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Antimicrobial therapy of left-sided native valve endocarditis

Antimicrobial therapy of left-sided native valve endocarditis
Literature review current through: Jan 2024.
This topic last updated: Aug 31, 2023.

INTRODUCTION — Issues related to the antimicrobial therapy of native valve infective endocarditis (IE) will be reviewed here; the content reflects American, British, and European guidelines [1-3].

An overview of the management of IE in adults is presented separately. (See "Overview of management of infective endocarditis in adults".)

General issues related to echocardiography are discussed separately. (See "Role of echocardiography in infective endocarditis".)

Issues related to clinical manifestations and diagnosis of native valve endocarditis, complications of IE, and indications for surgery are discussed separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Complications and outcome of infective endocarditis" and "Surgery for left-sided native valve infective endocarditis".)

Issues related to right-sided IE are discussed separately. (See "Right-sided native valve infective endocarditis".)

Issues related to management of prosthetic valve IE are discussed separately. (See "Antimicrobial therapy of prosthetic valve endocarditis" and "Surgery for prosthetic valve endocarditis".)

Issues related to management of cardiac device infections are discussed separately. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Infections involving cardiac implantable electronic devices: Treatment and prevention".)

Issues related to management of mycotic aneurysm and brain abscess are discussed separately. (See "Overview of infected (mycotic) arterial aneurysm" and "Treatment and prognosis of bacterial brain abscess".)

GENERAL CONSIDERATIONS — Bactericidal agents are necessary for effective treatment of endocarditis. Therefore, antimicrobial therapy should be dosed to optimize sustained bactericidal serum concentrations throughout as much of the dosing interval as possible. In vitro determination of the minimum inhibitory concentration should be performed routinely.

Early consultation with a cardiac surgeon should be obtained for cases in which complications are observed or expected (such as in infections complicated by moderate to severe heart failure). In addition, consultation by specialists in infectious diseases and cardiology may be very useful.

Empiric therapy — In general, therapy for infective endocarditis (IE) should be targeted to the organism isolated from blood cultures; cultures are positive in over 90 percent of patients with IE. For patients with suspected IE who present without acute symptoms, empiric therapy is not always necessary, and therapy can await blood culture results. Results of blood cultures are usually available within one to three days, and an accurate diagnosis is a critical first step in designing a management strategy. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

In some cases, a clinician may choose to initiate antibiotic therapy prior to blood culture results; the decision to start or withhold antibiotic therapy prior to a microbiologic diagnosis must be individualized. For example, we initiate empiric antibiotic therapy for patients with hemodynamic instability and clinical presentation suggestive of acute endocarditis (eg, fever and new murmur, particularly in the setting of relevant cardiac risk factors [such as prior IE, history of valvular or congenital heart disease] or other predisposing conditions [intravenous drug use, indwelling intravenous lines, immunosuppression, or a recent surgical procedure]). Empiric therapy should be administered after at least two (preferably three) sets of blood cultures have been obtained from separate venipunctures and ideally spaced over 30 to 60 minutes. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

The choice of empiric therapy should take into consideration the most likely pathogens. In general, empiric therapy should cover staphylococci (methicillin susceptible and resistant), streptococci, and enterococci. Vancomycin (table 1) is an appropriate choice for initial therapy in most patients. Additional issues related to the approach to empiric treatment of Staphylococcus aureus bacteremia are discussed further separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Empiric antibiotic therapy'.)

Clinical response to initial therapy — Most patients with IE become afebrile three to five days after initiation of appropriate antimicrobial therapy. Patients with S. aureus endocarditis may respond somewhat more slowly, remaining febrile for five to seven days after initiation of therapy. Patients with right-sided endocarditis and septic pulmonary emboli may remain febrile for an even longer duration of time.

The initial microbiologic response to therapy should be assessed by obtaining repeat blood cultures 48 hours after antibiotics are begun; it is reasonable to obtain at least two sets of blood cultures every 24 to 48 hours until bloodstream infection has cleared [1]. Thereafter, careful serial physical examinations should be performed to evaluate for signs of heart failure, emboli, or other complications. Patients who develop new complications while on appropriate antimicrobial therapy (such as new emboli, heart failure, heart block, or other complications) should have a repeat echocardiogram to assess for worsening valve dysfunction, cardiac abscess, or fistula.

Duration of therapy — The duration of therapy depends on the site of valvular infection and on the specific pathogen, as discussed in the sections below and as summarized in the tables (see 'Specific pathogens' below). The duration of therapy should be counted from the first day of negative blood cultures (for cases in which blood cultures were initially positive) [1].

