2026 AHA Endocarditis Guidelines Expand Outpatient Antibiotic Options

Infective endocarditis is uncommon, affecting 3 to 10 of every 100,000 individuals each year, but its mortality rate of up to 30% makes proper recognition and treatment critical.¹ Historically, even patients who survived often experienced long-term, and sometimes lifelong, complications from acute illness. The aging population and increased use of implantable devices and artificial valves have changed the epidemiology of the infection, while advances in new medications and a better understanding of how to optimize older agents have shifted the approach to endocarditis care.

In early September 2026, the American Heart Association (AHA) published a long-awaited update to the American guidelines for endocarditis.² Although the European Society of Cardiology (ESC) published an update to its guidelines in 2023 and a nonaffiliated international group of health care professionals published a consensus statement that same year, the American guidelines had not been revised in 11 years.^3-5 Rather than offering subtle changes to the management of an infection that remains difficult to study, the panel took an intentional approach that resulted in fundamental changes to the therapeutic approach to endocarditis.

One of the most notable changes is the increased emphasis on outpatient antibiotics, either as an oral regimen to complete the long treatment course or as a 2-dose series of a long-acting lipoglycopeptide. This shift affords clinicians with minimal previous involvement in the acute treatment of endocarditis a more prominent role within the health care team during active treatment.²

Outpatient Completion Becomes a Larger Part of Endocarditis Care

The use of initial high-dose intravenous (IV) antibiotics targeted based on pathogen, susceptibility, and patient valve type remains foundational to endocarditis management. All patients will need to start antimicrobial therapy in the hospital.² Gram-positive organisms account for approximately 80% to 90% of cases.¹ For select patients, however, the 2026 AHA guidelines create a clearer pathway to complete therapy outside the hospital.

The guidelines offer more patients with gram-positive infections, as well as selected patients with other etiologies, the opportunity to complete treatment in an outpatient setting when pathogen, regimen feasibility, clinical stability, and source-control considerations are appropriate.²

Many patients with native-valve disease caused by staphylococci, streptococci, or HACEK organisms require 4 weeks of antibiotics, whereas prosthetic-valve infection and infections caused by other pathogens, including enterococci, generally require 6 weeks of antimicrobial therapy. For patients with bacteremia, the treatment-duration count begins on the first day that repeat blood cultures document clearance.² In most infections, negative cultures might indicate a test of cure, but vegetations provide a protective environment for microorganisms, and clearance of bacteremia simply indicates that the patient is responding to initial IV antibiotics.

In practice, the total treatment period often extends beyond 4 to 6 weeks for the average patient, a reality that has not changed from previous guidelines. Patients would not be expected to be discharged until bacteremia has cleared, they are clinically stable, and there is strong evidence of infection response to initial treatment.^2,6 However, when these factors are present, much of the remaining treatment period may be completed in a more comfortable and flexible environment. Additionally, the use of oral or long-acting injectable antibiotics is estimated to prevent 10% to 60% of IV-related adverse events, reduce the need for medication-related procedures, improve anxiety and depression related to infection, and reduce overall health care costs.^6-8

Not Every Patient Is a Candidate

The evidence supporting outpatient completion strategies is practice-changing, but it does not apply to every patient with endocarditis. Multiple studies published in recent years support the shift away from the historical approach of weeks of IV antibiotics.^6,9,10

The guideline notes important evidence gaps for some groups, including patients with vancomycin-resistant Enterococcus faecium or prosthetic-valve staphylococcal infection, which limits recommendations for oral or long-acting lipoglycopeptide approaches in these settings. For patients whose endocarditis is caused by another pathogen, the decision to transition away from daily IV antimicrobials depends on patient access, adherence reliability, regimen feasibility, and other patient- and drug-specific variables (Table).² Patients for whom oral or lipoglycopeptide antibiotics are not desirable or feasible will have to complete the entire 4 to 6 weeks with an IV agent. However, these patients may still be able to complete treatment outside the hospital, particularly if the regimen can be simplified to once- or twice-daily administration when clinically appropriate, such as with daptomycin or IV or oral linezolid.

