1114. Exploring bactericidal activity and emergence of resistance for carbapenem-resistant Enterobacterales (CRE) with and without Klebsiella pneumoniae carbapenemase (KPC) treated with optimized meropenem (MEM) and meropenem-vaborbactam (MEV) exposures
Authors: Squires Kevin M , Kline Ellen G , Jones Chelsea , Shields Ryan K 
Published: November 2023

Abstract

Background
KPC producing CRE are common in the US; however non-carbapenemase producing (CP) CRE are as common. KPC- and non-CP Escherichia coli (ECOL) and Enterobacter cloacae complex (ENTCC) demonstrate a range of MEM MICs. The objective of this study was to assess the in vitro killing activity of dose-optimized MEM against CRE with or without KPC that demonstrate variable MEM MICs and to determine if vaborbactam potentiates the killing activity of MEM against non-CP CRE.

Methods
8 ECOL and 8 ENTCC were characterized by whole-genome sequencing (Table); isolates demonstrated MEM MICs ranging from 1 to 8 mg/L. MEM standard (1g q8h over 30 minutes) and optimized (2g q8h over 3 hours) regimens were tested in 1-compartment and hollow fiber infection models (HFIM); targeted exposures were confirmed by LC-MS/MS. In HFIM, MEV (4g q 8h over 3 hours) was also tested. Resistant subpopulations were selected by agar plates containing MEM at 4x baseline MIC.

Results
Standard MEM regimens were largely not bactericidal against ECOL (Figure 1) or ENTCC (Figure 2). Bacterial regrowth occurred more rapidly against KPC compared to non-CP isolates. For MEM optimized regimens, 72-hour log-kills decreased as MEM MICs increased against non-CP ECOL; optimized MEM regimens were not bactericidal against KPC ECOL with MICs ≥2 mg/L. For ENTCC, optimized MEM resulted in greater log-kills against non-CP than KPC isolates at each MIC level. Across all non-CP and KPC isolates with MEM MICs ≤2 mg/L (n=4 each), mean log-kills at 72 hours with optimized MEM were -4.43 and -0.26 logs, respectively (P=0.04). Colonies selected on MEM containing agar demonstrated a median (range) MEM MIC of 64 mg/L (16 – &gt;256 mg/L). Next, we compared optimized MEM and MEV in 10 day HFIMs against isolates with MEM MICs of 4mg/L. MEV demonstrated potent bactericidal killing against KPC isolates. Unexpectedly, MEV was also bactericidal against both non-CP isolates, and potentiated MEM killing against ECOL0174 (Figure 3).Figure 1.Log-growth of clinical CR ECOL exposed to humanized meropenem exposures during 72 hour 1-compartment study.
Standard dosing MEM 1g q8h, 30 minute infusion (red). Optimized dosing MEM 2g q8h, 3 hour infusion (green). Limit of detection is 0.7 log colony forming units (CFU)/mL, denoted by dashed line. BMD = broth microdilution. KPC = Klebsiella pneumoniae carbapenemase.Figure 2.Log-growth of clinical CR ENTCC exposed to humanized meropenem exposures during 72 hour 1-compartment study.
Standard dosing MEM 1g q8h, 30 minute infusion (red). Optimized dosing MEM 2g q8h, 3 hour infusion (green). Lower limit of detection is 0.7 log CFU/mL, denoted by dashed line. BMD = broth microdilution. KPC = Klebsiella pneumoniae carbapenemaseFigure 3.Log-growth of clinical CR ECOL and ENTCC (meropenem MIC=4mg/L) exposed to humanized exposures of meropenem and meropenem-vaborbactam in 10 day hollow fiber infection model.
Standard dosing meropenem 1g q8h, 30 minute infusion (red). Optimized dosing meropenem 2g q8h, 3 hour infusion (green), or meropenem-vaborbactam 4g q8h, 3 hour infusion (purple). Lower limit of detection is 0.7 log CFU/mL. MIC = minimum inhibitory concentration.

Conclusion
Our data show in vitro killing of CR ECOL and ENTCC is dependent on MEM MICs and presence of KPC. Even at low MICs, optimized MEM exposures were ineffective against KPC isolates. Against non-CP CRE, killing decreases as a function of increased MEM MIC. MEV may play an additive role in killing against non-CP isolates that are not killed by MEM alone.

Disclosures
Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support