Sections

Treatment

Approach Considerations

Experience has been gained with completing the last 2 to 3 weeks of antibiotic treatment via the oral route. Candidates for this switch are those that had rapidly cleared their BSI; rapidly defervesced; and showed no evidence of embolization or growth of their vegetations. There is no apparent need for cardiac surgery in the near future. Antibiotics are given orally for long term suppression of an infected device that cannot be removed. At least 1 of the prescribed agents must be documented to achieve bactericidal levels when taken by mouth. There must be no evidence of malabsorption. There should be no concerns about compliance with the treatment regimen (eg, cases of OUDIE). The evidence that supports the oral route is best established for gram-positive pathogens such as enterococci, MRSA, and CoNS.^{[86, 96]}

The major goals of therapy for IE are to eradicate the infectious agent from the thrombus and to address the intra and extacardiac complications of valvular infection. The latter includes both the intracardiac and extracardiac consequences of IE. Some of the effects of IE require surgical intervention. Emergent care should focus on making the correct diagnosis and stabilizing the patient. General measures include the following:

Treatment of congestive heart failure
Supplemental oxygenation if required
Hemodialysis may be necessary in the setting of severe renal failure

No special diets are recommended for patients with endocarditis. The presence of congestive heart failure calls for a sodium-restricted diet. Activity limitations are determined by the severity of the illness, complications (eg, stroke), and the presence of significant congestive heart failure.

Antibiotic Therapy

General principles

All patients with proven or highly suspected IE initially should be assessed by and actively followed by an infectious diseases consultant, especially as regards initial antibiotic therapy and any changes in such during the entire theraputic course.

Avoid empiric use of antibiotics with a high potential for developing resistance. These include ciprofloxacin, trimethoprim-sulfamemethoxazole, gentamicin, tobramycin, and ceftazadime.

Generally avoid synergistic combinations except for those pathogens for which such therapy is clearly indicated, such as enterococci, S Viridans, HACEK isolates, and infections of intracardiac devices. For other pathogens, true synergistic effect seldom is achieved, and possible side effects are more frequent. A possible exception may be the combination of daptomycin and fosfomycin in severely immunosuppressed individuals (eg, patients being treated for acute leukemia).^[97]

In general, avoid use of vancomycin. It is extremely challenging to acheive and sustain theraputic levels in situations of unstable renal function. Gentamicin may need to be added because a growing degree of tolerance of staphylococci and enterococci to vancomycin may induce partial resistance of bacteria to daptomycin and other antibiotics by inducing cellular wall thickening.

In the setting of acute IE, institute antibiotic therapy as soon as possible to minimize valvular damage. Three to 5 sets of blood cultures are obtained within 60 to 90 minutes, followed by the infusion of the appropriate antibiotic regimen. If molecular blood testing is not available, the initial antibiotic choice is arrived at by SA and attention to local resistance patterns.

Native valve endocarditis (NVE) has often been treated with penicillin G and gentamicin for synergistic coverage of streptococci. Patients with a history of IV drug use have been treated with nafcillin and gentamicin to cover for methicillin-sensitive staphylococci. The emergence of methicillin-resistant S aureus (MRSA) and penicillin-resistant streptococci have led to a change in empiric treatment.

Prosthetic valve endocarditis (PVE) usually is caused by MRSA or CoNS.^[30] Vancomycin and gentamicin classically have been administered despite the risk for renal insufficiency. Rifampin is necessary for individuals with infection of prosthetic valves or other intravascular devices because it penetrates the biofilm that protects the primary pathogens of these devices (CoNS, MSSA,MRSA). These latter 2 agents serve to prevent the development of resistance to the rifampin.

Linezolid or daptomycin are options for patients with intolerance to vancomycin or resistant organisms.^[98]Organisms with a minimum inhibitory concentration (MIC) to vancomycin of 2 mcg/mL or higher should be treated with alternative agents. Appropriate regimens should be devised in consultation with a specialist in infectious disease.

In the cases of SBE, treatment generally may be safely delayed until culture and sensitivity results are available. If the patient's condition is stable, waiting does not increase the risk for complications in this form of the disease.

Eradicating bacteria from the fibrin-platelet thrombus is extremely difficult because of (1) the high concentration of organisms present within the vegetation (ie, 10-100 million bacteria per gram of tissue), (2) their position deep within the thrombus, (3) their location in both a reduced metabolic and reproductive state, and (4) the interference of fibrin and white cells with antibiotic action. For all these reasons, bactericidal antibiotics are considered necessary for cure of valvular infection.

Evidence has shown that patients with left-sided endocarditis in stable condition who received at least 10 days of intravenous antibiotics could be switched to oral administration for the remainder of their therapeutic course.^[96] Anecdotally, highly absorbed antibiotics such as linezolid have been used when intravenous access has been impossible to procure.

Treat all patients in a hospital or skilled nursing facility to allow adequate monitoring of the development of complications and the response to antibiotic therapy.

The American Heart Association (AHA) has developed guidelines for treating IE caused by the most frequently encountered microorganisms.^{[99, 100]}.The below represents an updating of the guidelines of the AHA that is necessitated by changing sensitivity patterns of the infecting organisms. In addition, the value of IV/PO linezolid and minocycline in the treatment of gram positive cocci and transitioning to oral therapy is more clear.

