relebactam

HFIMs using previously described PSA isolates [CL 5701 (constitutive PDC producer, OprD deleted) and MB 14080 (daughter isolate, IMP-1-producer)] were performed. Simulated exposures of the FDA-approved I/R regimen (0.5/0.5/0.25g q6h, 0.5 h infusion) was evaluated against CL 5701 while I/R + ATM (2g q6h, 2 h infusion) was evaluated against MB 14080. Each regimen was tested in duplicate at starting inocula of 6 log10 cfu/mL (standard) and 7.5 log10 cfu/mL (high). Each set of HFIM experiments was performed using paired C2011 and C7011 cartridges (same syringe, DuetTM, and peristaltic pumps for each pair). Changes in bacterial density from baseline were evaluated at hours 24 and 96.

For CL 5701, bacterial killing was limited in the C2011 HFIM at the standard inoculum HFIM studies and regrowth observed after 24 hours. In contrast, bactericidal activity was observed at hours 24 and 96 (-3.53 and -4.55 log10 cfu/mL, respectively) with C7011. In the high inoculum HFIM of CL 5701, no notable differences in killing were observed between cartridges at hours 24 (C2011:-0.74 and C7011: -1.26 log10 cfu/mL) and 96 (-1.05 vs -0.85 log10 cfu/mL). For HFIM of MB10480 at the standard inoculum, bacterial killing was greater in C7011 relative to C2011 at hours 24 (-1.46 vs -2.29 log10 cfu/mL) and 96 (-1.72 vs -2.00 log10 cfu/mL). In high inoculum MB 10480 HFIM studies, killing was greater in C2011 relative to C7011 at hour 24 (-1.27 vs -0.35 log10 cfu/mL), however there was more pronounced killing and less regrowth with C7011 vs C2011 at hour 96 (-0.85 vs -1.76 log10 cfu/mL).

Differences in bacterial killing were apparent when comparing the effect of I/R and I/R+ATM in HFIM of PSA with different infection cartridges, likely due to more β-lactamase retention in less porous standard cartridges (C2011).

J Nicholas O'Donnell, Pharm.D., MSc, Merck and Co., Inc: Grant/Research Support Nicole L. Shakerley, PhD, Merck and Co., Inc: Grant/Research Support Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds (Public Company) Thomas Lodise, Jr., PharmD, PhD, GSK: Advisor/Consultant

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