Infective Endocarditis — Management and Prevention

Clinical Snapshot

Infective endocarditis (IE) is a life-threatening infection of the endocardial surface of the heart — most often a native or prosthetic heart valve, but sometimes a septal defect or an indwelling intracardiac device — that develops when endothelial injury from turbulent flow, a structural or congenital abnormality, or an indwelling catheter/device allows fibrin and platelets to deposit and bacteria (or, less commonly, fungi) from a bacteremic episode to adhere and form a vegetation.^[1] Left untreated or inadequately treated, the infected vegetation can destroy the valve itself, extend into adjacent cardiac tissue as an abscess, and shower septic emboli to the brain, lungs, spleen, kidneys, or extremities — making IE a genuinely multisystem emergency that needs a coordinated antimicrobial, surgical, and multidisciplinary "endocarditis team" response, not antibiotics alone.^[2]

Recognize the Condition

Presentation ranges from fulminant to indolent

IE does not present as one syndrome — the same infection can appear as a fulminant, rapidly destructive illness (typical of Staphylococcus aureus) or as a subacute, low-grade illness evolving over weeks (typical of viridans streptococci) — so a well-appearing patient does not rule out IE, particularly with a known predisposing risk factor.

Constitutional and cardiac findings

Fever — the most consistent finding, though it may be low-grade or intermittent in subacute disease.
Fatigue, malaise, anorexia, weight loss, night sweats, and arthralgia/myalgia.
A new or changing heart murmur — a new regurgitant murmur is typical; a long-standing, unchanged murmur is far less suggestive.
Signs of heart failure — dyspnea, orthopnea, pulmonary edema — from acute valvular destruction.
Rigors, pleuritic chest pain, cough, and hemoptysis, particularly in right-sided IE from septic pulmonary emboli.

Extracardiac (immunologic and embolic) stigmata

Splinter hemorrhages (nail bed).
Janeway lesions — painless, erythematous macules, typically on the palms or soles (embolic).
Osler nodes — painful, tender nodules on the finger or toe pads (immunologic).
Roth spots — retinal hemorrhages with a pale centre.
Conjunctival or buccal/oral mucosal petechiae.
Splenomegaly.
Clubbing — usually reflects more chronic, longstanding infection.
Focal neurologic deficits, flank pain/hematuria, or limb ischemia from embolization to the brain, kidney, or extremities.

Clinical patterns of IE

Native valve IE

The most common pattern. Community-acquired cases are often due to viridans streptococci or S. aureus; healthcare-associated native valve IE (e.g., following an invasive procedure or with an indwelling catheter) skews toward S. aureus and coagulase-negative staphylococci.

Prosthetic valve IE — early (under 1 year post-implantation)

Reflects perioperative or early nosocomial contamination — coagulase-negative staphylococci and S. aureus predominate, often with more resistant, biofilm-associated organisms, which is why definitive prosthetic-valve staphylococcal regimens add rifampin.

Prosthetic valve IE — late (1 year or more post-implantation)

The organism spectrum shifts back toward that of native valve IE (streptococci, enterococci, community-acquired S. aureus), though staphylococci and biofilm-forming organisms remain important.

IV drug use-associated (typically right-sided) IE

S. aureus, including MRSA, is the dominant pathogen; the tricuspid valve is most often affected, and septic pulmonary emboli (pleuritic pain, cough, hemoptysis) are a characteristic presentation rather than systemic embolization.

Risk Factors

Structural or congenital heart disease, including valvulopathy (rheumatic, degenerative, or bicuspid aortic valve) and unrepaired or incompletely repaired congenital heart defects.
A prosthetic heart valve or other implanted prosthetic cardiac material (annuloplasty ring, transcatheter valve, ventricular assist device).
A previous episode of infective endocarditis.
An indwelling intravascular catheter, a cardiac implantable electronic device (pacemaker/ICD), or hemodialysis vascular access.
Injection drug use.
Poor dental hygiene or active periodontal/dental infection.
A recent invasive dental, surgical, or genitourinary/gastrointestinal procedure in a patient with a predisposing cardiac condition.
Immunosuppression, including HIV infection and long-term immunosuppressive therapy.
Diabetes mellitus and chronic hemodialysis-dependent kidney disease.

Red Flags & Refer

Any confirmed or strongly suspected IE warrants early infectious diseases and cardiology/cardiothoracic surgery involvement — the following findings specifically identify a patient who needs urgent surgical evaluation, not just continued antibiotics:

Heart failure from acute valvular regurgitation or obstruction — the single most common indication for surgery during active IE; if severe or refractory it is a surgical emergency regardless of how much of the antibiotic course remains.^[1]
Uncontrolled infection — persistent fever or bacteremia despite 5-7 or more days of appropriate antibiotic therapy, a perivalvular abscess, a new atrioventricular conduction block (suggests abscess extension into the conduction system), fungal IE, or infection with a highly resistant organism.
Embolic events — a systemic or cerebral embolic event, particularly with a large (over 10 mm) or mobile vegetation, or a recurrent embolic event despite appropriate antibiotic therapy.
Valve dysfunction requiring urgent surgical referral — dehiscence, perforation, rupture, or a new significant paravalvular leak of a prosthetic valve.
Relapsing infection after a prior adequate course of therapy.
Arrange early transfer to a cardiovascular surgery centre proactively if surgical capability is not available locally — do not wait for hemodynamic collapse to initiate transfer.

Assessment & Diagnosis

Conditions commonly confused with IE on presentation

Feature	Infective endocarditis	Acute rheumatic fever	Marantic (non-bacterial thrombotic) endocarditis	Atrial myxoma
Typical context	Predisposing structural/prosthetic cardiac disease plus a bacteremic source	Weeks after untreated group A streptococcal pharyngitis, usually children/young adults	Advanced malignancy or a severe hypercoagulable state	Sporadic cardiac tumour — no infectious or rheumatologic trigger
Blood cultures	Typically positive	Typically negative — a post-infectious process, not an active bacteremia	Negative — sterile vegetations	Negative
Echocardiographic finding	A true vegetation, often at the valve coaptation surface	Verrucous lesions along the valve closure line are possible; a destructive vegetation is atypical	Small, sterile, friable vegetations, often at the valve tips	A discrete pedunculated mass — classically left atrial, attached near the fossa ovalis — not a vegetation
Key distinguishing feature	Fulfills the Modified Duke Criteria (below)	Migratory polyarthritis, carditis, chorea, erythema marginatum, subcutaneous nodules, and preceding pharyngitis (Jones criteria)	Underlying malignancy or hypercoagulable state; embolization without evidence of infection	Constitutional symptoms, emboli, and a positional murmur can mimic IE, but imaging shows a discrete mass rather than a valvular vegetation
Management	Antibiotics ± surgery, per this chapter	Anti-inflammatory therapy and secondary antibiotic prophylaxis (a separate topic, not covered here)	Treat the underlying malignancy/hypercoagulable state; anticoagulation	Surgical resection

History and physical examination

Time course of illness and predisposing risk factors — recent dental or surgical procedures, dental health, known cardiac disease/malformation, prior cardiac surgery or valve replacement, prior IE, injection drug use, and any recent placement or manipulation of an intravascular device.
A thorough medication history, including drug allergies. In a patient receiving oral anticoagulation, assess the ongoing need for anticoagulation (including temporarily holding it) if IE is suspected or documented, and note any antibiotic already taken that could suppress blood culture results.
Physical findings beyond the extracardiac stigmata above: spinal tenderness or focal neurologic deficits (metastatic infection); a new murmur, pulmonary edema, or hypotension (cardiac decompensation).

