1563. Population Pharmacokinetics and Pharmacodynamics of Daily and Extended Interval Dalbavancin Dosing Regimens for Salvage Therapy of Staphylococcus aureus Endocarditis: Mechanistic Modeling of Rabbit Infection Data to Support Human Dosing Regimens

Abstract Background Dalbavancins’ (DAL) long half-life and favorable susceptibility profile makes it an attractive option for salvage therapy for endocarditis caused by Staphylococcus aureus (SA), including those with elevated vancomycin (VAN) MIC. The aim of our study was to establish the PKPD of DAL based on a rabbit model of infection and extrapolate those results to the design of human treatment regimens. Methods Data from a rabbit endocarditis model of SA with VAN MICs of 2 and 8 mg/L were fitted using an inoculum-size dependent model and the Pmetrics software. Then, the results were linked to a human PK model to simulate regimens with or without a loading dose. Probability of target attainment (PTAs) for achieving bacterial density of <2 log CFU per gram of vegetation was compared with outcomes based on standard antibiotic therapy (SAT) at 3, 10, 21, 31, and 42 days. Results Mean (SD) PTAs of 34.3% (10.5%), 61.3% (7.0%), 73.5% (5.4%), 79.5% (4.3%), and 83.1% (3.4%) were estimated for all regimens combined with maximum PTAs of 41.8%, 63.6%, 77.8%, 86.6%, and 88.9% for the highest weekly dose at 3, 10, 21, 31 and 42 days of therapy, respectively. While all approaches should achieve an adequate probability of clearing of the colonies by day 21, only doses near 2,000 mg/week are likely to approximate sterilization rates similar to that expected by the SAT at day 42. We observed no meaningful differences in PTAs for weekly vs. daily dosing given with a load. Also, increasing the total weekly dose over 2,000 mg seems to offer minimal additional benefit (Figure 1A–D). Trough-level accumulation is expected as total weekly doses increase, showing a median (IQR) of 62.6 (73.1,85.2) [101.8 (89.9,117.4)] mg/L and 106.5 (91.63,123.6) [135.3 (118.3,156.0)] mg/L at 42 days for the 1,000 mg and 1,500 mg weekly [in equal daily fractions] doses, respectively. Conclusion Our design suggests that these DAL dosing regimens in humans are likely to provide reasonable rates of sterilization when treating endocarditis caused by SA isolates, and administration of near 2,000 mg weekly doses may be considered to improve upon sterilizing effect, but at the cost of accumulating DAL levels. Efficacy and safety of new regimens should be confirmed in well-controlled clinical trials. Disclosures All authors: No reported disclosures.