Antibiotic doses are predicated on normal renal function.

Adult NVE caused by penicillin-susceptible S viridans, S bovis, and other streptococci (MIC of penicillin of ≤0.1 mcg/mL) should be treated with 1 of the following regimens:

Administer penicillin G at 12-18 million units/day (U/d) IV by continuous pump or in 6 equally divided doses for 4 weeks.
Administer ceftriaxone at 2 g/d IV for 4 weeks. It may be given intramuscularly (IM) for short periods if venous access problems develop; ceftriaxone allows once-a-day outpatient IV therapy for clinically stable patients.
Administer penicillin G and gentamicin at 1 mg/kg (on the basis of ideal body weight) every 8 hours for 2 weeks; short-course therapy with ceftriaxone and gentamicin for 2 weeks is a cost-effective regimen and is effective in selected patients; short-course therapy is recommended for those with uncomplicated NVE caused by sensitive S viridans and of less than 3 months’ duration.
In patients who are allergic to penicillin, give vancomycin at 30 mg/kg/d IV in 2 equally divided doses for 4 weeks; the vancomycin dose should not exceed 2 g/d unless serum levels are monitored and can be adjusted to attain a peak vancomycin level of 30-45 mcg/mL 1 hour after completion of the intravenous infusion of vancomycin.

For NVE caused by relatively resistant streptococci (MICs of penicillin of 0.1-0.5 mcg/mL), the following regimens are recommended:

Administer penicillin G at 18 million U/d IV, either by continuous pump or in 6 equally divided doses, for 4 weeks.
Administer cefazolin at 6 g/d IV in 3 equally divided doses for 4 weeks.
Both of the above regimens are combined with gentamicin at 1 mg/kg (on the basis of ideal body weight) IM or IV every 8 hours for the first 2 weeks of therapy.
For patients who are allergic to penicillin, administer vancomycin at 30 mg/kg/d IV in 2 equally divided doses (usually, do not exceed 2 g/d unless serum levels are monitored) for 4 weeks; peak vancomycin levels of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.

Enterococcal Therapy

Infective endocarditis caused by nonresistant enterococci, resistant S viridans (MICs of penicillin G of >0.5 mcg/mL), or nutritionally variant S viridans and PVE caused by penicillin-G–susceptible S viridans or S bovis should be treated as follows:

Administer penicillin G at 18-30 million U/d IV, either by continuous pump or in 6 equally divided doses daily, combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4-6 weeks.
Alternatively, administer ampicillin at 12 g/d by continuous infusion or in 6 equally divided doses daily, combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4-6 weeks.
In patients who are allergic to penicillin, administer vancomycin at 30 mg/kg/d in 2 equally divided doses (usually, do not exceed 2 g/24 h unless serum levels are monitored). This may be combined with gentamicin for 4-6 weeks of treatment. A peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.

Enterococcal PVE generally responds as well as disease involving native valves. Six weeks of treatment is recommended for patients with symptoms of enterococcal IE of more than 3 months’ duration, with relapsed infection, or with PVE. Combination treatment for resistant E faecium with ceftriaxone 2 grams every 24 hours for at least 8 weeks plus ampicillin 12 g every 24 hours for at least 8 weeks appears to be the preferred approach.

A combination of an inhibitor of cell wall synthesis (ie, penicillin) with an aminoglycoside (ie, gentamicin, streptomycin) is necessary to achieve bactericidal activity against the enterococci. Tobramycin or amikacin do not act synergistically with antibiotics active against the bacterial cell wall.

Increasing numbers of enterococci have aminoglycoside-inactivating enzymes that make them relatively resistant to the usual synergistic combinations. These aminoglycoside-resistant strains have an MIC of 2000 mcg/mL or more for streptomycin and 500 mcg/mL or more for gentamicin. Of gentamicin-resistant enterococcal strains, 25% are susceptible to streptomycin.

Continuously infused ampicillin (serum level of 16 mcg/mL) is probably the best therapy for aminoglycoside-resistant enterococci. Alternative choices are imipenem, ciprofloxacin, or ampicillin with sulbactam. Vancomycin does not appear to be as useful as the aforementioned antibiotics.

Double beta-lactam therapy (ampicillin 2 g IV every 4 hours and ceftriaxone 2 g IV every 12 hours) is recommended for treatment of enterococci susceptible to penicillin and gentamicin when the creatinine clearance is less than 50 mL/min. This combination may be effective against enterococcal isolates that are resistant to high doses of gentamicin.^[132]

High peak levels of gentamicin are not necessary to establish synergistic bactericidal activity against enterococci. Peak gentamicin levels of 3-5 mcg/mL, with a trough of less than 2 mcg/mL, frequently can be obtained with a dose of gentamicin of 1 mg/kg IV every 8 hours. Once-a-day gentamicin dosing should not be used because a prolonged postantibiotic effect against gram-positive organisms does not occur, and synergistic killing requires the simultaneous presence of an agent active in the cell wall and an aminoglycoside.

A study indicates that gentamicin usage, even for synergy, is associated with decreasing renal function^[101]; however, overall mortality does not appear to be increased. Certainly, gentamicin therapy should be continued to achieve synergy against enterococci, but the practice of administering gentamicin for 5 days in the treatment of S aureus IVDA IE should be questioned.