Laboratory investigations

Blood cultures before starting antibiotics are essential to identify the pathogen and its susceptibilities. Take at least 3 blood culture sets from separate venipuncture sites, with the first and last samples at least 1 hour apart (or, alternatively, at least 3 sets within a 1-2 hour interval), using an adequate blood volume per bottle to maximize yield. Repeat blood cultures 24-72 hours into therapy to confirm clearance of bacteremia — this also marks the actual start date for counting treatment duration.^[1]
CBC and differential, electrolytes, glucose, urea, creatinine, liver function tests, ESR and/or CRP, and complement C3/C4.
Urinalysis — hematuria, proteinuria, pyuria, or red cell casts.
If blood cultures remain negative, pursue serologic and/or molecular diagnostics for difficult-to-grow pathogens such as Coxiella burnetii and Bartonella spp., and involve infectious diseases and clinical microbiology.

Imaging

Baseline ECG and chest x-ray.
Echocardiography in every patient with suspected or documented IE. Transthoracic echocardiography (TTE) is typically performed first, especially with low clinical suspicion. Transesophageal echocardiography (TEE) is more sensitive for an abscess, a small vegetation, extension into tissue surrounding the valve, or assessment of a prosthetic valve, and should be used for high-risk patients (e.g., S. aureus bacteremia) or moderate-to-high clinical suspicion.
Repeat or follow-up echocardiography to assess response to therapy, disease progression, or a new complication (unexplained worsening heart failure, a new murmur, a new conduction abnormality), or to help decide on surgery.

The Modified Duke Criteria

The Modified Duke Criteria remain the widely accepted clinical standard for classifying suspected IE as definite, possible, or rejected, based on pathologic, clinical, laboratory, and radiologic findings — clinical judgment should still be applied alongside the criteria given how heterogeneous IE presentations can be.^[3]

Classification	Criteria
Definite IE	Pathologic criteria — organisms demonstrated by culture or histology of a vegetation, an embolized vegetation, or an intracardiac abscess specimen; or pathologic lesions showing active endocarditis on histology. OR clinical criteria: 2 major criteria; or 1 major + 3 minor criteria; or 5 minor criteria.
Possible IE	1 major + 1 minor criterion; or 3 minor criteria.
Rejected	A firm alternative diagnosis explains the findings; or resolution of the syndrome with 4 days or less of antibiotic therapy; or no pathologic evidence of IE at surgery/autopsy with 4 days or less of antibiotic therapy; or the case does not meet criteria for possible IE.

Criteria type	Definition
Major	Blood culture positive for IE — typical organisms (viridans streptococci, Streptococcus gallolyticus [bovis], HACEK group, S. aureus) from 2 separate cultures; or community-acquired enterococci without a primary focus; or persistently positive cultures (at least 2 samples drawn over 12 hours apart, or a majority of 4 or more separate cultures with first/last at least 1 hour apart); or a single positive culture for Coxiella burnetii or an antiphase 1 IgG titre over 1:800. Evidence of endocardial involvement — an oscillating intracardiac mass on a valve, supporting structure, or implanted material without an alternative explanation; an abscess; a new partial prosthetic valve dehiscence; or new valvular regurgitation (a worsening or changing pre-existing murmur alone is not sufficient).
Minor	A predisposing heart condition or injection drug use; fever over 38°C; vascular phenomena (major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions); immunologic phenomena (glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor); microbiological evidence not meeting a major criterion (excluding a single positive culture for coagulase-negative staphylococci or an organism that does not typically cause endocarditis), or serologic evidence of active infection with an organism consistent with IE.

Criteria type

Definition

Major

Blood culture positive for IE — typical organisms (viridans streptococci, Streptococcus gallolyticus [bovis], HACEK group, S. aureus) from 2 separate cultures; or community-acquired enterococci without a primary focus; or persistently positive cultures (at least 2 samples drawn over 12 hours apart, or a majority of 4 or more separate cultures with first/last at least 1 hour apart); or a single positive culture for Coxiella burnetii or an antiphase 1 IgG titre over 1:800.

Evidence of endocardial involvement — an oscillating intracardiac mass on a valve, supporting structure, or implanted material without an alternative explanation; an abscess; a new partial prosthetic valve dehiscence; or new valvular regurgitation (a worsening or changing pre-existing murmur alone is not sufficient).

Minor

A predisposing heart condition or injection drug use; fever over 38°C; vascular phenomena (major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions); immunologic phenomena (glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor); microbiological evidence not meeting a major criterion (excluding a single positive culture for coagulase-negative staphylococci or an organism that does not typically cause endocarditis), or serologic evidence of active infection with an organism consistent with IE.

HACEK refers to Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp. A proposed 2023 Duke-International Society for Cardiovascular Infectious Diseases (Duke-ISCVID) revision updates the organism list, blood-sampling and imaging criteria, and the treatment of prior IE and cardiac devices; external validation studies since publication have found increased sensitivity but decreased specificity compared with the modified Duke criteria above, so it has not replaced the modified Duke criteria as the adopted clinical standard.^[4] Unlike a simple additive point-sum score, both versions combine pathologic findings with a categorical count of major/minor clinical criteria rather than a single numeric total — a teaching table is provided above, but no live calculator, since a checkbox point-sum cannot safely represent this categorical logic or the pathologic/imaging criteria it also depends on.

Treatment Targets

Eradicate the infecting organism and sterilize the vegetation.
Prevent and manage complications — heart failure, periannular abscess, systemic or septic embolization, and conduction abnormalities.
Preserve or restore valve function, including appropriately timed surgery when antibiotics alone cannot achieve this.
Avoid or minimize drug toxicity, particularly nephrotoxicity and ototoxicity from prolonged aminoglycoside, vancomycin, or daptomycin therapy.
Prevent relapse and reinfection.
Prevent IE in patients with a cardiac condition genuinely at highest risk of a severe outcome, through targeted antibiotic prophylaxis before qualifying dental procedures.

