1553. Human-Simulated Pharmacokinetic Profiles of Cefiderocol and Meropenem Are Conserved in Murine Models of Thigh Infection With or Without Iron Overload

Abstract

BackgroundA translational murine model of thigh infection with comorbid iron overload was previously developed to study the efficacy of iron-dependent siderophore-antibiotic conjugates under conditions where the hypoferremic response of innate immunity may be compromised. Given the potential for functional organ damage from excessive tissue iron, which could alter the pharmacokinetic (PK) profiles of antibiotics being compared for efficacy using this model, the effects of iron overload on a siderophore-β-lactam conjugate, cefiderocol (CFDC), and a non-siderophore β-lactam, meropenem (MEM), were studied.MethodsFemale CD-1 mice received iron dextran (Fe-D) 100 mg/kg intraperitoneally for 14 days as previously shown to produce vastly supranormal iron concentrations in serum, liver, and spleen (ASM Microbe 2019 abstract HMB-373). Age-matched control mice were not dosed with Fe-D. Mice were rendered neutropenic. On day 15, both thighs of iron-overloaded and control mice were inoculated intramuscularly with Acinetobacter baumannii suspensions of 107 CFU/mL. Two hours after inoculation, mice in each model were dosed with previously developed human-simulated regimens (HSR) of CFDC or MEM simulating human PK profiles after doses of 2g q8h (3 hours infusion) for both drugs. At 4 time points per regimen, 6 mice per model were sacrificed for blood collection. Plasma total MEM and CFDC concentrations were measured with HPLC and LC-MS-MS, respectively. Free concentrations were calculated with murine protein binding. At each time point, mean free concentrations in both models were compared using Student’s t-test.ResultsObserved murine-free plasma concentrations ± 95% CI of CFDC and MEM are overlaid with simulated human and murine profiles in the figure. In both models, these regimens approximated human exposures after clinical doses. For all time points and both drugs, concentrations were not significantly different (P > 0.05) between models with or without iron overload.ConclusionIron overload did not significantly alter PK profiles of a siderophore-β-lactam conjugate, CFDC, or a non-siderophore β-lactam, MEM. These data support the use of CFDC and MEM HSR for pharmacodynamic studies utilizing both iron-overloaded and standard murine thigh infection models. Disclosures All authors: No reported disclosures.