Vancomycin-resistant isolates of Enterococcus faecium and Enterococcus faecalis (ie, vancomycin-resistant enterococci [VRE]) produce some of the most challenging nosocomial infections. No therapy has been proven highly effective for IE caused by strains of VRE.

NVE caused by methicillin-sensitive S aureus (MSSA) should be treated as follows:

Administer nafcillin or oxacillin at 2 g IV every 4 hours for 4-6 weeks.
Administer cefazolin at 2 g IV every 8 hours for 4-6 weeks.
For patients who are allergic to penicillin, administer vancomycin at 30 mg/kg (usually, do not to exceed 2 g/24 h unless serum levels are monitored) for 4-6 weeks and obtain a peak vancomycin level of 30-45 mcg/mL 1 hour after completion of the IV infusion.

Vancomycin therapy is associated with a significant failure rate (up to 35%) in the treatment of MSSA and MRSA BSI/IE. It appears that vancomycin should not be used to treat infections with staphylococci with an MIC of greater than 1.5-2 mcg/mL. In these cases, alternative agents such as linezolid or daptomycin should be used.

Outpatient treatment of nonenterococcal streptococci, MSSA, MRSA, VISA, CoNS, and VSE IE may be facilitated by use of dalbavancin, which requires IV administration every 7 days.^[102]

Treat PVE caused by MSSA as follows:

Administer nafcillin or oxacillin at 2 g IV every 4 hours for 6 weeks or longer.
Alternatively, administer cefazolin at 2 g IV every 8 hours for 6 weeks or longer.
Each of these options should be combined with rifampin at 300 mg orally every 8 hours for 6 weeks or longer and with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for the first 2 weeks.
Treat PVE caused by MRSA with vancomycin at 30 mg/kg (not to exceed 2 g/d unless serum levels are monitored) for 6 weeks or longer combined with rifampin and gentamicin as outlined above; a peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the IV infusion; a significant concern is that MRSA may become resistant to vancomycin.

Treatment with linezolid appears to result in outcomes superior to those with vancomycin against many types of infections caused by MRSA and MSSA. Another advantage of linezolid is that its dose does not need to be adjusted in patients with renal failure. Its excellent GI absorption facilitates transition to complete treatment orally. White blood cell counts, red blood cell counts, and platelet counts need to be monitored frequently while the patient is on linezolid. The risk of developing serotonin syndrome is low. After the fourth week of therapy, the risk for hematologic and neuropathic complications rapidly increases.

Daptomycin (6 mg/kg/24 h) has been approved for the treatment of S aureus BSI and right-sided IE. Higher doses of daptomycin (12 mg/kg/24 h) are more effective, with little increase in adverse effects. Patients who have received vancomycin have a higher rate of resistance to daptomycin.

Treat HACEK microorganisms as follows:

Administer ceftriaxone at 2 g/d IV for 4 weeks.
Alternatively, administer ampicillin at 12 g/d by continuous pump or in 6 equally divided doses daily; this may be combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4 weeks.

Culture-negative NVE is usually treated with vancomycin and gentamicin. In patients who previously have received antibiotics, initial therapy should consist of either ampicillin-sulbactam plus gentamicin (3 mg/kg/d) or vancomycin plus gentamicin and ciprofloxacin. Because of the increased risk for renal failure with gentamicin, the latter regimen is preferred.

Patients with culture-negative PVE should be given daptomycin or meropenem or linezolid targeting possible enterococcal or CoNS infections. In patients with suspected PVE who have previously received antibiotics, therapy should consist of daptomycin or linezolid for 6 weeks and rifampin for 6 weeks. There is a risk of developing resistance to rifampin; therefore, many clinicians would start this antibiotic only after the blood cultures results become negative.

Treatment of other microorganisms is as follows:

For P aeruginosa, administer ceftazidime, cefepime, or imipenem, combined with high-dose tobramycin at 8 mg/kg/d in 3 divided doses, to attain peak blood levels of 15-20 mcg/mL, for 6 weeks.
For enteric gram-negative rods (eg, E coli, Proteus mirabilis), administer ampicillin, ticarcillin-clavulanic acid, piperacillin, piperacillin-tazobactam, ceftriaxone, or cefepime combined with gentamicin or amikacin for 4-6 weeks.
For Streptococcus pneumoniae, administer ceftriaxone at 2 g/d IV or vancomycin (if penicillin allergy or high-level penicillin G resistance [MIC of 2 mcg/mL or more]) for 4 weeks.
For diphtheroids, administer penicillin G at 18-24 million U/d in 6 divided doses or vancomycin combined with gentamicin for 4 weeks.
For Q fever ( C burnetii infection), administer doxycycline combined with rifampin, trimethoprim-sulfamethoxazole, or a fluoroquinolone for 3-4 years.

Prosthetic valve endocarditis is especially difficult to treat, as the microorganisms adhere to the foreign body and may make them impervious to the bactericidal action of agents active in the cell wall. All patients with PVE require at least 6 weeks of antimicrobial therapy. Rifampin is the key drug in the treatment of PVE, as it is one of the only antimicrobial agents that penetrate the biofilm laid down by S aureus and CoNS. As a result of the risk of these organisms developing resistance to rifampin, many clinicians withhold the addition of rifampin until blood cultures have cleared.