Choose Initial Treatment

Direct treatment rule

Empiric IV antibiotic therapy while blood cultures are pending

Native valve, community-acquired, non-toxic-appearing start vancomycin plus ceftriaxone — this combination covers MRSA, coagulase-negative staphylococci, streptococci, enterococci (partially), and HACEK/gram-negative organisms without added aminoglycoside toxicity risk.

Native valve, severe/toxic presentation, or IV drug use-associated start vancomycin plus gentamicin; reassess and stop gentamicin once an organism is identified — do not continue it routinely once staphylococcal native valve IE is confirmed.

Prosthetic valve, early (under 1 year post-implantation), or strong suspicion of staphylococcal prosthetic valve infection start vancomycin plus gentamicin plus rifampin, mirroring the definitive staphylococcal prosthetic-valve regimen given the high pretest probability of staphylococci in this group.

Prosthetic valve, late (1 year or more post-implantation) treat empirically as for native valve IE (vancomycin plus ceftriaxone, or vancomycin plus gentamicin), adding rifampin if staphylococcal infection is confirmed or strongly suspected.

Culture-negative IE there is no single default empiric regimen — base the choice on a thorough review of host factors, exposures, and the most likely pathogen, in consultation with infectious diseases and clinical microbiology; consider Coxiella burnetii and Bartonella spp. specifically when the exposure history supports it.^[1]

Organism-directed (definitive) therapy

Once an organism and susceptibilities are available, narrow to the pathogen-specific regimen in Drug Tables — the choice depends on the organism, native versus prosthetic valve status, and (for streptococci) the penicillin MIC. Count the treatment duration from the date of the first negative blood culture, not the date treatment started.^[1]

Surgical referral

Refer urgently for cardiothoracic surgical evaluation for any Red Flags & Refer criterion — heart failure from valvular damage, uncontrolled infection, a major or recurrent embolic event, or valve dysfunction. Surgery is not a last resort reserved for antibiotic failure; it is a parallel, often life-saving intervention decided jointly with the endocarditis multidisciplinary team.^[2]

IV-to-oral stepdown

Selected stable patients only consider transitioning from IV to an oral combination antibiotic regimen partway through therapy in a hemodynamically stable, afebrile patient with left-sided IE due to a streptococcus species, Enterococcus faecalis, methicillin-susceptible S. aureus, or coagulase-negative staphylococci, once the acute phase has responded and no unresolved surgical indication or complication remains. This decision requires infectious diseases consultation and is not a routine, unsupervised switch.^[5]

Dental and procedural antibiotic prophylaxis

Give single-dose antibiotic prophylaxis only to a patient with one of the specific high-risk cardiac conditions listed below who is undergoing a dental procedure that involves manipulation of gingival tissue, the periapical region of a tooth, or perforation of the oral mucosa — administered 30-60 minutes before the procedure (up to 2 hours after, only if the pre-procedure dose was inadvertently missed). Do not give prophylaxis to patients outside this specific high-risk list, and do not give it for a dental procedure that does not involve this kind of manipulation (e.g., a routine anesthetic injection through non-infected tissue, radiographs, orthodontic adjustment, or shedding of primary teeth).^[6]

High-risk cardiac conditions warranting dental antibiotic prophylaxis

Prosthetic cardiac valve or material

A prosthetic cardiac valve, including a transcatheter-implanted valve.
Cardiac valve repair using prosthetic material — annuloplasty rings or clips.
A left ventricular assist device or an implantable heart.

Previous infective endocarditis

Any prior episode, including relapse or recurrence.

Congenital heart disease (CHD)

Unrepaired cyanotic CHD, including palliative shunts and conduits.
A completely repaired congenital heart defect with prosthetic material or a device — whether placed surgically or by transcatheter — during the first 6 months after the procedure.
Repaired CHD with a residual defect at, or adjacent to, the site of a prosthetic patch or device.
Surgical or transcatheter placement of a pulmonary artery valve or conduit (e.g., a Melody valve or Contegra conduit).

Cardiac transplant recipients

Only if the recipient develops cardiac valvulopathy.

Not high-risk — prophylaxis is not suggested: a cardiac implantable electronic device (pacemaker/ICD), a septal defect closure device once complete closure is achieved, a peripheral vascular graft or patch (including hemodialysis access), a coronary or other vascular stent, a CNS ventriculoatrial shunt, a vena cava filter, or pledgets. Most other structural or valvular heart disease — including mitral valve prolapse — no longer meets criteria for prophylaxis under current guidance; maintaining good oral hygiene and regular dental care is considered more protective than antibiotic prophylaxis for these patients.^[6]

Non-Pharmacologic Treatment

Surgical intervention is a core part of therapy, not a last resort — indicated for life-threatening heart failure from valvular damage, persistent or recurrent emboli, a large (over 10 mm) vegetation (especially with prior embolization or on the anterior mitral leaflet), failure of appropriate antimicrobial therapy to control infection, severe valvular failure (abscess, dehiscence, perforation, or rupture), extension into surrounding cardiac tissue, or relapsing infection. Timing is decided jointly with cardiothoracic surgery and infectious diseases as part of a multidisciplinary "endocarditis team"; arrange early transfer to a cardiovascular surgery centre if this capability is not available locally.^[1]
Remove or exchange any infected intravascular catheter or cardiac implantable electronic device (pacemaker/ICD lead) — source control is essential, since antibiotics alone will not sterilize an infected foreign body.
For people who inject drugs, involve addiction medicine and harm-reduction services from the outset — ongoing injection drug use increases both relapse and reinfection risk, and a multidisciplinary approach, including consideration of valve-sparing rather than valve-replacing surgery where feasible, improves long-term outcomes.^[7]
Optimize dental health and arrange dental evaluation, especially before elective valve surgery/prosthetic material placement or in a patient with poor dentition — good oral hygiene and regular dental care meaningfully reduce IE risk in a high-risk patient, independent of antibiotic prophylaxis.
Educate the patient and family to seek prompt medical attention for recurrent fever, new or worsening shortness of breath, or a new neurologic or embolic symptom during and after treatment.