In general, the suggested duration of therapy in patients with native valve endocarditis (NVE) ranges up to six weeks (with the exception of NVE due to highly resistant enterococcus, for which the duration is at least six weeks). Some data suggest that a shortened duration of intravenous therapy may be sufficient in some cases [4,5]; however, thus far, the weight of this evidence has been insufficient to change practice. A full course of therapy is particularly important for patients with virulent or relatively resistant pathogens, secondary cardiac or extracardiac complications, and in the setting of prolonged infection prior to diagnosis.

This approach is based upon our understanding of the pathogenesis of vegetation formation and pathogen susceptibility, rather than on an evidence-based approach based on outcome data. Prolonged therapy is presumed to be necessary because bacterial concentrations within vegetations are as high as 109 to 1011 colony-forming units/gram of tissue; in addition, organisms within vegetations are not accessible to phagocytic cells and may be in a state of reduced metabolic activity [6]. (See "Pathogenesis of vegetation formation in infective endocarditis".)

Shorter regimens may be reasonable in selected patients. These include:

Patients with right-sided endocarditis (see "Right-sided native valve infective endocarditis")

Patients with endocarditis due to susceptible viridans streptococci [7] (see 'Viridans streptococci and S. bovis/S. equinus complex' below)

Patients with endocarditis due to HACEK organisms (see 'HACEK organisms' below)

A shortened duration of parenteral therapy has been studied in select patients with left-sided endocarditis. In one study (Partial Oral Treatment of Endocarditis, or POET trial), including 400 Danish patients with NVE due to methicillin-susceptible S. aureus (23 percent), streptococci (54 percent), Enterococcus faecalis (25 percent), or coagulase-negative staphylococci (13 percent) who completed at least 10 days of intravenous therapy, patients in stable condition were randomly assigned to continue intravenous treatment or switch to oral treatment with a two-drug antibiotic regimen; the groups completed a similar duration of therapy (median 19 versus 17 days, respectively) [4]. Treatment completion with oral antibiotic therapy was noninferior to continued intravenous antibiotic therapy; the primary outcome (a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen [from the time of randomization until six months after completion of therapy]) occurred in 12 versus 9 percent of patients (between-group difference 3.1 percentage points, 95% CI 3.4-9.6).

In subsequent follow-up of patients in the POET trial [5,8], the primary composite outcome at five years occurred less frequently among those who completed oral treatment (32.8 versus 45.2 percent; hazard ratio 0.65, 95% CI 0.47-0.90). While these are encouraging findings, the results are difficult to generalize given a number of factors including microbial etiology (streptococci were the most common pathogen among study participants; methicillin-resistant S. aureus was relatively uncommon among study participants), high rate of surgical therapy; selection bias (only 20 percent of assessed patients were randomly assigned), and referral bias (all patients received care in tertiary centers). Therefore, we have not altered our treatment approach based on these data; further study of oral antibiotic therapy for completing treatment of IE is needed.

Completing therapy — Patients may complete intravenous therapy as outpatients once hemodynamically stable. They must be capable of managing the technical aspects of intravenous therapy. Such patients require careful monitoring and must have ready access to full medical care should complications occur [1,9]. Patients should be counseled regarding the need for immediate evaluation in the setting of new fever, chills, or other signs of systemic toxicity, including a thorough clinical evaluation and repeat blood cultures [1]. (See "Outpatient parenteral antimicrobial therapy".)

While on antimicrobial therapy, patients should be monitored for antimicrobial toxicity. Weekly laboratory monitoring (complete blood count, chemistries, liver function tests) should be performed. Serial audiograms may be appropriate for patients receiving long-term aminoglycosides [1].

Issues related to echocardiographic monitoring during therapy are discussed separately. (See "Overview of management of infective endocarditis in adults", section on 'Echo monitoring during therapy'.)

Patients should be monitored for development of complications related to IE, including embolic complications and heart failure (see "Complications and outcome of infective endocarditis"). Development of complications should prompt evaluation for cardiac surgery. (See "Surgery for left-sided native valve infective endocarditis".)

Follow up — Issues related to follow up after completion of antibiotic therapy for IE are discussed separately. (See "Overview of management of infective endocarditis in adults", section on 'Follow-up'.)

Relapse — Patients with relapse of NVE following completion of appropriate antimicrobial therapy should receive a repeat course of antibiotics as described in the following sections.

Bacterial isolates should be retested carefully for complete antibiotic susceptibility profiles.

SPECIFIC PATHOGENS

Staphylococci — The success of therapy for staphylococcal endocarditis depends on a number of factors, including involvement of right- versus left-sided valvular structures and the susceptibility of the staphylococcal isolate.

