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*I recently completed my postdoctoral training fellowship and no longer have access to the email previously used (joella.adams@bmc.org <joella.adams@bmc.org>). Please use this email or my new organizational email (jadams@rti.org <jadams@rti.org>) for any correspondence. Thank you for your understanding. * *ABSTRACT* *Background:* The incidence of drug-use associated infective endocarditis (DUA-IE) is rising and posing significant costs on the healthcare system. Alternative treatment strategies that shorten hospitalizations such as outpatient parenteral antimicrobial therapy (OPAT) and partial oral antibiotics (PO) may be as effective as the standard of care (prolonged hospitalization for intravenous antibiotics [IVA]) while also decreasing healthcare utilization costs. We evaluated long-term healthcare costs associated with four antibiotic treatment strategies for DUA-IE. *Methods*: We used a microsimulation model to perform a cost analysis of the following DUA-IE treatment strategies: 1) 4-6 weeks of inpatient IVA along with opioid detoxification, *status quo *(*SQ*); 2) 4-6 weeks of inpatient IVA along with inpatient addiction care services (ACS) (*SQ with ACS*); 3) 3 weeks of inpatient IVA with ACS followed by OPAT (*OPAT*); and 4) 3 weeks of IVA with ACS followed by PO antibiotics (*PO)*. We derived costs from the Federal Supply Schedule, Physician Fee Schedule, and claims data. Patients were eligible for OPAT either at home or in post-acute care. We estimated life expectancy (LE) and total- and per-person inpatient and outpatient costs ($US) from the payer perspective. *Results*: The *SQ *scenario resulted in an average LE of 73.31y at a total lifetime cost of $416,800/person, hospitalization costs = $14,000/person and outpatient costs = $40,000/person. Both PO and OPAT substantially decreased hospitalization costs compared to SQ: -$8,600/person (OPAT) and -$5,500/person (PO) but did not significantly increase outpatient costs (+$200-700/person). Compared to SQ, total lifetime costs were lower for OPAT ($412,300/person) and PO ($414,000/person), but higher for SQ with ACS ($417,000/person). Compared to *SQ, *LE was extended in the other strategies: 73.36 in *SQ with ACS*, 73.34 in *OPAT*, and 73.37 in *PO*. *Conclusion*: Treating DUA-IE with OPAT or PO may decrease total lifetime and hospitalization costs while simultaneously extending LE. *Funding: *This work was supported by the National Institute on Drug Abuse (JAB, AS: K01DA051684, JAB: DP2DA051864) and the National Institute of Allergy and Infectious Diseases (JA, RJ:T32-AI052074, BPL: R01DA046527, P30DA040500).
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