Penicillin-sensitive S viridans PVE should be treated with 2 weeks of penicillin G or ceftriaxone combined with gentamicin, followed by 4 weeks of penicillin G or ceftriaxone.

If the S viridans PVE is caused by an organism with a penicillin MIC of 0.2 mcg/mL or more, penicillin G or ceftriaxone combined with gentamicin combination therapy should be administered for 4 to 6 weeks. If the combination therapy is administered for only 4 weeks, penicillin G or ceftriaxone should be continued for an additional 2 weeks. Linezolid may be substituted for penicillin or ceftriaxone if the patient has a history of severe, immediate penicillin hypersensitivity, such as urticaria, anaphylaxis, or angioedema.

Enterococcal PVE therapy is complicated by the multiple types of enterococcal antimicrobial resistance, including beta-lactamase production (rare), different types of aminoglycoside-inactivating enzymes (more common), and VRE (increasingly common). If the enterococci are highly resistant to both gentamicin and streptomycin, ampicillin should be administered for 8 to 12 weeks by continuous infusion.

Patients with PVE must be monitored carefully for signs of valve dysfunction, congestive heart failure, and heart block. They also should be monitored for clinical response to therapy, conversion of positive blood culture results, renal function status, and serum blood levels of vancomycin and aminoglycosides.

Valve replacement surgery should be performed promptly if any of the following occurs: moderate-to-severe congestive heart failure, valve dysfunction, perivalvular or myocardial abscess formation, the presence of an unstable valve that is becoming detached from the valve ring, more than 1 embolic episode with persistent vegetations observed on transesophageal echocardiogram, or the presence of vegetations larger than 1 cm in diameter.

If PVE does not respond to antimicrobial therapy and blood cultures results remain positive or if a relapse of bacteremia occurs after infection, the prosthetic valve should be replaced. In the presence of microorganisms that have no microbicidal agent (eg, VRE, fungi) or in the presence of other recalcitrant organisms (eg, P aeruginosa, S aureus, enteric gram-negative rods, Brucella species, C burnetii), past clinical experience shows that early replacement of the prosthetic valve improves the chances for cure.

Fungal endocarditis is rare, and it primarily occurs after prosthetic valve surgery and in individuals who abuse intravenous drugs. Candida species and Aspergillus species are the organisms most frequently encountered. Available antifungal agents have been unsuccessful in eliminating fungal IE. The only cures for proven fungal IE have resulted when surgical excision of the infected valves was combined with amphotericin B therapy.

Empiric therapy of OUDIE should be aimed at S aureus. The choice between using vancomycin or oxacillin/nafcillin depends on the incidence of MRSA in the community. Generally, gram-negative organisms occur infrequently, and delay in covering them initially is acceptable.

Monitoring During Therpy

Some clinicians obtain peak and trough blood samples during the course of antimicrobial therapy of IE in order to run serum bactericidal tests. These tests are performed by incubating serial 2-fold dilutions of serum that contains antimicrobials with an inoculum of 100,000 colony-forming units per milliliter of the target microorganism that previously has been isolated from the patient’s blood for 24-48 hours.^{[86, 99, 100, 103, 104, 105, 106, 107, 108, 109]}

Peak antimicrobial concentrations that inhibit and kill the bacteria at a 1:32 or greater dilution in serum are a consistent predictor of a favorable clinical response. Antimicrobial dosages are adjusted to try to attain this goal. However, many clinicians feel that the serum bactericidal test does not have a reproducible result, and these clinicians rely on standardized tests of antimicrobial susceptibility (ie, MICs) and serum antimicrobial assays of peak and trough levels to determine whether sufficient amounts of antimicrobial agents are being administered.^{[86, 96, 98, 99, 100, 103, 104]}

The basic criticism of these tests is that they are conducted in an in vitro environment outside the area of infection. Infected tissue can be hypoxic and acidotic with significant levels of inflammation. Such an environment can markedly interfere with the effectiveness of a wide range of antibiotics. It is not rare that after 4-8 weeks of therapy the patient appears to be cured. Two weeks after stopping the antibiotics, the individual relapses. More specific and sensitive laboratory tests must be developed to more accurately monitor therapeutic response.

Management of S aureus Bacteremia

In the past, management of S aureus bacteremia in the presence of an intravascular catheter required prompt removal of the catheter, initiation of appropriate antibiotic therapy, monitoring of blood culture results in 24 to 48 hours, and performance of transthoracic echocardiography (TTE).

If follow-up blood culture and TTE findings were negative and no evidence of metastatic infection was found, 2 weeks of antistaphylococcal therapy was believed to be appropriate.

If the follow-up blood culture findings are positive, TEE should be performed. If TEE demonstrates findings of valvular infection, the patient is to be treated for 4 to 6 weeks with antistaphylococcal antibiotics.

Although resorting immediately to TEE is becoming more common, it often is unnecessary. A scoring system has been developed to help differentiate patients with valvular infection from those with S aureus bacteremia that represents metastatic infection from sites such as splenic abscesses or osteomyelitis. Individuals with an underlying implantable cardiac device or whose S aureus BSIs developed in the community are at highest risk for IE and therefore should undergo immediate TEE. If the TEE findings are negative, it should be repeated in 5 days^[107] if the cause of persistent BSI is not identified. A good deal of these may be explained by endotheliosis. For the time being, the duration of antibiotic therapy for each case of S aureus catheter-related BSI must be individualized. The author and others would treat cases that meet the criteria of continuous bacteremia for a total of 4 weeks despite a negative TEE result.^{[101, 106, 107, 108, 109, 110]}

Anticoagulation Therapy

Although thrombosis may be a key element of IE, anticoagulation with warfarin (Coumadin, Jantoven) is controversial. Indeed, evidence indicates patients who are anticoagulated have worse outcomes than those who are not anticoagulated. Cases of non COVID-19 IE that are treated with anticoagulation appear to have a higher rate of intracerebral bleeding. If an established reason for anticoagulation (eg, deep venous thrombosis, presence of a mechanical prosthetic valve) exists, a standard regimen of anticoagulation should be followed.

Please see COVID-19 associated IE.

Indications for Surgery

Approximately 15% to 25% of patients with IE eventually require surgery.

Indications for surgical intervention in patients with NVE are as follows^[111]:

Congestive heart failure refractory to standard medical therapy
Fungal IE (except that caused by Histoplasma capsulatum)
Persistent sepsis after 72 hours of appropriate antibiotic treatment
Recurrent septic emboli, especially after 2 weeks of antibiotic treatment
Rupture of an aneurysm of the sinus of Valsalva
Conduction disturbances caused by a septal abscess
Kissing infection of the anterior mitral leaflet in patients with IE of the aortic valve

Congestive heart failure in a patient with NVE is the primary indication for surgery. A second relapse, during or after completion of treatment, requires replacement of the valve.

Paravalvular abscess and intracardiac fistula almost always require surgical intervention. Patients with culture-negative NVE who remained febrile for more than 10 days should be considered surgical candidates. Persistent hypermobile vegetations, especially those with a history of embolization beyond 7 days of antibiotic therapy, should be treated with surgery. Cardiac surgery should be considered in patients with multiresistant organisms (eg, enterococci).

The indications for surgery in patients with PVE are the same as those for patients with NVE, with the addition of the conditions of valvular dehiscence and early PVE. Orally administered antibiotics have been used as suppressive therapy for incurable valvular infections (ie, inoperable PVE).

Surgery often is required for treatment of metastatic infections (eg, cerebral and other types of aneurysms and macroabscesses of the brain and spleen). Many cerebral abscesses may not be accessible. If this is the case, they can be monitored because 30% may heal when treated medically.

Occasionally, local debridement and the administration of appropriate antibiotics may be sufficient to cure an uncomplicated pacemaker pocket infection; however, most studies indicate that complete removal of the system is necessary for cure in most cases. Many patients in whom this is not possible eventually die of complications from relapsing infection. This aggressive approach is especially necessary when dealing with pacemaker IE.

The AHA guidelines on CIED infections and their management recommend complete removal of infected CIED and leads for the following patients^[56]:

All patients with definite CIED infection, as shown by valvular and/or lead endocarditis or sepsis ^{[101, 111, 112, 113]}
All patients with CIED pocket infection, as shown by abscess formation, device erosion, skin adherence, or chronic draining sinus without involvement of the transvenous section of the lead system
All patients with valvular endocarditis without definite involvement of the lead(s), device, or both

Patients with occult staphylococcal bacteremia

The guideline states that complete removal is reasonable in patients with persistent occult gram-negative bacteremia despite appropriate antibiotic therapy.^[56]

Removal of the device and leads is not indicated in the following cases:

A superficial or incisional infection that does not involve the device, leads, or both
Relapsing BSI resulting from a non-CIED source and for which long-term suppressive antimicrobials are required

After removal of the infected device, placing a temporary transvenous pacer is best. Immediate insertion of a permanent pacemaker at a new site can be safely accomplished.

The AHA guideline on CIED infection recommends careful evaluation of each patient to determine if a CIED is still needed. Replacement device implantation should not be ipsilateral to the extraction site. The guideline suggests the contralateral side, the iliac vein, and epicardial implantation as preferred alternative locations.^[56]

The AHA guideline recommends that if blood cultures were positive before the device extraction, blood cultures should be taken after the device removal and new device placement should be delayed until blood cultures have been negative for at least 72 hours. If valvular infection is present, placement of new transvenous leads should be delayed for at least 14 days after CIED system removal.

In the past, removal of the intracardiac leads that had been in place for several months often necessitated open heart surgery. The use of laser technology to dissolve the pacemaker lead adhesions has a 94% success rate. The risk of dislodging vegetations during removal of infected leads is negligible. Patients whose leads cannot be removed are started on permanent antibiotic suppression.^{[111, 114, 115, 116, 117, 118]}

The AHA CIED guideline states that long-term suppressive antimicrobial therapy should be considered for patients with CIED infection who are not candidates for CIED removal. Such therapy should not be administered to patients who are candidates for CIED removal.^{[112, 113, 119, 120, 121, 122, 123, 124]}

Prevention of Infective Endocarditis

Approximately 15-25% of cases of IE are a consequence of invasive procedures that produce a significant bacteremia. As only 50% of those who developed valvular infection after a procedure were identified as being candidates for antibiotic prophylaxis, only approximately 10% of cases of IE can be prevented by the administration of preprocedure antibiotics. Maintaining good oral hygiene probably is more effective in the overall prevention of valvular infection because gingivitis is the most common source of spontaneous bacteremias.

Since implementation of IE prevention guidelines in 2009 of the European Society of Cardiology, there has been a marked increase in cases of IE, the age of patients with mitral valve involvement, mortality, and associated comorbidities (renal failure, heart failure, diabetes).^[125]

A follow-up in 2021 of the American Heart Association Gudelines did not document any increase in S viridans IE.^[126]

Antimicrobial prophylaxis against IE should be given in patients at higher risk, including those with the following conditions:

Presence of prosthetic heart valve
History of endocarditis
Cardiac valvulopathy in cardiac transplant recipients
Congenital heart disease with a high-pressure gradient lesion

The presence of a coronary artery stent is not considered to place the patient at high risk for endocarditis.

Also consider prophylaxis in patients before they undergo procedures that may cause transient bacteremia, such as the following^[110]:

Any procedure involving manipulation of gingival tissue or the periapical region of teeth, or perforation of the oral mucosa
Any procedure involving incision in the respiratory mucosa
Procedures on infected skin or musculoskeletal tissue including incision and drainage of an abscess
Prophylaxis no longer is routinely recommended for gastrointestinal or genitourinary procedures.

Prevention of vascular catheter infections is an important prophylactic approach in preventing NIE. Protective factors include the insertion and maintenance of catheters by an infusion therapy team, the use of topical disinfectants and antibiotics, and the practice of coating catheters with antimicrobial agents.

No double-blind studies have been performed to support the use of systemically administered antibiotics for the prevention of pacemaker or intracardiac defibrillator infections. However, awaiting definitive studies, the authors recommend prophylactic antibiotics, as with any implantable device. Of course, strict sterile technique must be followed. Antibiotic prophylaxis is not recommended for prevention of CIED infection in patients with pacemakers or intracardiac defibrillators during invasive procedures not directly related to device manipulation. Pacemaker infection due to transient bacteremias is uncommon.^[110]

There has been a significant increase in cardiac device infections and extractions of infected leads, especially among those older than 65 years.^[87]

The use of an absorbable envelope impregnated with rifampin and minocycline shows promise as a prophylactic measure to prevent CIED infections.^[127]

American Heart Association guidelines for prophylaxis

The AHA periodically compiles recommendations for IE prophylaxis.^[111]It is important to remember that these are not standards but guidelines, and thus they may be modified in particular circumstances. The guidelines remain unproven by randomized controlled clinical trials; indeed, many examples of failure of these recommendations have been noted, even when they are applied appropriately.^{[111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 127, 128, 129, 130]}

The 3 major steps in the pathogenesis of IE that are vulnerable to antibiotic prophylaxis are the following:

Killing of the pathogen in the bloodstream before it can adhere to the valve
Preventing adherence to the valve/fibrin-platelet thrombus
Eradicating any organisms that have attached to the thrombus

Successful antibiotic prophylaxis requires identifying those patients who are at risk, prioritizing the procedures that require prophylaxis, and selecting an appropriate antibiotic regimen. In general, bactericidal antibiotics are used; however, bacteristatic agents probably are effective in most circumstances.

Although the guidelines are a marked improvement because they prioritize the cardiac conditions and procedures that require antibiotic prophylaxis and emphasize the importance of promoting good oral hygiene, they offer little direction in dealing with the ever-growing problem of antibiotic-resistance patterns of S viridans and enterococci.

The importance of antibiotic prophylaxis of calcific valvular disease in elderly patients also needs to be more fully discussed. Calcific valvular disease is the most common underlying cardiac risk factor for the development of IE in this age group.

The author’s preference is to administer parenteral prophylactic antibiotics to patients with prosthetic valves because of the severe consequences of PVE.

The United Kingdom’s NICE guidelines on prophylaxis against IE differ from the AHA recommendations. The NICE guidelines do not recommend antibiotic prophylaxis for IE in patients undergoing dental procedures; however, they agree with the AHA guidelines in not recommending prophylaxis for those undergoing procedures in the upper and lower gastrointestinal tracts, the genitourinary tract, or the upper and lower respiratory tracts.^[50]

Subsequent to the NICE guidelines recommending abolition of all IE antibiotic prophylaxis, prescriptions for such prophylaxis dropped almost 80% without any apparent cases of IE; however, the authors of this article recommend continuing to follow the current AHA guidelines, especially in the presence of an intracardiac prosthetic device.

The rise in the rate of IE cases has called into serious question the validity of abolishing IE antibiotic prophylaxis. This increase has particularly affected individuals who would be deemed at high risk of developing valvular infection.^{[119, 120]}

Special Considerations

Failure to consider the diagnosis, especially in patients with a history of IV drug use and a low-grade fever, is a medicolegal pitfall. Many malpractice suits are caused by a failure to diagnose and a delay in diagnosis accompanied by a poor outcome for the patient.

As a rule for primary care clinics, do not administer antimicrobial agents to febrile patients with heart murmurs without first obtaining at least 2 sets of blood cultures.

The outcomes of staphylococcal bactermia by telephone consults are significantly inferior to those of bedside evaluation.^[121]

The perception that most IE is preventable is wrong. Frequent episodes of transient bacteremia occur with chewing and other activities of daily life. Proving that a failure to give prophylaxis before dental and surgical procedures resulted in IE is difficult; however, this does not prevent legal action alleging IE as a consequence of failing to give the antimicrobial prophylaxis recommended by the AHA.

When a central venous line is needed, not inserting the line when a patient is known to be bacteremic is advisable. If no alternative to placing the line is available, bactericidal antimicrobial agents should be administered to try to prevent the development of IE.

Consultations

In general, both a cardiologist and an infectious diseases specialist should be involved in the care of patients with IE. A bedside consultation by an infectious disease specialist results in far better outcomes than the more frequent telephone consultation.^[121] Consulting a cardiothoracic surgeon may be necessary. Personnel in the clinical microbiology laboratory must have the skill to isolate the organism, properly identify it, and perform susceptibility testing appropriate for the growth characteristics and requirements of the organism (with determination of the MIC of clinically relevant antimicrobial agents). To obtain the best possible information, the attending physician should work closely with the microbiology laboratory personnel.

Long-Term Monitoring

Monitoring for posttreatment bacteremia

Patients should have blood cultures taken after 3 to 4 days of treatment to document eradication of the bacteremia. Blood cultures during treatment are essential if persistent fever or other signs develop that suggest failing treatment.

Failure to sterilize the bloodstream, despite adequate serum levels of appropriate antibiotics, should prompt a search for metastatic infection (eg, abscesses, especially splenic, or mycotic aneurysm).

Fever lasting longer than 10 days into therapy with an indicated antibiotic regimen should be of concern and should prompt a search for suppurative complications. Approximately 30% of patients have a return of fever after the initial response. This usually is caused by an intracardiac abscess or metastatic infection. Causes of unresponsive fever include myocardial or septal abscesses, large vegetations that resist sterilization, and metastatic infection. Occasionally, fever in patients with uncomplicated IE may take as long as 3 weeks to abate.

Monitoring for complications

Patients should be monitored for the development of the following complications:

Valvular dysfunction, usually insufficiency of the mitral or aortic valves
Myocardial or septal abscesses
Congestive heart failure
Metastatic infection
Embolic phenomenon
Organ dysfunction resulting from immunological processes

Complications, such as congestive heart failure resulting from valvular insufficiency and embolization, may occur after bacteriologic cure has been achieved. (Note that the diagnosis of developing congestive heart failure or valvular insufficiency is based on clinical findings, not solely on echocardiographic measurements.) The onset of valve dysfunction or moderate-to-severe congestive heart failure should lead to an evaluation for immediate valve replacement.

Monitoring for relapse

Relapse of IE usually occurs within 2 months of finishing clinically effective therapy. Infection with S aureus, enterococci, and gram-negative organisms (especially P aeruginosa) is associated with a high rate of relapse. Enterococcal infection of the mitral valve has the greatest potential for relapse.

Recurrent IE most often occurs in individuals who abuse IV drugs. Valvular infections in these patients recur at a rate of 40%. Those with pretreatment symptoms of IE of more than 3 months’ duration are at greater risk for relapse. Other significant risk factors for recurrence include a previous episode of IE, the presence of a prosthetic valve, and congenital heart disease.

In general, infected vascular catheters should be removed and should not be replaced over a guidewire. Surgically implanted devices, such as Broviac or Hickman catheters,^[122]do not necessarily need to be removed unless evidence of IE, a tunnel infection, or suppurative thrombophlebitis is present or if the infecting organism is a Corynebacterium species, a Pseudomonas species, a fungus, S aureus, or a Mycobacterium species. If bacteremia persists longer than a few days, the catheter must be removed.

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Media Gallery

Acute bacterial endocarditis caused by Staphylococcus aureus with perforation of the aortic valve and aortic valve vegetations. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Affairs Medical Center.
Acute bacterial endocarditis caused by Staphylococcus aureus with aortic valve ring abscess extending into myocardium. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Affairs Medical Center.
A middle-aged man with a history of intravenous drug use who presented with severe myalgias and a petechial rash. He was diagnosed with right-sided staphylococcal endocarditis.
This is a magnified portion of a parasternal long axis view from a transthoracic echocardiogram. There is a small curvilinear vegetation on the mitral valve as indicated. The patient presented with a headache and fever, and CT scan of the brain revealed an occipital hemorrhage. The patient had a history of intravenous drug use and multiple blood cultures grew Staphylococcus aureus.
A young adult with a history of intravenous drug use, endocarditis involving the tricuspid valve with Staphylococcus aureus, and multiple septic pulmonary emboli. Pulmonary lesions on chest radiograph are most prominent in the right upper lobe with both solid and cavitary appearance.
Mitral valve: endocarditis with valve destruction and vegetation. Note the posterior leaflet of the mitral valve, with an irregular vegetation on the atrial surface, resulting in valve destruction at the commissure between the anterior leaflet and the posterior leaflet.
Aortic valve: healed endocarditis. Note the gaping hole with the fibrous rim, and a small strand at the free edge. The hole is at the line of closure. The affected valve is the left cusp. Note the right noncoronary cusp (immediate to the left in this image) demonstrates a small, multichanneled fenestration at the commissure, immediately adjacent to similar fenestrations in the left coronary cusp. These are physiologic lesions occurring with age and are unrelated to endocarditis.
Aortic valve: bicuspid, with infectious endocarditis. In this excised valve, note the bulky vegetations on the ventricular surfaces, with distortion of the valve surfaces.
Mitral valve: postrheumatic, with infectious endocarditis. A defect is seen in the scarred valve, with focal surface hemorrhage. The patient also underwent aortic valve replacement, as there was contiguous infection.
The surface of the valves, in most cases, demonstrates areas of acute neutrophilic inflammation with admixed fibrin and platelets. Degenerated bacterial colonies are seen at the left. Also, areas of microcalcification may mimic bacterial deposits.
Infectious endocarditis, subacute phase. Hemorrhage and prominent granulation tissue with neovascularity is apparent throughout. This aortic valve showed fibrin exudate on the ventricular surface (below), with more prominent organization and granulation on the aortic surface (above).
Infectious endocarditis, surface of valve leaflet with fibrin; higher magnification of previous image. A chronic infiltrate is seen, just under the denuded thrombosed surface, with primarily macrophages and focal macrophage giant cells.
Bioprosthetic valve with endocarditis. Note the large bacterial colony (staphylococci by culture) in the absence of significant inflammation; the xenograft tissue is not viable, and nuclear detail is not apparent.