Occasional strains of S. aureus are penicillin susceptible; however, laboratory screening procedures for detecting penicillin susceptibility may not be reliable [10]. Therefore, infective endocarditis (IE) caused by these organisms should be treated with regimens outlined for methicillin-susceptible S. aureus (MSSA) unless penicillin susceptibility can be confirmed (table 2) [1].

Methicillin susceptible

General approach — Treatment for NVE due to MSSA consists of a semisynthetic penicillin, such as nafcillin or oxacillin (table 2). Cefazolin is an acceptable alternative agent [11].

Cefazolin may be used for patients with intracerebral septic emboli (in the absence of meningitis or brain abscess) since cefazolin is capable of reaching sites of endovascular infection. For patients with NVE in the setting of meningitis and/or brain abscess, treatment with nafcillin or oxacillin is preferred over cefazolin because of concerns about the ability of cefazolin to enter the CSF [1]. Nevertheless, limited clinical series and pharmacokinetic considerations suggest that cefazolin at higher doses and/or continuous infusion may be a reasonable treatment for CNS infections [12,13]. More clinical studies are needed to clarify this issue.

Some experts caution against substituting cefazolin for nafcillin in the treatment of staphylococcal endocarditis because of concerns about the inoculum effect [14]; this issue is discussed further separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Methicillin-sensitive S. aureus'.)

However, to our knowledge, there are only two studies suggesting cefazolin was inferior to nafcillin for treatment of MSSA endocarditis; one was based on anecdotal observations of two patients with S. aureus endocarditis who relapsed after treatment or failed therapy [15], and another reported relapse in a patient with a retained cardiac device [16].

Low-dose aminoglycosides should NOT be combined routinely with antistaphylococcal penicillins or vancomycin for treatment of native valve S. aureus endocarditis. The evidence for clinically significant benefit relative to potential harm is minimal [17-19]. In a randomized trial including more than 230 patients with S. aureus bacteremia and endocarditis treated with either daptomycin monotherapy or gentamicin combined with a antistaphylococcal penicillin (or vancomycin), those who received gentamicin experienced significantly more renal impairment than those who did not (22 versus 8 percent, respectively) [18,19].

The duration of therapy for uncomplicated left-sided staphylococcal IE is six weeks; longer duration of therapy may be warranted in complicated IE [1].

Patients with penicillin allergy — Patients with NVE due to S. aureus who have a history of penicillin allergy can be treated with a first-generation cephalosporin such as cefazolin (2 g intravenously (IV) every eight hours), if there is no prior history of penicillin reaction that is typical of an immediate-type allergy [1]. Alternately, if penicillin desensitization is undertaken and successful, treatment with an antistaphylococcal penicillin may be used. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Because of concerns about limited blood-brain barrier penetrability with cefazolin, cefazolin is not considered first-line therapy for the treatment of patients with MSSA meningitis or brain abscess. If patients with MSSA IE and meningitis or brain abscess cannot tolerate nafcillin or oxacillin, vancomycin should be used. In situations where the patient does not tolerate vancomycin as well, cefazolin at higher doses and/or continuous infusion may be considered [12,13]. (See 'General approach' above.)

The American Heart Association (AHA) and the European Society for Cardiology (ESC) recommend cefazolin as an alternative in patients with penicillin allergy that is not anaphylactoid type [1,2]; however, the British Society for Antimicrobial Chemotherapy (BSAC) recommends vancomycin therapy for all patients with penicillin allergy regardless of type [3]. In addition, the BSAC recommends adding rifampin (300 to 600 mg orally every 12 hours) to vancomycin when treating methicillin-susceptible NVE in patients with penicillin allergy [3].

Vancomycin and daptomycin are acceptable alternative agents for treatment of NVE due to MSSA in patients with immediate-type penicillin allergy (documented by formal allergy evaluation) [1]. Vancomycin should not be used on the basis of convenience in patients without a true history of penicillin allergy, since clinical experience and in vitro studies have suggested that vancomycin is a less effective antistaphylococcal antibiotic than nafcillin or oxacillin. Issues related to use of vancomycin for treatment of MSSA infection are discussed further separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Methicillin-sensitive S. aureus'.)

Clindamycin is not an acceptable alternative agent for treatment of staphylococcal endocarditis, because relapse is common [1].

Methicillin resistant — Treatment of NVE due to methicillin-resistant S. aureus (MRSA) consists of vancomycin for six weeks (table 2) [1,2,20]. However, there have been a number of reports of vancomycin treatment failure in serious infections due to MRSA, even when isolates are proven to be susceptible using current microbiologic testing methods [21-23]. Furthermore, there is some concern that infections due to S. aureus isolates with high minimum inhibitory concentration (MIC) yet still within the susceptible range may be associated with poorer outcomes (see "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia"). In clinical cases where patients are responding poorly to therapy or there is concern about vancomycin susceptibility, an alternative approach may be needed.