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Vancomycin Preferred	Empiric coverage; MRSA or beta-lactam-allergic native/prosthetic valve staphylococcal IE; penicillin-allergic streptococcal/enterococcal IE	See Drug Tables — dosed and monitored to a target trough or AUC	Nephrotoxicity, ototoxicity, infusion-related flushing	Monitor trough (10-15 mg/L) or AUC-guided levels; reserve for confirmed MRSA, beta-lactam allergy, or empiric coverage pending cultures.
Cloxacillin Preferred	MSSA native valve IE (first-line)	See Drug Tables	Rash, hypersensitivity, interstitial nephritis	First-line for MSSA native valve IE; cefazolin is an acceptable substitute for a non-anaphylactic penicillin reaction.
Cefazolin Alternative	MSSA native/prosthetic valve IE, non-anaphylactic penicillin allergy	See Drug Tables	Rash, hypersensitivity, drug fever	Use in place of cloxacillin for a well-defined non-anaphylactic penicillin reaction.
Daptomycin Special situation	Reserved for vancomycin hypersensitivity/intolerance in MRSA IE, per infectious diseases direction	See Drug Tables	Creatine kinase elevation, myopathy	Monitor CK weekly at minimum; do not use for pneumonia (inactivated by surfactant).
Penicillin G Preferred	Penicillin-susceptible viridans streptococcal native/prosthetic valve IE	See Drug Tables	Rash, hypersensitivity, interstitial nephritis, seizure at high dose	Ampicillin or ceftriaxone may be substituted.
Ceftriaxone Preferred	Streptococcal IE alternative to penicillin G; part of the ampicillin + ceftriaxone enterococcal regimen	See Drug Tables	Rash, hypersensitivity, elevated transaminases	Combined with ampicillin specifically for <em>E. faecalis</em> IE, especially with reduced renal function.
Ampicillin Preferred	Enterococcal IE, combined with gentamicin or ceftriaxone	See Drug Tables	Rash, hypersensitivity, interstitial nephritis	Penicillin G may be substituted where the enterococcal isolate is penicillin-susceptible.
Gentamicin Special situation	Synergy in selected streptococcal/enterococcal combination regimens only	See Drug Tables	Nephrotoxicity, ototoxicity	No longer routine for staphylococcal native valve IE — reserve for the specific streptococcal/enterococcal synergy regimens in Drug Tables.
Rifampin Special situation	Adjunct for confirmed staphylococcal prosthetic valve IE only	See Drug Tables	Hepatotoxicity, orange discolouration of body fluids	Always combine with another active agent — never use as monotherapy, to prevent rapid resistance.
Amoxicillin Preferred	Dental procedure antibiotic prophylaxis, standard oral regimen	See Drug Tables	GI upset, hypersensitivity	Give as a single dose 30-60 minutes before the procedure.
Cephalexin Alternative	Dental prophylaxis, penicillin-allergic (non-anaphylactic reaction only)	See Drug Tables	GI upset, hypersensitivity	Do not use in a patient with a history of anaphylaxis, angioedema, or urticaria to a penicillin.
Doxycycline Alternative	Dental prophylaxis when penicillins, cephalosporins, and macrolides cannot be used	See Drug Tables	GI upset, photosensitivity	Now the preferred fallback after clindamycin was removed from prophylaxis guidance given its <em>C. difficile</em> risk.

Special Populations

Pregnancy

IE in pregnancy is uncommon but carries substantial maternal and fetal risk; manage with combined obstetric, cardiology, and infectious diseases input. Beta-lactams (penicillin G, ampicillin, cloxacillin, cefazolin, ceftriaxone) are considered safe throughout pregnancy and remain first-line whenever the organism is susceptible. Vancomycin can be used when indicated, with the same trough/AUC-based monitoring as in a non-pregnant patient. Gentamicin crosses the placenta and carries a recognized risk of fetal ototoxicity — use only when no equally effective alternative exists, for the shortest effective duration, with close monitoring. Rifampin is generally continued when genuinely needed for confirmed prosthetic valve staphylococcal IE, since the maternal benefit of adequate source control outweighs its modest signal of risk; discuss with obstetrics. Doxycycline is avoided in pregnancy (fetal bone/teeth effects) — use a cephalosporin or macrolide alternative for prophylaxis instead. Surgery, when indicated, should not be withheld because of pregnancy — the maternal risk of unrepaired severe valvular disease or uncontrolled infection generally exceeds the surgical risk, though timing and technique are planned jointly with obstetrics.

Breastfeeding

Penicillins, cephalosporins, and vancomycin are compatible with breastfeeding. Gentamicin has minimal oral bioavailability in the infant and is generally considered compatible for a short, defined course. For dental prophylaxis, amoxicillin, cephalexin, azithromycin, and clarithromycin are all compatible with breastfeeding; avoid doxycycline where a compatible alternative exists.

Pediatrics

Pediatric IE is uncommon and is managed with pediatric cardiology and infectious diseases involvement — dosing for organism-directed IV therapy is weight-based and follows dedicated pediatric IE guidance rather than a simple adult-dose conversion; do not extrapolate adult mg doses without pediatric-specific confirmation.^[8] Pediatric dosing for dental antibiotic prophylaxis is well established and included directly in Drug Tables (weight-based, not to exceed the adult dose).

Renal impairment

Adjust vancomycin, aminoglycoside (gentamicin, streptomycin), and daptomycin dosing and intervals for renal function, and monitor levels/AUC closely — these are the agents most likely to cause, or be affected by, acute kidney injury during a prolonged IE course.^[9] Ampicillin plus ceftriaxone (rather than an aminoglycoside-containing regimen) is specifically preferred for enterococcal IE when creatinine clearance is reduced.

Older adults

Older patients are at higher risk of both ototoxicity and nephrotoxicity from aminoglycoside therapy — this is part of why gentamicin has been removed from routine staphylococcal native valve regimens, and why any aminoglycoside-containing regimen in an older adult warrants closer monitoring and, where an equally effective alternative exists, avoidance.

People who inject drugs

Right-sided (typically tricuspid) IE due to S. aureus is the dominant pattern. Address ongoing substance use with addiction medicine and harm-reduction involvement from admission — this materially affects both relapse risk and eligibility for outpatient parenteral therapy. Outpatient parenteral antimicrobial therapy (OPAT) can be used in this population but requires stringent entry criteria and close follow-up given lower acceptance and higher barriers to structured support; a valve-sparing surgical approach is preferred over valve replacement where feasible, given the elevated reinfection risk with continued injection drug use.^[7]

Monitoring & Follow-Up

Repeat blood cultures 24-72 hours into therapy to confirm clearance of bacteremia — this also sets the actual start date for counting treatment duration (from the first negative culture, not from day 1 of antibiotics).
Vancomycin and aminoglycoside trough/AUC monitoring per current consensus guidance, plus periodic renal function; weekly creatine kinase for daptomycin; audiometric/vestibular assessment for any prolonged (beyond about 2 weeks) or high-dose aminoglycoside course.^[9]
Periodic CBC and liver function tests — beta-lactam-induced cytopenias/interstitial nephritis, linezolid myelosuppression, and rifampin hepatotoxicity are all monitored this way.
Follow-up (and, where clinically indicated, repeat) echocardiography to assess response to therapy, detect a new complication (worsening regurgitation, new abscess, new conduction abnormality), and support surgical planning — repeat urgently for a new murmur, new heart failure, a new embolic event, or persistent fever/bacteremia despite appropriate therapy.
Colonoscopy referral for any patient with Streptococcus gallolyticus (bovis) IE or bacteremia, to investigate for an underlying colorectal malignancy.
Dental evaluation and ongoing routine dental care — both as part of the initial workup (looking for a dental source) and as long-term secondary prevention.
Distinguish relapse (same organism, typically within weeks to a few months of completing therapy) from reinfection (a new organism or a new exposure) at any recurrence, since this changes both the antibiotic plan and the surgical/source-control assessment.

Treatment Failure / Next Step

Persistent fever or bacteremia beyond 5-7 days of appropriate, organism-directed therapy: obtain (or repeat) echocardiography — preferably TEE — to look for an undrained abscess, extension into adjacent tissue, or another undrained metastatic focus of infection, and reassess for an infected device/catheter requiring removal.
Confirm the antibiotic choice, dose, and (for vancomycin/aminoglycosides) actual achieved levels are appropriate for the identified organism and its susceptibilities — involve infectious diseases if this has not already happened.
New heart block, worsening regurgitation, or new/worsening heart failure at any point: urgent surgical evaluation — do not wait for the antibiotic course to finish.
A new embolic event: reassess vegetation size and mobility and the case for earlier surgery, but weigh timing carefully against recent neurologic injury — surgery after a major stroke is typically deferred in consultation with neurology and the endocarditis team unless an urgent indication (heart failure, uncontrolled infection, a very high ongoing embolic risk) outweighs the risk of surgery-associated hemorrhagic transformation.
Suspected relapse or reinfection after completing therapy: confirm which one it is (the same organism on a similar timeline suggests relapse; a new organism or a new exposure suggests reinfection), obtain new cultures before any retreatment, and reassess the case for surgery rather than simply repeating the same antibiotic course.
A true, well-documented beta-lactam allergy that is limiting first-line options: refer for allergy evaluation and possible desensitization rather than defaulting to a broader-spectrum or less effective alternative for the entire course.

Common Errors to Avoid

Starting empiric antibiotics before an adequate set of blood cultures has been drawn — one of the most consequential and avoidable errors in suspected IE, since it can permanently obscure the diagnosis.
Continuing gentamicin routinely for staphylococcal native valve IE — no longer recommended given its toxicity without a proven added benefit in this specific setting.
Using rifampin as monotherapy, or adding it before source control/adequate bactericidal partner-drug levels are established — rifampin should always be combined with another active agent to prevent rapid resistance.
Giving dental antibiotic prophylaxis to a patient who does not have one of the current, narrower high-risk cardiac conditions — a common holdover from older, broader guidance.
Using clindamycin for dental antibiotic prophylaxis — no longer recommended given its association with Clostridioides difficile infection; use doxycycline (or a macrolide/cephalosporin, as appropriate) instead.
Missing the prophylaxis dosing window — the dose must be given 30-60 minutes before the procedure; if it was missed beforehand, it may still be given up to 2 hours afterward, but later than that is not effective.
Forgetting the colonoscopy referral for S. gallolyticus (bovis) IE.
Treating a static, long-standing, unchanged heart murmur as a new finding suggestive of IE.
Deciding on IV-to-oral stepdown without infectious diseases involvement — this is a selected-patient, specialist-directed decision, not a routine step.
Counting treatment duration from the first dose of antibiotics rather than from the first negative blood culture.

Clinical Decision Algorithm

Algorithm A — Diagnostic approach to suspected IE

Suspected IE: fever with a new/changing murmur, an unexplained embolic event, or bacteremia with a predisposing cardiac condition

Draw at least 3 blood culture sets from separate sites before starting antibiotics; obtain baseline labs, ECG, chest x-ray, and echocardiography (TTE first-line)

Apply the Modified Duke Criteria — pathologic criteria, or major/minor clinical criteria^[3]

Definite IE — pathologic criteria met, or 2 major, or 1 major + 3 minor, or 5 minor clinical criteria

Begin empiric IV antibiotic therapy immediately and assess surgical indications in parallel — proceed to Algorithm B

Possible IE — 1 major + 1 minor, or 3 minor clinical criteria

Maintain high suspicion: repeat blood cultures and echocardiography (consider TEE), reassess criteria over time, and start empiric therapy if the clinical picture supports it — obtain infectious diseases input

Rejected — firm alternative diagnosis, resolution with 4 days or less of antibiotics, no pathologic evidence at surgery/autopsy with 4 days or less of antibiotics, or does not meet possible-IE criteria

Reconsider the diagnosis and evaluate alternative causes of fever, murmur, or bacteremia

Algorithm B — Empiric IV antibiotic therapy while cultures are pending

IE confirmed or strongly suspected — blood cultures already drawn

Native valve — community-acquired, non-toxic-appearing

Vancomycin + ceftriaxone

Native valve — severe/toxic presentation, or IV drug use-associated

Vancomycin + gentamicin; stop gentamicin once staphylococcal native valve IE is confirmed

Prosthetic valve — early (under 1 year), or strong suspicion of staphylococcal PVE

Vancomycin + gentamicin + rifampin

Narrow to the organism-directed regimen in Drug Tables once culture and susceptibility results are available; count duration from the first negative blood culture

Any Red Flags & Refer criterion develops at any point

Urgent cardiothoracic surgery and infectious diseases consultation — do not wait for the antibiotic course to finish

Stable clinical response, no red flags

Continue the full organism-directed IV course; reassess IV-to-oral stepdown eligibility once stable (see Algorithm C)

Algorithm C — IV-to-oral stepdown eligibility

Patient stable and afebrile on IV therapy, with a clear organism identified^[5]

Left-sided IE due to a streptococcus species, E. faecalis, MSSA, or coagulase-negative staphylococci, with no unresolved surgical indication or complication

Discuss oral combination stepdown with infectious diseases — e.g., amoxicillin, or linezolid plus rifampin, chosen by organism and susceptibility — to complete the planned total duration

Right-sided/complicated IE, an organism outside this list, or any unresolved surgical indication

Continue full IV therapy for the planned duration — oral stepdown evidence does not support this group

Algorithm D — Dental procedure antibiotic prophylaxis decision

Patient with a cardiac condition is scheduled for a dental procedure

One of the defined high-risk cardiac conditions is present (see Choose Initial Treatment)

Does the procedure involve gingival/periapical manipulation or oral mucosal perforation?