Partial Oral Therapy: Evidence, Eligibility, and Medication-Safety Considerations

The transition to oral therapy, termed partial oral therapy (POT), is recommended based on the 2019 Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis (POET) study. In POET, 400 stable adults with left-sided gram-positive endocarditis and a body mass index (BMI) less than 40 kg/m² were randomly assigned to oral antibiotic treatment or continued IV treatment. Oral therapy was noninferior for the composite outcome of all-cause mortality, unplanned cardiac surgery, embolism, or bacteremia relapse from randomization through 6 months following treatment completion (12.1% vs 9.0%; 95% CI, −3.4% to 9.6%; P = .40).⁹ With long-term follow-up (mean, 5.4 years), mortality was significantly lower in patients transitioned to POT (23.4% vs 35.2%; HR, 0.65; 95% CI, 0.44-0.96).⁶ Importantly, all patients in POET were required to complete at least 10 days of IV antibiotics after bacteremia clearance before being switched to an oral regimen.

The retrospective ENDO-ORAL study enrolled 333 patients, including patients with characteristics that would have excluded them from POET, such as earlier oral transition, obesity, or other exclusion criteria, and found that oral therapy resulted in more days alive and out of the hospital (59 vs 57; P = .001) and no excess in adverse events (20.0% vs 14.6%; P = .22).¹⁰ Outcomes were consistent across groups who would have been excluded from the POET study, except for those with early IV-to-oral transitions, in whom treatment failure was higher (27.8% vs 6.1%; P = .006).¹⁰ Accordingly, the 2026 AHA guidelines recommend a minimum of 10 days of IV antibiotics after bacteremia clearance, as required in the POET study.² Some patients may be able to receive therapy out of the hospital throughout those 10 days, but variables such as affordability and administration logistics may delay discharge for others. A major practical advantage of POT is the potential for a shorter hospital stay.

One retrospective study involving 4748 patients with first-time endocarditis before or after POET publication found an overall 8-day reduction in hospital stay (41 vs 33 days; P < .001), with similar reductions across age groups and microbiological etiologies.¹¹ The same study also showed a significant decrease in bacteremia relapse within 6 months (3.5% vs 1.6%; P < .001). Guideline-recommended POT regimens for gram-positive endocarditis use 2-drug, pathogen-specific combinations to ensure adequate antibiotic penetration into the vegetation while minimizing the risk of emergent resistance.^2,6,9 Some of the recommended regimen components may be unexpected in the endocarditis setting, and individual agents may pose practical challenges that should be considered for each patient. Of the 11 unique combinations, 7 include rifampin; 5 include linezolid, moxifloxacin, or both; and all include at least 1 of the 3.

Pharmacist-led drug interaction screening is particularly important because these therapies are used for extended durations and several recommended agents have a high potential for clinically significant interaction-related complications. Equally important is remembering to readjust any medication modifications once the antibiotic course is completed. The risk of serotonin syndrome should be carefully weighed in any patient for whom linezolid is contemplated. For patients already receiving serotonergic medications, a β-lactam allergy and/or infection with methicillin-resistant staphylococci or β-lactamase–producing enterococci may limit the ability to use POT safely, because all available regimens in those scenarios include linezolid.

Although levofloxacin is recommended for POT for certain gram-negative endocarditis cases, only moxifloxacin should be used for streptococcal or enterococcal infections because of concerns for in vivo resistance mutations with other fluoroquinolones.⁶ Clinicians should be aware of and monitor for adverse events that become strong concerns when these agents are administered for the extended durations required for endocarditis. These include, but should not be limited to, hematologic and electrolyte abnormalities with linezolid and cardiovascular and tendon risks with moxifloxacin.⁶ Ironically, rifampin is known to decrease linezolid blood concentrations, yet the combination is recommended repeatedly for gram-positive endocarditis with the caveat that therapeutic monitoring of linezolid may be required. Unfortunately, samples can be processed at only a few select laboratories in the US, and the added cost may be financially prohibitive for patients.

Patient and caregiver counseling is also essential. Patients should be counseled that rifampin can stain contact lenses and turn body fluids a red-orange tint before they become concerned that they are crying, urinating, or sweating blood. Dicloxacillin and clindamycin both require administration with a full glass of water, and the patient should remain upright after each dose to prevent esophageal irritation. Generally, pharmacokinetics are thought to be acceptable for recommended oral agents, but dicloxacillin’s 49% bioavailability and high protein binding require it to be administered on an empty stomach, which may be challenging with its 4-times-daily dosing.⁶

Long-Acting Lipoglycopeptides Offer Another Outpatient Pathway

Although POT offers a substantial treatment advancement, many clinically stable patients will not qualify or may face barriers to oral therapy. Additionally, the long-term IV access necessary for daily IV antibiotics, either preceding POT or for the entire duration of endocarditis treatment, can be difficult or undesirable in select patients. The 2026 AHA endocarditis guidelines incorporate practice-changing recommendations for the use of 2 long-acting lipoglycopeptides—dalbavancin and oritavancin—that open an opportunity for outpatient treatment following bacteremia clearance for patients who otherwise may require prolonged hospitalization for no other reason than to complete their antibiotic course.²