For patients with MRSA IE who are unable to tolerate vancomycin or for patients infected with an isolate with a vancomycin MIC >1 (by broth microdilution, given high variability among other testing methods) [24], daptomycin (8 mg/kg/day) is an acceptable alternative agent [1]. Daptomycin may be used for treatment of left- or right-sided IE, even if septic pulmonary emboli are present [25,26]. Daptomycin should not be used in the setting of concomitant MRSA pneumonia [1,20]. In one randomized trial including more than 240 patients with S. aureus bacteremia with or without endocarditis treated with daptomycin or standard therapy, the frequency of treatment success was comparable (44 versus 42 percent) [18]. In a subsequent prospective cohort study including more than 170 patients with gram-positive left-sided IE treated with daptomycin or conventional therapy, the median time to clearance of bacteremia among patients treated with daptomycin was shorter (1 versus 5 days) [27].

We are in agreement with the AHA which recommends against addition of rifampin to vancomycin for treatment of NVE due to MRSA [1]; in contrast, the BSAC favors this approach [3]. In addition, we do not favor adjunctive use of rifampin for patients with staphylococcal NVE who undergo surgical management with prosthetic valve placement [28]. The risk of rifampin-induced drug interactions and hepatic toxicity should be weighed carefully.

Gentamicin should NOT be combined with vancomycin for treatment of MRSA native valve IE [20]. (See 'Methicillin susceptible' above.)

Alternative agents for treatment of MRSA bacteremia are discussed separately (see "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia"). Thus far, there is insufficient evidence for routine use of agents such as teicoplanin, ceftaroline, telavancin, dalbavancin, oritavancin, linezolid, or tedizolid for treatment of MRSA IE. Agents such as quinupristin-dalfopristin, tigecycline, linezolid, tedizolid, or fluoroquinolones are generally not recommended for treatment of IE due to MRSA because of lack of sufficient evidence for treating IE and/or associated adverse effects.

Coagulase-negative staphylococci — Treatment regimens for NVE due to coagulase-negative staphylococci are identical to those for coagulase-positive staphylococci. Most strains of coagulase-negative staphylococci are methicillin resistant. As a result, unless susceptibility to methicillin can be demonstrated conclusively, coagulase-negative staphylococci causing endocarditis should be assumed to be methicillin resistant and treated accordingly [1]. (See 'Methicillin resistant' above.)

Streptococci

Viridans streptococci and S. bovis/S. equinus complex — Members of the viridans group include S. mitis, S. mutans, S. oralis, S. sanguinis, S. sobrinus, and the S. milleri group (S. anginosus, S. constellatus, and S. intermedius).

The nomenclature of the S. bovis/S. equinus complex is summarized in the table (table 3). (See "Infections due to Streptococcus bovis/Streptococcus equinus complex (SBSEC; formerly group D streptococci)".)

The MIC breakpoints differ between the guidelines published by the AHA, British Society for Antimicrobial Chemotherapy (BSAC), and ESC; the MIC breakpoints are summarized in the tables (table 4 and table 5).

Penicillin-susceptible strains — MIC breakpoints and treatment regimens for endocarditis due to highly penicillin-susceptible streptococci are summarized in the table (table 4) [1-3].

For treatment of patients with NVE due to highly penicillin-susceptible streptococci (defined by the AHA as MIC ≤0.12 mcg/mL), we are in agreement with the AHA and ESC which favor aqueous crystalline penicillin G (12 to 18 million units daily for four weeks) or ceftriaxone (2 g per day) for four weeks [1,2].

In the setting of uncomplicated infection in the absence of pre-existing renal disease, patients who have a prompt response to therapy may be treated with a shortened (two week) duration of combination therapy with gentamicin. In such cases, gentamicin may be given as a single daily dose (3 mg/kg per day; preferred in outpatients) or in two to three equally divided doses (adjusted to achieve a peak serum level of 3 to 4 mcg/mL; preferred in hospitalized patients when serum concentrations can be followed). In one randomized study including 61 patients with IE due to penicillin-susceptible streptococci treated with a four-week ceftriaxone regimen or a two-week combination of ceftriaxone plus gentamicin, cure rates were similar [29]. In choosing between these regimens, one must weigh the risk of longer therapy with the potential risk of renal toxicity with gentamicin.

