1546. Efficacy of Daptomycin Combinations Against Daptomycin-Resistant Enterococcus faecium Differs by β-lactam

BACKGROUND: We have previously demonstrated that daptomycin (DAP) combinations with β-lactams offer enhanced bactericidal activity and prevent the emergence of resistance in Enterococcus faecium infections. Although the mechanisms of DAP resistance in enterococci are not fully comprehended, they are associated with alterations in cell envelope phospholipids assembly which leads to either repulsion of the drug from cell exterior or diversion from the cell septum. In this context, we sought to evaluate combinations of DAP with a panel of β-lactams including ampicillin (AMP), amoxicillin (AMX), ceftaroline (CPT), ceftriaxone (CRO) and ertapenem (ERT). METHODS: E. faecium R497 harboring liaSFR mutations (DAP MIC of 16 mg/L) was evaluated in a simulated endocardial vegetation (SEV) pharmacokinetic and pharmacodynamic model over 336 h at a starting inoculum of 10(9) log(10) CFU/g. DAP 10 mg/kg/day combinations with AMP, AMX (2 g continuous infusion), CPT 600 mg q 12 h, CRO 2g q 24 h or ERT 1 g q 24 h were evaluated. The emergence of DAP resistance was determined daily over the course of treatment. RESULTS: DAP alone was not bactericidal and high-level DAP resistance was observed (MIC increase from 16 to 64 µg/mL). Combination of DAP+AMP offered a significant reduction in log(10)CFU/g amounts (Up to 7 log(10) CFU/g and to detection limits) in 24h in with no emergence of DAP resistance. DAP 10+ AMX caused 6–6.5 log(10) CFU/g reduction and counts were maintained around the detection limit while demonstrating no increased resistance. Dose de-escalation with AMP indicated that even DAP 4 mg/kg/d with AMP (2g) combination, reached detection limit at 168 h with no further resistance. None of the CPT, CRO or ERT regimens in combination with DAP was effective against R497 and elevated DAP MICs (>64 µg/mL) was observed during the 14-day model. CONCLUSION: Combination of DAP+AMP offered the most encouraging results against E. faecium R497, while DAP+AMX caused enhanced reduction. The reason for this discrepancy in various β-lactam activity may be related to diverse β-lactam targeting or affinity toward PBP proteins. Further dissection of our observations is warranted to understand the optimized DAP-β-lactam combination and consequently improve patient outcomes and prevention of resistance. [Image: see text] [Image: see text] [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures.