Endocarditis medical therapy
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Endocarditis Microchapters |
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Diagnosis |
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Treatment |
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2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease |
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Case Studies |
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Endocarditis medical therapy On the Web |
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Risk calculators and risk factors for Endocarditis medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] Anum Ijaz M.B.B.S., M.D.[3]
Overview
Antimicrobial therapy is the cornerstone of infective endocarditis (IE) management. Core principles are prolonged courses of bactericidal antibiotics, intensive dosing to achieve adequate drug exposure within vegetations, and source control. Recommendations rest largely on observational data, expert consensus, and a small number of randomized trials. Empiric therapy is selected by valve type (native vs. prosthetic), acuity, epidemiologic risk factors, and local resistance patterns; definitive therapy is directed by organism identification and susceptibility. Infectious disease consultation and a multidisciplinary endocarditis team are recommended for all cases.[1][2]
Empiric Antibiotic Therapy
Little high-quality evidence guides empiric selection; regimens should be chosen with infectious disease input and account for valve type and time since implantation, acuity, suspected source (dental, gastrointestinal, skin/soft tissue, intravascular catheter), prior antibiotic exposure, local resistance, and organism-specific risk factors (e.g., injection drug use, healthcare exposure).[1][2]
Timing of Initiation
- Acute/fulminant presentation: Start empiric antibiotics promptly after obtaining ≥3 sets of blood cultures from separate venipuncture sites.[3]
- Subacute, hemodynamically stable presentation: Initiation may be deferred until cultures result, particularly after recent antibiotic exposure, to avoid confounding.[3][4]
Recommended Empiric Regimens
| Setting | Regimen | Notes |
|---|---|---|
| Native valve | Vancomycin + ceftriaxone | Covers MRSA, streptococci, enterococci[4][2][1] |
| Native valve, low MRSA risk / MSSA suspected | Cefazolin or ceftriaxone monotherapy | May suffice[1] |
| Native valve, oral/GI source suspected | Ampicillin-sulbactam (in place of ceftriaxone) | [2] |
| Prosthetic valve | Vancomycin + cefepime (or piperacillin-tazobactam) | Covers MRSA, enterococci, CoNS, gram-negatives incl. Pseudomonas[2][1] |
| Late-onset PVE (>3–12 mo) | Substitute ceftriaxone for cefepime | Microbiology resembles NVE[1] |
- Aminoglycosides and rifampin should generally be reserved for definitive therapy rather than empiric use.[1]
- Daptomycin (8–10 mg/kg for suspected S. aureus; 10–12 mg/kg for suspected enterococcus) is an alternative to vancomycin as the principal empiric agent.[1]
Duration of Antibiotic Therapy
- Native valve IE: minimum 4 weeks for most organisms; 6 weeks for enterococcal and complicated infections.[2][4]
- Prosthetic valve IE: minimum 6 weeks.[2][5]
- Duration is counted from the first day of effective therapy (first day of negative blood cultures for most organisms).[4]
- For uncomplicated right-sided S. aureus NVE, a shortened 2-week nafcillin/oxacillin plus gentamicin course has been used in select populations (e.g., IDU-associated tricuspid IE) but is not universally endorsed.[6]
Definitive Pathogen-Directed Therapy
Viridans Group Streptococci and Streptococcus gallolyticus
| Susceptibility / Setting | Regimen |
|---|---|
| Penicillin MIC ≤0.12 μg/mL (highly susceptible), NVE | Penicillin G 12–18 million U/day IV in 4–6 divided doses × 4 weeks; OR ceftriaxone 2 g IV daily × 4 weeks (Class IIa; LOE B)[5][4] |
| Penicillin MIC ≤0.12 μg/mL, NVE (2-week regimen) | Penicillin G or ceftriaxone + gentamicin 3 mg/kg IV once daily × 2 weeks — for uncomplicated IE with rapid response and no renal disease (Class IIa; LOE B)[5][4] |
| Penicillin MIC ≤0.12 μg/mL, NVE (beta-lactam intolerance) | Vancomycin 30 mg/kg/day IV in 2–3 divided doses × 4 weeks (Class IIa; LOE B)[5] |
| Penicillin MIC >0.12 to <0.5 μg/mL (relatively resistant), NVE | Penicillin G 24 million U/day IV in 4–6 divided doses × 4 weeks + gentamicin 3 mg/kg IV once daily × first 2 weeks; OR ceftriaxone 2 g IV daily × 4 weeks + gentamicin × first 2 weeks (Class IIa; LOE B)[5][4] |
| Penicillin MIC >0.12 to <0.5 μg/mL, NVE (beta-lactam intolerance) | Vancomycin 30 mg/kg/day IV in 2–3 divided doses × 4 weeks — alternative[5][4] |
| Penicillin MIC ≥0.5 μg/mL, Abiotrophia, Granulicatella, NVE | Penicillin G 24 million U/day IV + gentamicin 3 mg/kg IV in 2–3 doses × 4–6 weeks. ESC guidance: penicillin or ceftriaxone × 6 weeks + gentamicin ≥2 weeks[4] |
| Streptococcal PVE (all) | Penicillin G 24 million U/day IV or ceftriaxone 2 g IV daily × 6 weeks ± gentamicin × first 2 weeks (Class IIa; LOE B). For MIC >0.12 μg/mL, give both penicillin/ceftriaxone and gentamicin for the full 6 weeks (Class IIa; LOE C). Note the higher penicillin G dose for PVE (24 million U/day) vs. NVE (12–18 million U/day)[5] |
Gentamicin precautions: avoid in elderly, preexisting renal disease, or concurrent nephrotoxic/ototoxic agents; limit to 2 weeks when used.[2][4]
Staphylococcal IE — definitive therapy
| Pathogen | Regimen |
|---|---|
| MSSA, NVE (preferred) | Nafcillin or oxacillin 12 g/day IV in 6 divided doses × 6 weeks[4][7] |
| MSSA, NVE (non-anaphylactoid penicillin allergy) | Cefazolin 6 g/day IV in 3 divided doses × 6 weeks[4] |
| MRSA, NVE | Vancomycin 30–60 mg/kg/day IV in 2–4 divided doses × 6 weeks (target AUC/MIC 400–600 μg·hr/mL)[4][8] |
| MRSA, NVE (alternative) | Daptomycin 10 mg/kg/day IV × 6 weeks[4][9][5] |
| MSSA, PVE | Nafcillin/oxacillin 12 g/day IV + rifampin 900 mg/day in 3 doses ≥6 weeks + gentamicin 3 mg/kg/day × first 2 weeks[4] |
| MRSA or MR-CoNS, PVE | Vancomycin + rifampin ≥6 weeks + gentamicin × first 2 weeks (Class I; LOE B)[5] |
- Beta-lactams are preferred over vancomycin for MSSA due to higher cure rates.[7][2]
- A vancomycin loading dose of 25–30 mg/kg (actual body weight) is recommended for seriously ill patients.[8]
- Adjunctive gentamicin or rifampin is not recommended for NVE — no benefit, increased toxicity.[4][7]
- Daptomycin FDA-approved dose is 6 mg/kg (S. aureus bacteremia/right-sided IE); expert consensus and IDSA recommend 8–10 mg/kg for IE, especially left-sided.[4][9][5][7]
- In staphylococcal PVE, some authorities delay rifampin by 3–5 days to allow vancomycin penetration and reduce treatment-emergent rifampin resistance.[5]
Newer Agents: Ceftaroline and Ceftobiprole
Ceftaroline has in vitro activity against MRSA and has been used as salvage or adjunctive therapy (often combined with daptomycin) for complicated S. aureus IE and multidrug-resistant enterococcal IE; the 2015 AHA statement notes promising observations but states that appropriately designed clinical studies are needed before widespread recommendation. Ceftobiprole (Zevtera) received FDA approval in 2024 for S. aureus bloodstream infections including right-sided IE in adults, making it the first cephalosporin with an FDA indication for IE. The approved dose for SAB/right-sided IE is 667 mg IV every 6 hours (Days 1–8), then every 8 hours (Day 9 onward), for up to 42 days; the pivotal ERADICATE trial demonstrated noninferiority to daptomycin.[5][10][11] Neither agent has robust data for left-sided IE.
Enterococcal IE — definitive therapy
Enterococcal IE requires prolonged therapy (typically 6 weeks regardless of valve type) owing to tolerance to bactericidal killing.[5][7]
| Resistance profile | Regimen |
|---|---|
| Susceptible E. faecalis (penicillin, aminoglycoside, vancomycin) | Ampicillin 12 g/day IV in 6 doses + gentamicin 3 mg/kg/day IV in 2–3 doses × 4–6 weeks (NVE) or 6 weeks (PVE) (Class IIa; LOE B)[5][4] |
| Susceptible E. faecalis (double beta-lactam) | Ampicillin 12 g/day IV + ceftriaxone 2 g IV q12h × 6 weeks (Class IIa; LOE B) — saturates distinct penicillin-binding proteins and avoids aminoglycoside nephrotoxicity[5][7] |
| High-level aminoglycoside resistance (E. faecalis) | Ampicillin + ceftriaxone × 6 weeks preferred (Class IIa; LOE B)[5][7] |
| Penicillin-resistant, vancomycin-susceptible | Vancomycin + gentamicin × 6 weeks[4] |
| Multidrug-resistant (penicillin, aminoglycoside, vancomycin) | Linezolid 600 mg IV/PO q12h ≥8 weeks; or daptomycin 10–12 mg/kg/day (limited data); ID consultation essential[5][7] |
The ampicillin-ceftriaxone regimen shows comparable efficacy with significantly lower nephrotoxicity and is increasingly preferred, particularly in the elderly and those with renal impairment.[7][5]
HACEK IE - definitive therapy
| Agent | Regimen / Notes |
|---|---|
| Ceftriaxone (preferred) | 2 g IV once daily × 4 weeks (NVE) or 6 weeks (PVE)[4] |
| Ciprofloxacin (alternative) | 800 mg/day IV or 1000–1500 mg/day PO in 2 doses × 4 weeks (Class IIb; LOE C); fluoroquinolones only if unable to tolerate cephalosporins and ampicillin. AHA 2015 specifies no dose; NEJM 2020 lists 1500 mg/day PO[5][4] |
| Levofloxacin (alternative) | 750 mg IV/PO once daily × 4 weeks — per NEJM 2020 review; AHA 2015 endorses fluoroquinolones only generally (Class IIb; LOE C), not levofloxacin specifically[4][5] |
| Ampicillin-sulbactam | Option if the isolate is non–beta-lactamase-producing[4] |
Culture-Negative IE
Approach depends on prior antibiotic exposure:[12]
| Scenario / Pathogen | Regimen |
|---|---|
| Prior antibiotics (most common) | Target staphylococci, streptococci, enterococci[12][5] |
| No prior antibiotics | Consider fastidious organisms (Bartonella spp., Coxiella burnetii, Tropheryma whipplei, Brucella spp.) and pursue serologic/molecular testing[12][5] |
| Suspected Bartonella | Ceftriaxone 2 g IV daily × 6 weeks + gentamicin 3 mg/kg/day IV in 3 doses × 2 weeks ± doxycycline 200 mg/day × 6 weeks[13] |
| Documented Bartonella | Doxycycline 200 mg/day × 6 weeks + gentamicin 3 mg/kg/day × 2 weeks; if gentamicin cannot be used, substitute rifampin 600 mg/day PO/IV in 2 doses[13][5] |
| Q fever (Coxiella burnetii) | Doxycycline 100 mg PO twice daily + hydroxychloroquine 200 mg PO three times daily for ≥18 months (native valve) or ≥24 months (prosthetic valve); monitor IgG phase I titers to guide duration[14][12] |
| Brucella IE | Doxycycline plus rifampin (and/or an aminoglycoside), typically prolonged courses; valve surgery frequently required; ID consultation essential[12] |
| Culture-negative NVE (no fastidious organism identified) | Ampicillin-sulbactam 12 g/day IV + gentamicin; or vancomycin + gentamicin + ciprofloxacin × 4–6 weeks[5] |
| Culture-negative early PVE (≤1 yr) | Vancomycin + gentamicin + cefepime + rifampin × 6 weeks[5] |
| Culture-negative late PVE (>1 yr) | Treat as culture-negative NVE with extended (6-week) duration[5] |
ID consultation is essential for all culture-negative cases.[12][5]
Outpatient Parenteral Antibiotic Therapy (OPAT)
OPAT is efficacious, safe, and cost-effective for completing prolonged IV courses in selected patients no longer requiring inpatient care.[5]
Patient Selection
Patients should be stabilized in hospital first. Eligibility criteria include:[5][15]
- Negative blood cultures ≥72 hours
- Afebrile and clinically improving
- No severe complications (heart failure, conduction abnormality, perivalvular abscess)
- No ongoing embolic events
- Stable anticoagulation (if applicable)
- TEE excluding severe valve dysfunction requiring surgery
- Adequate social support and outpatient monitoring
Contraindications
- Poorly controlled heart failure
- Persistent fever or positive blood cultures
- New neurologic findings suggesting emboli or mycotic aneurysm
- Conduction abnormality suggesting perivalvular extension
- Active injection drug use (relative — see below)
OPAT in Injection Drug Use–Associated IE
Evidence suggests catheter misuse is rare and antibiotic completion rates are high among people who inject drugs receiving OPAT. OPAT should not be categorically denied; risk-assessment tools and co-location with medication for opioid use disorder (MOUD) care improve outcomes.[16] A 2025 systematic review/meta-analysis (25 studies, 2,654 patients) showed low mortality (0% during treatment, 5% during follow-up) and low relapse (2–4%), though readmission approached 20% and a significant proportion required cardiac surgery.[17][15]
Anticoagulation Management
- Anticoagulation has no proven therapeutic benefit in NVE and is not recommended as adjunctive therapy.[5]
- Adjunctive aspirin showed no benefit and a trend toward increased bleeding; initiation of antiplatelet agents for IE treatment is not recommended.[5]
Mechanical Prosthetic Valve IE
- Management is controversial. The general recommendation is to discontinue all anticoagulation for ≥2 weeks in mechanical-valve IE patients who sustain a CNS embolic event, allowing thrombus organization and reducing hemorrhagic transformation.[5]
- Reintroduction should be cautious: begin with IV unfractionated heparin (target aPTT 50–70 s), then transition carefully to warfarin.[5]
- When continued (no CNS event), maintain INR 2.0–3.0 with careful monitoring.[5]
Direct Oral Anticoagulants (DOACS)
- DOACs are not approved for mechanical heart valves and should not be used in that setting.[5]
- For bioprosthetic valves with concurrent atrial fibrillation, DOACs may be considered per standard AF guidelines, but data specific to active IE are lacking.
Adjunctive Aminoglycosides and Rifampin
Aminoglycosides
- S. aureus NVE: adjunctive gentamicin is not recommended (no mortality benefit, increased nephrotoxicity).[4][7]
- Streptococcal NVE: short-course (2-week) gentamicin with penicillin/ceftriaxone permits a shortened 2-week total regimen in uncomplicated cases.[5][4]
- Enterococcal IE: gentamicin is standard combination therapy but limited to 2 weeks when possible; ampicillin-ceftriaxone avoids aminoglycoside toxicity entirely.[5][7]
- Staphylococcal PVE: gentamicin for the first 2 weeks is part of the standard triple regimen.[5]
Rifampin
- Recommended only for prosthetic valve IE caused by staphylococci (biofilm activity).[5][7]
- Not recommended for NVE (hepatotoxicity, drug interactions, no demonstrated benefit).[4][7]
- Some experts delay initiation 3–5 days after starting vancomycin/beta-lactam to reduce treatment-emergent resistance.[5]
- Never use as monotherapy (rapid resistance).
Monitoring: Weekly creatine phosphokinase (CPK) for daptomycin; per the FDA label, discontinue for CPK >1000 U/L (~5× ULN) with myopathy symptoms, or CPK >2000 U/L (~10× ULN) without symptoms. Weekly complete blood count for linezolid (risk of thrombocytopenia and myelosuppression increases with courses >2 weeks). For Q fever IE, periodic ophthalmologic monitoring is required during prolonged hydroxychloroquine therapy.[5][9][14]
Long-Acting Lipoglycopeptides
Dalbavancin and oritavancin are long-acting lipoglycopeptides active against gram-positives including MRSA, FDA-approved only for acute bacterial skin and skin structure infections — not for IE.[18] Prolonged half-lives (weekly or less frequent dosing) and elimination of indwelling IV access have generated interest for IE.[19]
- Case reports/small series suggest possible efficacy in selected patients.[19]
- No randomized trial data exist for IE.
- May be considered in highly selected cases (e.g., unable to maintain IV access, high line-complication risk) with ID input.
Areas of Uncertainty and Controversy
- No comparative-effectiveness trials exist for empiric regimens.[1]
- Generalizability of oral step-down to complex S. aureus, right-sided, and drug use–associated IE is uncertain (few such patients in POET).[19][16]
- Rifampin benefit in staphylococcal PVE rests largely on experimental models; optimal initiation timing is debated.[5][7]
- No consensus on optimal daptomycin dose for left-sided IE; FDA labeling omits left-sided IE.[5][9]
- The role of newer anti-MRSA cephalosporins (ceftaroline, ceftobiprole) in left-sided IE is not yet established by randomized data.[5][11]
- Duration of anticoagulation interruption and reintroduction strategy after CNS events in mechanical-valve IE lack high-quality evidence.[5]
High-Yield Clinical Pearls
- Beta-lactams are superior to vancomycin for MSSA IE — use nafcillin/oxacillin or cefazolin when susceptible.[4][7]
- Ampicillin-ceftriaxone is preferred for E. faecalis IE with renal impairment or high-level aminoglycoside resistance.[7][5]
- Do not add gentamicin or rifampin to S. aureus NVE regimens.[4][7]
- Rifampin is reserved exclusively for staphylococcal PVE.[5][7]
- Oral step-down requires TEE confirmation of no abscess and no surgical indication.[20]
- Count antibiotic duration from the first day of negative blood cultures.[4]
- Daptomycin is inactivated by pulmonary surfactant — avoid when pneumonia is the primary concern in right-sided IE, though it remains effective for right-sided IE per se.[9]
- All IE patients should have infectious disease consultation.[1][2]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 McDonald EG, Aggrey G, Aslan AT; et al. (2023). "Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement". JAMA Network Open. 6 (7): e2326366. doi:10.1001/jamanetworkopen.2023.26366.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 Nohria R, Romaine A, Garcia-Sampson G (2026). "Infective Endocarditis: Diagnosis and Treatment". American Family Physician. 113 (2): 145–152.
- ↑ 3.0 3.1 Li M, Kim JB, Sastry BKS, Chen M (2024). "Infective Endocarditis". Lancet. 404 (10450): 377–392. doi:10.1016/S0140-6736(24)01098-5.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 4.25 4.26 4.27 4.28 Chambers HF, Bayer AS (2020). "Native-Valve Infective Endocarditis". N Engl J Med. 383 (6): 567–576. doi:10.1056/NEJMcp2000400.
- ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 5.21 5.22 5.23 5.24 5.25 5.26 5.27 5.28 5.29 5.30 5.31 5.32 5.33 5.34 5.35 5.36 5.37 5.38 5.39 5.40 5.41 5.42 5.43 5.44 5.45 5.46 Baddour LM, Wilson WR, Bayer AS; et al. (2015). "Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement From the American Heart Association". Circulation. 132 (15): 1435–1486. doi:10.1161/CIR.0000000000000296.
- ↑ Yucel E, Bearnot B, Paras ML; et al. (2022). "Diagnosis and Management of Infective Endocarditis in People Who Inject Drugs: JACC State-of-the-Art Review". J Am Coll Cardiol. 79 (20): 2037–2057. doi:10.1016/j.jacc.2022.03.349.
- ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 Wang A, Gaca JG, Chu VH (2018). "Management Considerations in Infective Endocarditis: A Review". JAMA. 320 (1): 72–83. doi:10.1001/jama.2018.7596.
- ↑ 8.0 8.1 Rybak MJ, Le J, Lodise TP; et al. (2020). "Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline". Am J Health Syst Pharm. 77 (11): 835–864. doi:10.1093/ajhp/zxaa036.
- ↑ 9.0 9.1 9.2 9.3 9.4 "Daptomycin — FDA label". U.S. Food and Drug Administration. 2026-05-08. Missing or empty
|url=(help) - ↑ "ZEVTERA (ceftobiprole) — FDA label". U.S. Food and Drug Administration. 2024. Missing or empty
|url=(help) - ↑ 11.0 11.1 Holland TL, Cosgrove SE, Doernberg SB; et al. (2023). "Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia". N Engl J Med. 389 (15): 1390–1401. doi:10.1056/NEJMoa2300220.
- ↑ 12.0 12.1 12.2 12.3 12.4 12.5 DeSimone DC, Garrigos ZE, Marx GE; et al. (2025). "Blood Culture-Negative Endocarditis: A Scientific Statement From the American Heart Association". J Am Heart Assoc. 14 (8): e040218. doi:10.1161/JAHA.124.040218.
- ↑ 13.0 13.1 Bonow RO, Carabello BA, Chatterjee K; et al. (2008). "2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease". J Am Coll Cardiol. 52 (13): e1–e142. doi:10.1016/j.jacc.2008.05.007.
- ↑ 14.0 14.1 Anderson A, Bijlmer H, Fournier PE; et al. (2013). "Diagnosis and Management of Q Fever — United States, 2013: Recommendations from CDC and the Q Fever Working Group". MMWR Recomm Rep. 62 (RR-03): 1–30.
- ↑ 15.0 15.1 Pericàs JM, Llopis J, González-Ramallo V; et al. (2019). "Outpatient Parenteral Antibiotic Treatment for Infective Endocarditis: A Prospective Cohort Study From the GAMES Cohort". Clin Infect Dis. 69 (10): 1690–1700. doi:10.1093/cid/ciz030.
- ↑ 16.0 16.1 Wurcel AG, Suzuki J, Schranz AJ; et al. (2024). "Strategies to Improve Patient-Centered Care for Drug Use-Associated Infective Endocarditis: JACC Focus Seminar 2/4". J Am Coll Cardiol. 83 (14): 1338–1347. doi:10.1016/j.jacc.2024.01.034.
- ↑ Ashraf H, Nadeem ZA, Rehman KA; et al. (2025). "Safety and Efficacy of Outpatient Parenteral Antibiotic Therapy (OPAT) in Patients With Infective Endocarditis: A Systematic Review and Meta-Analysis". Clin Cardiol. 48 (5): e70147. doi:10.1002/clc.70147.
- ↑ "FDA Orange Book". U.S. Food and Drug Administration. 2025. Missing or empty
|url=(help) - ↑ 19.0 19.1 19.2 Dayer MJ, Quintero-Martinez JA, Thornhill MH; et al. (2024). "Recent Insights Into Native Valve Infective Endocarditis: JACC Focus Seminar 4/4". J Am Coll Cardiol. 83 (15): 1431–1443. doi:10.1016/j.jacc.2023.12.043.
- ↑ Iversen K, Ihlemann N, Gill SU; et al. (2019). "Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis". N Engl J Med. 380 (5): 415–424. doi:10.1056/NEJMoa1808312.