Patients with penicillin allergy (in the absence of immediate-type hypersensitivity) may be treated with ceftriaxone. Patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin for four weeks, or may be desensitized to penicillin and treated with a standard regimen. In general, treatment with penicillin is preferred over vancomycin; therefore, when feasible, we favor desensitization to penicillin over treatment with vancomycin. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Relatively penicillin-resistant strains — MIC breakpoints and treatment regimens for endocarditis due to relatively penicillin-resistant streptococci are summarized in the table (table 5).

For treatment of patients with NVE due to relatively penicillin-resistant streptococci (defined by the AHA as MIC >0.12 mcg/mL and <0.5 mcg/mL), we are in agreement with the AHA which recommends aqueous penicillin G (24 million units daily, either continuously or in four to six equally divided doses) for a total of four weeks, in combination with gentamicin for the first two weeks. Ceftriaxone monotherapy for four weeks is a reasonable alternative regimen (if the isolate is susceptible) [1].

Patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin monotherapy for four weeks. If feasible, we favor desensitization to penicillin over use of vancomycin [1].

Fully penicillin-resistant strains — For treatment of patients with NVE due to fully penicillin-resistant streptococci (defined by the AHA as MIC ≥0.5 mcg/mL) and streptococcal-like organisms (eg, Abiotrophia defectiva, Granulicatella spp, and Gemella spp) with penicillin resistance, we are in agreement with the AHA which recommends treatment with regimens used for treatment of enterococcal endocarditis (eg, penicillin G 18 to 30 million units IV per day plus gentamicin 3 mg/kg IV per day for 4 to 6 weeks, or, for patients with penicillin allergy, vancomycin 30 mg/kg/day for 4 to 6 weeks) (table 6) [1-3]. However, use of ampicillin and ceftriaxone is not an acceptable regimen for treatment of IE due to penicillin-resistant streptococci given insufficient clinical experience with this approach. (See 'Enterococci' below.)

For isolates susceptible to ceftriaxone, treatment with ceftriaxone for four weeks in combination with gentamicin for the initial two weeks may be a reasonable alternative regimen [1].

Patients with penicillin allergy — Patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin monotherapy; addition of gentamicin is not needed [1]. (See 'Enterococci' below.)

Daptomycin should not be used routinely as an alternative to vancomycin for the treatment of endocarditis caused by viridans streptococci; emergence of stable high-level resistance to daptomycin has been observed in at least 25 percent of the Streptococcus mitis group isolates (S. mitis, S. oralis, S. sanguinis) with exposure to daptomycin in vitro and in experimental models. Resistance has also emerged in Streptococcus parasanguinis, Abiotrophia, and Granulicatella species [30-32]. In vitro and endocarditis model studies suggest that emergence of daptomycin resistance in streptococci can be prevented with daptomycin is combined with gentamicin or ceftriaxone [33,34].

Streptococcus pneumoniae — Pneumococcal endocarditis occurs in the context of pneumococcal pneumonia and may be complicated by concurrent meningitis [35]. S. pneumoniae strains relatively or fully resistant to penicillin are emerging; such strains may also be resistant to other beta-lactams and other antimicrobial agents.

Absence of meningitis — In the absence of known or suspected concomitant meningitis, treatment of pneumococcal NVE consists of aqueous penicillin G (24 million units per day IV, either continuously or in four to six divided doses); or ceftriaxone for four weeks. Patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin for four weeks [1].

Ceftriaxone dosing should be guided by MIC data [1]:

For patients with infection due to penicillin-susceptible S. pneumoniae (MIC ≤0.1 mcg/mL) or penicillin-intermediate S. pneumoniae (MIC >0.1 to 1.0 mcg/mL), we use ceftriaxone 2 g IV every 24 hours.

For patients with infection due to penicillin-resistant pneumococcal endocarditis (MIC ≥2 mcg/mL), we use ceftriaxone 2 g IV every 12 hours.

While in vitro beta-lactam resistance among pneumococci may be overcome by using higher doses of beta-lactams, clinical data on the efficacy of different doses for beta-lactams in this setting are limited [36].

Presence of meningitis — In the setting of concomitant meningitis, in vitro susceptibility to cefotaxime or ceftriaxone should be obtained. For patients with isolates susceptible to cefotaxime or ceftriaxone, treatment of pneumococcal NVE consists of cefotaxime (2 g IV every 4 to 6 hours) or ceftriaxone (2 g IV every 12 hours) for 4 weeks [1].

For patients with isolates resistant to cefotaxime or ceftriaxone (MIC ≥2.0 mcg/mL, which is the MIC definition for central nervous system isolates), addition of vancomycin (table 1) and rifampin (900 mg every 24 hours IV or by mouth in three divided doses) may be warranted.

Issues related to extrameningeal infection with pneumococcal strains resistant to beta-lactam antibiotics are discussed further separately. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia in adults".)

Pneumococcal endocarditis is usually fulminant and causes severe valve damage and embolic complications; valve replacement may be necessary [37]. (See "Surgery for left-sided native valve infective endocarditis".)

Streptococcal groups A, B, C, F, and G — Streptococcal groups A, B, C, F, and G are occasional causes of endocarditis [35,38]. Regimens used to treat endocarditis due to viridans group streptococci are typically effective since most of these organisms are highly sensitive to penicillin.

For treatment of IE due to Streptococcus pyogenes, we are in agreement with the AHA which recommends treatment with penicillin G (24 million units IV continuously or in 4 to 6 divided doses) for four to six weeks; ceftriaxone (eg, IV every 12 hours) is a reasonable alternative and is easier to administer as an outpatient or in an intermediate care facility [1]. Vancomycin may be used for patients intolerant of beta-lactam therapy.

Some strains of groups B, C, F, and G streptococci are more resistant to penicillin than S. pyogenes. For this reason, depending on sensitivity results, we are in agreement with some experts who favor adding gentamicin to a penicillin or cephalosporin for the first two weeks of a four- to six-week course of therapy [1].

Enterococci — Most cases of enterococcal endocarditis are caused by E. faecalis strains [39]. Vancomycin resistance is observed most commonly among Enterococcus faecium strains, which are a less frequent cause of endocarditis.

Enterococci have a narrower spectrum of susceptibility than streptococcal species. In particular, members of the genus Enterococcus are all resistant to low concentrations of penicillin. They are also relatively resistant to expanded-spectrum penicillins, resistant to cephalosporins, and typically resistant to aminoglycosides at concentrations achieved with standard dosing regimens. However, many strains of enterococci are killed both in vitro and in vivo if penicillin, ampicillin, or vancomycin is given in synergistic combination with an aminoglycoside such as gentamicin. Issues related to enterococcal resistance are discussed further separately. (See "Mechanisms of antibiotic resistance in enterococci".)

Enterococci should be tested routinely for in vitro susceptibility to penicillin and vancomycin and for high-level resistance to gentamicin (>500 mcg/mL) to predict synergistic interactions [1]. For strains that are resistant to beta-lactams or vancomycin, in vitro susceptibility to daptomycin and linezolid should be obtained.

General principles related to treatment of enterococcal infections are discussed separately. (See "Treatment of enterococcal infections".)

Susceptible strains

General approach — Treatment regimens for NVE due to enterococcal strains susceptible to penicillin and gentamicin are summarized in the table (table 6) [1-3]. Regimens include a beta-lactam combination regimen (ceftriaxone plus ampicillin for six weeks, for IE due to E. faecalis) or an aminoglycoside combination regimen (penicillin or ampicillin plus gentamicin for four to six weeks; the duration of gentamicin may be shortened to two weeks in the setting of nephrotoxicity, as discussed below). Most strains of E. faecium are not susceptible to ampicillin; in the setting of IE due to E. faecium, the combination beta-lactam regimen should not be used.

For patients with NVE due to enterococcal strains susceptible to penicillin and gentamicin, we favor treatment with a beta-lactam combination regimen. This approach may be better tolerated and associated with fewer side effects than regimens containing an aminoglycoside, particularly in older patients and/or in patients with renal insufficiency [40-43]. In an observational study including more than 240 patients (mostly in Spain) with E. faecalis IE who were treated with either ampicillin and ceftriaxone or ampicillin and gentamicin (AG), rates of mortality, treatment failure, and relapse were comparable between the groups; renal failure occurred more frequently among those treated with AG [43]. Similarly, in a retrospective study including 279 patients in France with E. faecalis IE, the relapse rate was comparable among patients treated with ampicillin and ceftriaxone or AG (13 to 14 percent) [44].

For patients treated with an aminoglycoside combination regimen, some experts prefer penicillin over ampicillin because of the possibility of increased allergic reaction to ampicillin. Patients with duration of symptoms <3 months may be treated successfully with four weeks antimicrobial therapy [45]; six weeks of therapy is preferred for patients with duration of symptoms >3 months and patients with relapsed infection.

Longer duration of gentamicin treatment has been associated with increased likelihood for decline in renal function. In one nonrandomized study including more than 80 patients with enterococcal IE with absence of high-level aminoglycoside resistance and duration of symptoms <3 months, two weeks of gentamicin (in combination with a cell wall-active agent for four to six weeks) was adequate [46]. Pending further data, four to six weeks of gentamicin should be administered for patients with no concern for aminoglycoside toxicity.

Patients with penicillin allergy — Patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin plus gentamicin for six weeks (table 7), or may be desensitized to penicillin and treated with a standard regimen. In general, treatment with penicillin is preferred over vancomycin; therefore, when feasible we favor desensitization to penicillin over treatment with vancomycin. For patients treated with vancomycin, a six-week duration of therapy should be administered (rather than four weeks), because vancomycin has diminished activity against enterococci compared with penicillin [1,2]. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Gentamicin resistance — Treatment regimens for NVE due to enterococcal strains susceptible to penicillin, vancomycin, and streptomycin but resistant to gentamicin are summarized in the table (table 8) [1-3].

For patients with NVE due to enterococcal strains that are susceptible to penicillin, vancomycin, and streptomycin but resistant to gentamicin, we are in agreement with the AHA which recommends combination therapy with a beta-lactam combination regimen (ceftriaxone plus ampicillin for six weeks) (table 8) [1]. An aminoglycoside combination regimen (penicillin or ampicillin plus streptomycin, both for four to six weeks) is an alternative provided that the patient does not have pre-existing renal dysfunction or cranial nerve VIII dysfunction.

It is uncertain whether a shortened duration of streptomycin is adequate; thus far, data supporting shorter duration of aminoglycoside therapy are based on studies with gentamicin. (See 'General approach' above.)

Additional considerations regarding management of patients with immediate-type hypersensitivity reaction to beta-lactams are discussed above. (See 'Patients with penicillin allergy' above.)

Some gentamicin-resistant strains lack streptomycin resistance, and vice versa. For treatment of IE due to enterococci resistant to both streptomycin and gentamicin, aminoglycosides are not beneficial. (See 'Resistance to penicillin, aminoglycosides, and vancomycin' below.)

Penicillin resistance — Treatment regimens for NVE due to enterococcal strains with penicillin resistance are summarized in the table (table 7) [1-3].

For patients with NVE due to enterococcal strains with intrinsic high-level penicillin resistance (MIC ≥16 mcg/mL), we are in agreement with the AHA which recommends combination therapy with vancomycin plus gentamicin for six weeks (table 7) [1].

Resistance to penicillin, aminoglycosides, and vancomycin — Treatment regimens for NVE due to enterococcal strains with resistance to penicillin, aminoglycosides, and vancomycin are summarized in the table (table 9) [1,2].

The optimal approach to treatment of endocarditis due to enterococci with high-level aminoglycoside and/or vancomycin resistance is uncertain. We favor treatment with daptomycin (in combination with an additional agent such as ampicillin or ceftaroline) [47].

Data on management of vancomycin-resistant enterococcal IE are limited; the approach is guided by limited data in patients with bacteremia. In one retrospective cohort study including more than 600 patients with bloodstream infections due to vancomycin-resistant enterococci treated with daptomycin or linezolid, treatment with linezolid was associated with higher risk of treatment failure (risk ratio 1.15, 95% CI 1.02-1.30) [48].

Issues related to treatment of enterococcal bacteremia are discussed further separately. (See "Treatment of enterococcal infections".)

HACEK organisms — A number of fastidious gram-negative bacilli are grouped by the acronym "HACEK" – these include:

Haemophilus aphrophilus (subsequently called Aggregatibacter aphrophilus and Aggregatibacter paraphrophilus)

Actinobacillus actinomycetemcomitans (subsequently called Aggregatibacter actinomycetemcomitans)

Cardiobacterium hominis

Eikenella corrodens

Kingella kingae

HACEK organisms are isolated readily when incubated for five days with automated blood culture systems. Longer incubation periods (>6 days) may be required to detect growth if traditional (non-automated) blood culture systems are used.

HACEK organisms are considered ampicillin resistant. Unless growth in vitro is adequate to obtain susceptibility testing results, penicillin and ampicillin should not be used for treatment of IE due to these organisms [1].

Virtually all HACEK organisms are highly susceptible to third-generation cephalosporins such as ceftriaxone, even strains that produce beta-lactamase.

Treatment regimens for NVE due to HACEK organisms are summarized in the table (table 10) [1,2].

We are in agreement with the AHA which recommends treatment with ceftriaxone, ampicillin (if in vitro testing is feasible and the organism is susceptible), or ciprofloxacin for four weeks [1]. Gentamicin is generally not recommended because of risk for nephrotoxicity.

