P-1260. Beyond Plasma: Defining the Translation Value of Epithelial Lining Fluid Exposure Profiles for the Treatment of Pneumonia
Abstract
Abstract Background Pharmacodynamic (PD) targets based on plasma exposure are commonly used for pneumonia (PNA). However, the exposure required in plasma may differ at the target site of infection when considering drug penetration. This study defined plasma and pulmonary epithelial lining fluid (ELF) PD targets for meropenem (MEM), cefiderocol (FDC), levofloxacin (LVX), and tobramycin (TOB) against a challenge set of Klebsiella pneumoniae (KP) in a preclinical PNA model, and assessed the predicted CFU/lung response of average human exposures relative to susceptible, intermediate, and resistant (SIR) MICs.Table 1. Phenotypic and genotypic information of Klebsiella pneumoniae isolates FDC, cefiderocol; LVX, levofloxacin; MEM, meropenem; MIC, minimum inhibitory concentration; TOB, tobramycinTable 2. Plasma and ELF exposure targets in Klebsiella pneumoniae Methods To provide a robust PD profile in both plasma and ELF, two dosing regimens per antibiotic were administered to neutropenic mice infected with 17 KPs (Table 1) following the COMBINE murine PNA protocol. Efficacy was evaluated as change in log10 CFU/lung at 24 h. Emax models were fitted to composite CFU data for each antibiotic, and plasma and ELF exposures required (%fT >MIC, fAUC/MIC, fCmax/MIC) for stasis, 1- and 2-log10 reduction were calculated using the Hill equation. The average human plasma and ELF exposures achieved with MEM 2 g q8h over 3 h infusion, FDC 2 g q8h over 3 h infusion, LVX 750 mg q24h, and TOB 7…
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