Yes

Give single-dose prophylaxis 30-60 minutes before the procedure — amoxicillin (or an IM/IV or penicillin-allergy alternative from Drug Tables)

No — e.g., anesthetic injection through non-infected tissue, radiographs, orthodontic adjustment, shedding of primary teeth

No prophylaxis needed

Not one of the defined high-risk cardiac conditions

No antibiotic prophylaxis indicated — reinforce routine dental care and oral hygiene instead

Drug Tables

How to use these tables: Doses are adult doses and require patient-specific confirmation (renal function, weight, allergy history). Begin counting duration from the date of the first negative blood culture. Pediatric IE treatment dosing is weight-based and specialist-directed (pediatric cardiology/infectious diseases) unless a specific pediatric dose is shown. Select any drug name to open its complete Pharmasist Drug Database page.

Organism-directed therapy — Staphylococci

Staphylococci (MSSA, MRSA, and coagulase-negative staphylococci) account for a large share of both native and prosthetic valve IE.

Native valve	Regimen	Duration	Comments
MSSA	Cloxacillin or cefazolin	6 weeks (2 weeks may be used if right-sided and uncomplicated — no renal impairment, no extracardiac metastatic infection)	For a beta-lactam type-1 hypersensitivity reaction, consider desensitization; cefazolin may be used for a well-defined non-anaphylactic penicillin reaction; alternatively use vancomycin or daptomycin. Gentamicin is no longer recommended for staphylococcal native valve IE given toxicity concerns and a lack of supporting data.
MRSA	Vancomycin or daptomycin	6 weeks	Vancomycin trough 10-15 mg/L suggested. Daptomycin is reserved for select patients; optimal IE dosing has not been firmly established.

Prosthetic valve	Regimen	Duration	Comments
MSSA	Cloxacillin (or cefazolin) + rifampin + gentamicin (first 2 weeks only)	Beta-lactam ≥6 weeks; rifampin ≥6 weeks; gentamicin first 2 weeks only	For a beta-lactam type-1 hypersensitivity reaction, consider desensitization; cefazolin may be used for a well-defined non-anaphylactic reaction; alternatively cloxacillin may be replaced by vancomycin.
MRSA	Vancomycin + rifampin + gentamicin (first 2 weeks only)	Vancomycin/rifampin ≥6 weeks; gentamicin first 2 weeks only	Vancomycin trough 10-15 mg/L suggested.

Organism-directed therapy — Viridans group streptococci and Streptococcus gallolyticus (bovis)

Selection depends on penicillin MIC susceptibility tier.

Native valve	Regimen	Duration	Comments
Susceptible (MIC ≤0.12 mg/L)	Penicillin G or ceftriaxone (ampicillin may replace penicillin G)	4 weeks	Alternatively, penicillin G or ceftriaxone + gentamicin for 2 weeks — do not use this short 2-week course if a cardiac or extracardiac abscess is present. Vancomycin (4 weeks) is reserved for a beta-lactam hypersensitivity reaction.
Relatively resistant (MIC over 0.12 to 0.5 mg/L)	Penicillin G (ampicillin or ceftriaxone may replace) + gentamicin (first 2 weeks)	Penicillin 4 weeks total; gentamicin first 2 weeks only	Vancomycin (4 weeks) is reserved for a beta-lactam hypersensitivity reaction.
Resistant (MIC over 0.5 mg/L)	Treat as enterococcal IE	See Enterococci table below	Penicillin-resistant strains, <em>Abiotrophia defectiva</em>, and <em>Granulicatella</em> spp. are difficult to cure and should follow the enterococcal regimens.

Prosthetic valve	Regimen	Duration	Comments
Susceptible (MIC ≤0.12 mg/L)	Penicillin G or ceftriaxone (ampicillin may replace) ± gentamicin (first 2 weeks)	6 weeks; gentamicin first 2 weeks only if used	Vancomycin (6 weeks) is reserved for a beta-lactam hypersensitivity reaction.
Relatively/fully resistant (MIC over 0.12 mg/L)	Penicillin G or ceftriaxone (ampicillin may replace) + gentamicin	Both components for the full 6 weeks	Vancomycin (6 weeks) is reserved for a beta-lactam hypersensitivity reaction.

Organism-directed therapy — Enterococci

Enterococcal IE generally requires 4-6 weeks of combined beta-lactam and aminoglycoside (or alternative synergy) therapy; choice depends on penicillin, aminoglycoside, and vancomycin susceptibility.

Susceptibility tier	Regimen	Duration	Comments
Susceptible to penicillin, gentamicin, and vancomycin	Ampicillin or penicillin G + gentamicin	Native valve: 4 weeks if symptoms under 3 months, 6 weeks if 3 months or more. Prosthetic valve: 6 weeks.	Alternatively, ampicillin + ceftriaxone (6 weeks) — preferred if creatinine clearance is under 50 mL/min. Vancomycin + gentamicin (6 weeks) is reserved for a beta-lactam hypersensitivity reaction.
Susceptible to penicillin, streptomycin, and vancomycin; gentamicin-resistant	Ampicillin + ceftriaxone	6 weeks	Alternatively, ampicillin or penicillin G + streptomycin (same 4-6 week rule as above by symptom duration), or vancomycin + streptomycin (6 weeks) for a beta-lactam hypersensitivity reaction.
Susceptible to aminoglycosides and vancomycin; penicillin-resistant	Vancomycin + gentamicin	6 weeks
Resistant to aminoglycosides, penicillin, and vancomycin	Linezolid or daptomycin	6 weeks or more	Management of multidrug-resistant enterococcal IE is not clearly defined and clinical data remain limited — mandatory infectious diseases consultation; optimal daptomycin dosing has not been established.

Organism-directed therapy — Gram-negative bacteria (HACEK and non-HACEK)

HACEK organisms (Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, Kingella spp.) are fastidious, slow-growing Gram-negative bacilli.

Organism	Regimen	Duration	Comments
HACEK group	A third-generation (or higher) cephalosporin, e.g., ceftriaxone	Typically 4 weeks native valve, 6 weeks prosthetic valve	Ampicillin is not recommended given frequent beta-lactamase production. For a beta-lactam allergy, use a fluoroquinolone (ciprofloxacin, levofloxacin, or moxifloxacin). For demonstrated resistance, a carbapenem (meropenem, or imipenem/cilastatin) may be used — infectious diseases consultation required.<cite data-reference-id="dc298fdd-3545-45c2-a119-53b575f4800f"></cite>
Non-HACEK Gram-negative bacteria	Combination therapy guided by susceptibilities (typically a beta-lactam plus an aminoglycoside or fluoroquinolone)	Per infectious diseases direction	Uncommon; identification and susceptibility testing are essential to select the regimen and course.

Culture-negative IE

No single default empiric regimen — base the choice on a thorough review of host factors, comorbidities, injection drug use, animal/insect exposure, indwelling devices, and prior procedures, in consultation with infectious diseases and clinical microbiology.