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Table 1. Clinical Features of Infective Endocarditis According to Causative Organism

Causative Organism(s)	Clinical Features of IE
Staphylococcus aureus	Overall, S aureus infection is the most common cause of IE, including PVE, acute IE, and IVDA IE. Approximately 35-60.5% of staphylococcal bacteremias are complicated by IE. More than half of cases are not associated with underlying valvular disease. The mortality rate for S aureus IE is 40-50%. Staphylococcus aureus infection is the second most common cause of nosocomial BSIs, second only to CoNS infection. The incidence of MRSA infections, both the hospital- and community-acquired varieties, has dramatically increased (50% of isolates). Sixty percent of individuals are intermittent carriers of MRSA or MSSA. The primary risk factor for S aureus BSI is the presence of intravascular lines. Other risk factors include cancer, diabetes, corticosteroid use, IVDA, alcoholism, and renal failure. The realization that approximately 50% of hospital- and community-acquired staphylococcal bacteremias arise from infected vascular catheters has led to the reclassification of staphylococcal BSIs. BSIs are carried not only in the hospital but also in any type of healthcare facility (eg, nursing home, dialysis center). Of S aureus bacteremia cases in the United States, 7.8% (200,000) per year are associated with intravascular catheters.
Streptococcus viridans	This organism accounts for approximately 50-60% of cases of subacute disease. Most clinical signs and symptoms are mediated immunologically.
Streptococcus intermedius group	These infections may be acute or subacute. Streptococcus intermedius infection accounts for 15% of streptococcal IE cases. Members of the S intermedius group, especially S anginosus, are unique among the streptococci in that they can actively invade tissue and form abscesses, often in the CNS.
Abiotrophia	Approximately 5% of subacute cases of IE are due to infection with Abiotrophia species. They require metabolically active forms of vitamin B-6 for growth. This type of IE is associated with large vegetations that lead to embolization and a high rate of posttreatment relapse.
Group D streptococci	Most cases are subacute. The source is the gastrointestinal or genitourinary tract. It is the third most common cause of IE. They pose major resistance problems for antibiotics.
Nonenterococcal group D	The clinical course is subacute. Infection often reflects underlying abnormalities of the large bowel (eg, ulcerative colitis, polyps, cancer). The organisms are sensitive to penicillin.
Group B streptococci	Acute disease develops in pregnant patients and older patients with underlying diseases (eg, cancer, diabetes, alcoholism). The mortality rate is 40%. Complications include metastatic infection, arterial thrombi, and congestive heart failure. It often requires valve replacement for cure.
Group A, C, and G streptococci	Acute disease resembles that of S aureus IE (30-70% mortality rate), with suppurative complications. Group A organisms respond to penicillin alone. Group C and G organisms require a combination of synergistic antibiotics (as with enterococci).
Coagulase-negative S aureus	This causes subacute disease. It behaves similarly to S viridans infection. It accounts for approximately 30% of PVE cases and less than 5% of NVE cases.^[36]
Staphylococcus lugdunensis	Staphylococcus lugdunensis is another coagulase-negative Staphylococcus species but is extremely aggressive compared to coagulase-positive S aureus. S lugdunensis frequently causes IE. ^[37]
Pseudomonas aeruginosa	This is usually acute, except when it involves the right side of the heart in IVDA IE. Surgery is commonly required for cure.
HACEK (ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae)	These organisms usually cause subacute disease. They account for approximately 5% of IE cases. They are the most common gram-negative organisms isolated from patients with IE. Complications may include massive arterial emboli and congestive heart failure. Cure requires ampicillin, gentamicin, and surgery.
Fungal	These usually cause subacute disease. The most common organism of both fungal NVE and fungal PVE is Candida albicans. Fungal IVDA IE is usually caused by Candida parapsilosis or Candida tropicalis. Aspergillus species are observed in fungal PVE and NIE.
Bartonella	The most commonly involved species is Bartonella quintana. Infective endocarditis typically develops in homeless males who have extremely substandard hygiene. Bartonella must be considered in cases of culture-negative endocarditis among homeless individuals.
Multiple pathogens (polymicrobial)	Pseudomonas and enterococci are the most common combination of organisms. It is observed in cases of IVDA IE The cardiac surgery mortality rate is twice that associated with single-agent IE.^[37]