Infective endocarditis (IE) is a serious infection associated with significant morbidity and mortality. Recent studies demonstrated an increased risk of infective endocarditis in people who inject drugs (PWIDs). PWIDs have a high rate of non-compliance with hospital admissions and leaving against medical advice. A recent landmark randomized controlled trial demonstrated similar outcomes when comparing partial oral antimicrobial therapy to continued intravenous antimicrobial therapy in the general population. Performing a trial to explore the non-inferiority of oral compared to intravenous antimicrobial therapy in PWIDs is essential in advancing patient care in this high risk increasing population.

This is a randomized open-label study. Participants will be randomized 1:1 in blocks of 5 to either continued intravenous antimicrobial therapy or oral antimicrobial therapy after a minimum of 10 days of IV therapy. The antimicrobial choice will be based on antimicrobial susceptibility. All oral regimens for gram-positive organisms will include 2 different agents. Gram-negative pathogens will be treated with oral quinolones if susceptibility results are compatible. Decisions regarding ongoing inpatient or outpatient therapy will be made at the discretion of the attending physician. Outpatient follow up will be once weekly for 6 weeks and then at 3 months. At each follow-up visit, participants will undergo a general physical exam, and their adherence to therapy and general wellbeing will be assessed as well. Blood samples will be sent for a complete blood count, creatinine, C-reactive protein by the investigators to ensure continued improvement in response to therapy. Within 72 hours of stopping therapy, a transthoracic echocardiogram will be performed to determine response to therapy and to establish a new baseline to which subsequent echocardiograms if medically indicated would be compared to assess for relapse or development of a new IE. All lab tests are done at our affiliated hospitals. Investigators plan first on performing a feasibility study. In the feasibility study, investigators recruit a total of 50 patients and randomize 25 in each arm. Baseline characteristics, of clinical interest with a potential impact on prognosis, and patients' outcomes will be compared using the Chi-square test for categorical variables and the t-test and the Mann-Whitney test for continuous variables, when appropriate. To examine the association between oral antimicrobial therapy and 90-day mortality, investigators plan to perform a multivariable logistic regression analysis with oral therapy being the independent variable. The model will also include variables of clinical interest: diabetes, renal impairment, immune-compromising condition, age > 50, and evidence of embolization.

Inclusion Criteria:

1. Adults ≥ 18 years with self-reported intravenous drug use within 3 months of admission
2. Transthoracic and/or transesophageal echocardiogram for IE diagnosis should be done within 48 hours of randomization
3. Patients meet the modified Duke criteria for possible or definite infective endocarditis diagnosis
4. Infection with an organism susceptible to at least two oral antimicrobial agents from different classes. In gram-negative bacterial endocarditis, susceptibility to fluoroquinolones only would be acceptable for inclusion
5. Polymicrobial infections may be enrolled if an acceptable oral regimen can be constructed containing at least 2 agents against each gram-positive organism and one against each gram-negative
6. Fungal Endocarditis may be enrolled if susceptibility to an oral azole is confirmed
7. IE Patients who demonstrate improvement with initial intravenous therapy will be recruited
8. Patients should receive a minimum of 10 days initial IV therapy and should have a minimum of 14 days remaining of their antimicrobial therapy

Exclusion Criteria:

1. Undrained valvular, perivalvular, or cardiac abscess on echocardiogram studies
2. Failure to show improvement to initial intravenous antimicrobial therapy
3. Oral antibiotic malabsorption due to gastrointestinal disorders
4. Acutely intoxicated patients who are not able to provide informed consent