Consider serologic and molecular diagnostics for Coxiella burnetii, Bartonella spp., Tropheryma whipplei, or Chlamydia spp. when culture-negative IE is unexplained.^[1] Coxiella burnetii (Q fever) endocarditis specifically is treated with a prolonged combination of doxycycline plus hydroxychloroquine under infectious diseases direction, given for a duration measured in months to years rather than weeks — this is a distinctly different course than the standard bacterial IE regimens above and must be individualized by a specialist.

IV Antibiotic Reference — Aminoglycosides

Drug	Dosage	Adverse effects	Drug interactions	Comments
Gentamicin	Adults: 1 mg/kg IV/IM Q8H, or 3 mg/kg IV/IM once daily for viridans streptococci/S. gallolyticus synergy dosing Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Nephrotoxicity, ototoxicity	Enhanced nephrotoxicity/ototoxicity with other nephrotoxins/ototoxins (e.g., vancomycin, amphotericin B); increased respiratory depression with neuromuscular blockers	For enterococcal synergy, a peak of 3-4 mg/L and trough under 1 mg/L are suggested. No longer routine for staphylococcal native valve IE. Consider avoiding in older adults or those at risk of aminoglycoside toxicity. Monitor renal function and levels, especially with prolonged courses.
Streptomycin	Adults: 7.5 mg/kg IV/IM Q12H Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Nephrotoxicity, ototoxicity	Enhanced nephrotoxicity/ototoxicity with other nephrotoxins/ototoxins	An alternative aminoglycoside when gentamicin resistance is present (streptomycin-susceptible enterococcal or streptococcal IE). Serum concentration assay is not widely available; monitor renal and eighth-nerve function closely.

IV Antibiotic Reference — Cephalosporins

Drug	Dosage	Adverse effects	Drug interactions	Comments
Cefazolin	Adults: 2 g IV Q8H Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Rash, hypersensitivity, drug fever, diarrhea	Possible increased INR with warfarin
Ceftriaxone	Adults, most indications: 2 g IV Q24H Adults, combined with ampicillin for E. faecalis IE: 2 g IV Q12H Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Rash, hypersensitivity, drug fever, diarrhea, elevated AST/ALT, eosinophilia, thrombocytosis	Possible increased INR with warfarin; binds IV calcium salts to form an insoluble precipitate — do not co-administer through the same line

IV Antibiotic Reference — Glycopeptides

Drug	Dosage	Adverse effects	Drug interactions	Comments
Vancomycin	Adults: 15-20 mg/kg IV Q8-12H, adjusted to target trough/AUC Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Thrombophlebitis, rash, fever, anemia, nephrotoxicity, ototoxicity, infusion-related flushing	Increased nephrotoxicity when combined with an aminoglycoside	Dose to a target trough of 10-15 mg/L, or per an AUC-guided institutional protocol, for staphylococcal IE; avoid troughs over 15 mg/L. There is no separate recommended therapeutic range for non-MRSA pathogens (streptococci, enterococci) — the MRSA range is generally used.<cite data-reference-id="5d629681-8aba-49ae-8e99-c242cf6f82d5"></cite>

IV Antibiotic Reference — Lipopeptides

Drug	Dosage	Adverse effects	Drug interactions	Comments
Daptomycin	Adults: 6 mg/kg IV Q24H (some experts use 8 mg/kg or more) Children: Not established for routine pediatric use — specialist-directed only	Diarrhea, nausea, vomiting, constipation, thrombophlebitis, injection-site reaction, anemia, creatine kinase elevation, myalgia, rhabdomyolysis	Avoid with an HMG-CoA reductase inhibitor as a precaution, since daptomycin may increase statin levels	Monitor creatine kinase weekly at minimum, especially with renal impairment or concomitant statin use. Some experts use a higher dose (8 mg/kg or more) for IE. Reserve for vancomycin intolerance/hypersensitivity or per infectious diseases direction.

IV Antibiotic Reference — Oxazolidinones

Drug	Dosage	Adverse effects	Drug interactions	Comments
Linezolid	Adults: 600 mg IV/PO Q12H Children: Not established for routine pediatric use — specialist-directed only	Diarrhea, nausea, vomiting, myelosuppression (anemia, thrombocytopenia)	MAOI activity — evaluate concomitant serotonergic agents; avoid tyramine-rich foods	Monitor CBC weekly. Reserve for established resistance or when other appropriate agents are contraindicated.

IV Antibiotic Reference — Penicillins

Drug	Dosage	Adverse effects	Drug interactions	Comments
Penicillin G	Adults: 12-18 million units/day IV divided Q4-6H (up to 24 million units/day divided Q4-6H for prosthetic valve viridans streptococcal/S. gallolyticus IE) Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Rash, hypersensitivity, drug fever, interstitial nephritis, seizure at high dose	May increase methotrexate levels; may enhance the anticoagulant effect of warfarin	Use the higher end of the dose range for viridans streptococcal/S. gallolyticus prosthetic valve IE.
Ampicillin	Adults: 2 g IV Q4H Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Rash, hypersensitivity, drug fever, interstitial nephritis, seizure at high dose	May increase methotrexate levels; may enhance the anticoagulant effect of warfarin
Cloxacillin	Adults: 2 g IV Q4H Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Rash, hypersensitivity, drug fever, interstitial nephritis, seizure at high dose	May increase methotrexate levels; may enhance the anticoagulant effect of warfarin

IV Antibiotic Reference — Rifamycins

Drug	Dosage	Adverse effects	Drug interactions	Comments
Rifampin	Adults: 300 mg IV/PO Q8H Children: Weight-based, specialist-directed — see AHA pediatric IE statement	Rash, orange discolouration of body fluids (including contact lens staining), nausea, vomiting, hepatotoxicity, thrombocytopenia	Potent inducer of multiple CYP substrates — reduces levels of cyclosporine, tacrolimus, sirolimus, phenytoin, warfarin, and hormonal contraceptives	Use only in combination with another active agent, never as monotherapy.

IV Antibiotic Reference — Carbapenems

For resistant HACEK or other resistant Gram-negative organisms only, under infectious diseases direction.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Meropenem	Adults: Per institutional protocol, infectious diseases-directed Children: Weight-based, specialist-directed	GI upset, rash, hypersensitivity, rare seizure	May reduce valproic acid levels significantly
Imipenem / cilastatin	Adults: Per institutional protocol, infectious diseases-directed Children: Weight-based, specialist-directed	GI upset, rash, hypersensitivity, seizure risk (dose-related)	May reduce valproic acid levels significantly

IV/Oral Antibiotic Reference — Fluoroquinolones

Beta-lactam-allergic HACEK alternative; also used in specialist-selected oral stepdown combinations.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Ciprofloxacin	Adults: Per institutional protocol, infectious diseases-directed Children: Not established for routine pediatric use — specialist-directed only	GI upset, tendinopathy, QT prolongation	Chelation with divalent/trivalent cations (antacids, iron, calcium) reduces absorption
Levofloxacin	Adults: Per institutional protocol, infectious diseases-directed Children: Not established for routine pediatric use — specialist-directed only	GI upset, tendinopathy, QT prolongation	Chelation with divalent/trivalent cations reduces absorption
Moxifloxacin	Adults: Per institutional protocol, infectious diseases-directed Children: Not established for routine pediatric use — specialist-directed only	GI upset, tendinopathy, QT prolongation	Chelation with divalent/trivalent cations reduces absorption	Used in some specialist-selected oral stepdown combinations (with rifampin) for susceptible organisms.

IV/Oral Antibiotic Reference — Tetracyclines

Drug	Dosage	Adverse effects	Drug interactions	Comments
Doxycycline	Adults: 100 mg PO/IV Q12H for Q fever IE (see prophylaxis table below for the single-dose prophylaxis regimen) Children: Weight-based, specialist-directed — see AHA pediatric IE statement	GI upset, photosensitivity, esophageal irritation	Chelation with divalent/trivalent cations reduces absorption; may reduce hormonal contraceptive efficacy	Combined with hydroxychloroquine for culture-negative Coxiella burnetii (Q fever) IE, given for months. Also the dental prophylaxis fallback when penicillins, cephalosporins, and macrolides cannot be used.

Dental/Procedural Antibiotic Prophylaxis

For the specific high-risk cardiac conditions and qualifying dental procedures defined in Choose Initial Treatment only. Administer 30-60 minutes before the procedure (up to 2 hours after if inadvertently missed beforehand). Clindamycin is no longer recommended for this indication.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Amoxicillin (standard regimen)	Adults: 2 g PO, single dose Children: 50 mg/kg PO, single dose, not to exceed the adult dose	GI upset, hypersensitivity		First choice when the patient can take oral medication.

Unable to take oral medication

Avoid IM injection in an anticoagulated patient.

Drug	Dosage	Adverse effects	Comments
Ampicillin	Adults: 2 g IM or IV, single dose Children: 50 mg/kg IM or IV, single dose, not to exceed the adult dose	Rash, hypersensitivity
Cefazolin	Adults: 1 g IM or IV, single dose Children: 50 mg/kg IM or IV, single dose, not to exceed the adult dose	Rash, hypersensitivity	Do not use in a patient with a history of anaphylaxis, angioedema, or urticaria to a penicillin.
Ceftriaxone	Adults: 1 g IM or IV, single dose Children: 50 mg/kg IM or IV, single dose, not to exceed the adult dose	Rash, hypersensitivity	Do not use in a patient with a history of anaphylaxis, angioedema, or urticaria to a penicillin.

Allergic to penicillin or ampicillin, able to take oral medication

Drug	Dosage	Adverse effects	Drug interactions	Comments
Cephalexin (or another first- or second-generation oral cephalosporin)	Adults: 2 g PO, single dose Children: 50 mg/kg PO, single dose, not to exceed the adult dose	GI upset, hypersensitivity		Do not use in a patient with a history of anaphylaxis, angioedema, or urticaria to a penicillin.
Azithromycin	Adults: 500 mg PO, single dose Children: 15 mg/kg PO, single dose, not to exceed the adult dose	GI upset	Multiple CYP3A4 interactions
Clarithromycin	Adults: 500 mg PO, single dose Children: 15 mg/kg PO, single dose, not to exceed the adult dose	GI upset, metallic taste	Multiple CYP3A4 interactions
Doxycycline	Adults: 100 mg PO, single dose Children over 45 kg: 100 mg PO, single dose Children 45 kg or under: 2.2 mg/kg PO, single dose	GI upset, photosensitivity	Chelation with divalent/trivalent cations reduces absorption	Preferred fallback now that clindamycin is no longer recommended for this indication. Avoid in pregnancy — use a cephalosporin or macrolide instead.

Allergic to penicillin or ampicillin, unable to take oral medication

Drug	Dosage	Adverse effects	Drug interactions	Comments
Cefazolin	Adults: 1 g IM or IV, single dose Children: 50 mg/kg IM or IV, single dose, not to exceed the adult dose	Rash, hypersensitivity		Do not use in a patient with a history of anaphylaxis, angioedema, or urticaria to a penicillin.
Ceftriaxone	Adults: 1 g IM or IV, single dose Children: 50 mg/kg IM or IV, single dose, not to exceed the adult dose	Rash, hypersensitivity		Do not use in a patient with a history of anaphylaxis, angioedema, or urticaria to a penicillin.

References

Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association — Circulation, American Heart Association (Baddour LM, Wilson WR, Bayer AS, et al.). Circulation 2015;132(15):1435-1486
2023 ESC Guidelines for the management of endocarditis — European Heart Journal, European Society of Cardiology (Delgado V, Ajmone Marsan N, de Waha S, et al.). Eur Heart J 2023;44(39):3948-4042
Proposed Modifications to the Duke Criteria for the Diagnosis of Infective Endocarditis — Clinical Infectious Diseases (Li JS, Sexton DJ, Mick N, et al.). Clin Infect Dis 2000;30(4):633-638
The 2023 Duke-International Society for Cardiovascular Infectious Diseases Criteria for Infective Endocarditis: Updating the Modified Duke Criteria — Clinical Infectious Diseases (Fowler VG, Durack DT, Selton-Suty C, et al.). Clin Infect Dis 2023;77(4):518-526
Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis — New England Journal of Medicine (Iversen K, Ihlemann N, Gill SU, et al.). N Engl J Med 2019;380(5):415-424
Prevention of Viridans Group Streptococcal Infective Endocarditis: A Scientific Statement From the American Heart Association — Circulation, American Heart Association (Wilson WR, Gewitz M, Lockhart PB, et al.). Circulation 2021;143(20):e963-e978
Management of Infective Endocarditis in People Who Inject Drugs: A Scientific Statement From the American Heart Association — Circulation, American Heart Association (Baddour LM, Weimer MB, Wurcel AG, et al.). Circulation 2022;146(14):e187-e201
Infective Endocarditis in Childhood: 2015 Update: A Scientific Statement From the American Heart Association — Circulation, American Heart Association (Baltimore RS, Gewitz M, Baddour LM, et al.). Circulation 2015;132(15):1487-1515
Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review — American Journal of Health-System Pharmacy (Rybak MJ, Le J, Lodise TP, et al.). Am J Health Syst Pharm 2020;77(11):835-864

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.