These agents have a mechanism distantly similar to vancomycin and a half-life in excess of 200 hours; their 2-dose regimens, administered 8 days apart, can provide prolonged drug exposure that may support completion of a 6-week treatment course.^2,12

Both agents have potent activity against gram-positive bacteria, though only oritavancin has activity against some vancomycin-resistant enterococci.^2,12 Some data suggest dalbavancin is active against gram-positive biofilms, which would be particularly helpful in patients with prosthetic valves, but more studies are needed to confirm this finding.^2,13 This is an important distinction from POT. In selected clinically stable patients with documented bacteremia clearance and evidence of response to initial therapy, long-acting lipoglycopeptides may allow transition away from daily IV therapy without the 10-day post-clearance IV lead-in required before POT.² For many patients, this may mean that they can be discharged from the hospital sooner because the daily IV antibiotic regimen can be stopped.

The Dalbavancin as an Option for Treatment of Staphylococcus aureus Bacteremia (DOTS) study found that use of dalbavancin compared with standard IV therapy in S aureus bacteremia resulted in a 47.7% higher probability of a more desirable day 70 outcome based on a hierarchical composite end point (95% CI, 39.8%-55.7%), with noninferior clinical efficacy (difference, 1%; 95% CI, −11.5% to 13.5%) and no difference in safety.¹⁴ Other published studies support the efficacy and safety of lipoglycopeptide use in endocarditis, though dalbavancin has been evaluated in more patients. Overall, dalbavancin and oritavancin have fewer safety and interaction considerations than the oral antibiotics in the recommended POT regimens.^15,16

From a medication-safety standpoint, dalbavancin has no known significant drug interactions, but oritavancin’s weak inhibition of CYP2C9 and CYP2C19 and weak induction of CYP3A4 and CYP2D6 may occasionally require evaluation for any clinically meaningful interactions.15,16 It is unclear exactly how long concern for an interaction should last, but the drug’s label advises avoiding coadministration with narrow–therapeutic index drugs affected by these enzymes for as long as the antibiotic’s concentrations are clinically meaningful.15 Oritavancin use is infrequently limited by its interference with coagulation assays, and IV unfractionated heparin is contraindicated for 120 hours after oritavancin dosing.^2,15 Because it involves IV heparin, this interaction is unlikely to affect most patients. Dalbavancin can require dose adjustments in reduced kidney function and caution in moderate to severe liver impairment, but available dose-modification guidance is based on studies involving other infections, and what, if any, adjustment would be appropriate when treating endocarditis is not well understood.¹⁶

Access planning is likely to be one of the most practical barriers to use. Although these agents are used as outpatient therapy without the requirement for an indwelling line, administration most commonly occurs at an outpatient infusion center or through home infusion services. As with any drug, coverage will depend on the individual patient’s plan, prior authorization is often required, and a separate administration copay may be incurred. A generic formulation of dalbavancin is available, which may also affect coverage.2 Future access may be influenced by emerging data suggesting that overall costs are lower with lipoglycopeptide-based strategies, the use of which has been shown or projected to reduce hospital stay by 2.2 to 9.18 days and generate total cost savings of more than $17,000 ($22,000 in people who inject drugs).7,12 In one analysis, net costs of dalbavancin, which include inpatient and outpatient daily IV antibiotic administration, were $5931 and $4574 lower than standard IV therapy and IV-to-oral POT regimens, respectively.⁷

Pharmacist Takeaways

An infection once considered primarily the domain of inpatient clinicians, endocarditis now requires coordination across inpatient, outpatient, infusion, and community settings. As oral therapy, long-acting lipoglycopeptides, and outpatient IV regimens become more prominent, pharmacists are well positioned to support this transition by evaluating regimen feasibility, addressing access barriers, identifying drug interactions, counseling patients and caregivers, and monitoring for adherence, tolerability, and treatment response. Careful pharmacist involvement will be essential to ensuring these outpatient treatment pathways improve flexibility, access, and quality of life without compromising safety.

About the Author

Marilyn Bulloch, PharmD, BCPS, FCCM, is an associate clinical professor in the Department of Pharmacy Practice at the Auburn University Harrison College of Pharmacy in Alabama.

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