Other gram-negative organisms — NVE due to other gram-negative bacilli (such as Escherichia coli, Pseudomonas, Klebsiella, or Serratia) is extremely rare. The most common predisposing factor is an implanted endovascular device, and most cases occur in the setting of recent health care contact [49].

The choice of antimicrobial therapy depends on the antimicrobial susceptibility of the causative organism.

Combination antimicrobial therapy with a beta-lactam (penicillins, cephalosporins, or carbapenems) and either an aminoglycoside or fluoroquinolone for six weeks is reasonable [1].

Such patients may also warrant cardiac surgery, particularly in the setting of left-sided infection due to Pseudomonas. (See "Surgery for left-sided native valve infective endocarditis".)

Fungi — Treatment of fungal endocarditis consists of antifungal therapy and valve replacement.

Issues related to Candida endocarditis are discussed separately. (See "Candida endocarditis and suppurative thrombophlebitis".)

Issues related to endocarditis caused by Aspergillus are discussed separately. (See "Treatment and prevention of invasive aspergillosis", section on 'Antifungal therapy' and "Treatment and prevention of invasive aspergillosis", section on 'Duration' and "Treatment and prevention of invasive aspergillosis", section on 'Role of surgery'.)

CULTURE-NEGATIVE ENDOCARDITIS — Culture-negative infective endocarditis is defined as endocarditis without etiology following inoculation of three blood samples in a standard blood culture system (eg, negative cultures after seven days) [1].

Cultures are negative in IE for three major reasons:

Administration of antimicrobial agents prior to blood culture incubation

Inadequate microbiologic techniques

Infection with fastidious bacteria or nonbacterial pathogens

The most common causes of culture-negative IE are fastidious organisms (eg, zoonotic agents and fungi) and Streptococcus spp in patients who have received previous antibiotic treatment.

Coxiella burnetii and Bartonella spp are relatively common agents of culture-negative endocarditis; the frequency varies in different geographic locations.

Empiric treatment of patients with culture-negative NVE should cover both gram-positive and gram-negative organisms and should be selected in consultation with an infectious disease specialist. The American Heart Association suggests the following approach [1]:

For patients with acute clinical presentation (ie, symptomatic for days), antimicrobial therapy for coverage of infection due to S. aureus, beta-hemolytic streptococci, and aerobic gram-negative bacilli is reasonable. Empiric coverage could include vancomycin and cefepime as an initial regimen [1].

For patients with a subacute clinical presentation (ie, symptomatic for weeks), antimicrobial therapy for coverage of infection due to S. aureus, viridans group streptococci, HACEK organisms, and enterococci is reasonable. Empiric coverage could include vancomycin and ampicillin-sulbactam as an initial regimen [1].

The above approach to empiric treatment can be modified depending on individual patient circumstances, including whether the patient received antimicrobial therapy prior to blood cultures, the type and duration of prior antimicrobial therapy, epidemiologic risk factors, the suspected site of primary infection, risk of toxicity, and allergy history. As examples:

In patients for whom gram-positive cocci or HACEK organisms are the most likely cause of endocarditis, we sometimes use a combination of vancomycin plus ceftriaxone or vancomycin plus ampicillin-sulbactam.

In patients receiving dialysis, a regimen consisting of vancomycin alone may be reasonable.

In patients for whom there is a reasonable possibility of infection with an organism such as C. burnetii or Brucella, empiric therapy active against these pathogens is reasonable, pending test results. (See "Brucellosis: Treatment and prevention", section on 'Endocarditis'.)

Subsequent therapy should be directed to the specific microorganism if diagnostic tests such as polymerase chain reaction or serology identify the etiologic agent.

For patients with IE and negative blood cultures who undergo valve replacement, the approach to antibiotic therapy may be guided by valve culture data. (See "Surgery for left-sided native valve infective endocarditis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of infective endocarditis" and "Society guideline links: Outpatient parenteral antimicrobial therapy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient education: Endocarditis (The Basics)")

SUMMARY AND RECOMMENDATIONS

General considerations − Treatment of endocarditis requires bactericidal antimicrobial therapy, which should be dosed to optimize sustained bactericidal serum concentrations throughout as much of the dosing interval as possible. In vitro determination of the minimum inhibitory concentration should be performed routinely. (See 'General considerations' above.)

Consultation − Early consultation with a cardiac surgeon should be obtained for cases in which complications are observed or expected (such as in the presence of moderate to severe heart failure, heart block, or systemic emboli). In addition, consultation with specialists in infectious diseases and/or cardiology may be important. (See 'General considerations' above.)

Empiric treatment

Whom to treat − For patients with hemodynamic instability and clinical presentation suggestive of acute endocarditis (fever and new murmur, particularly in the setting of relevant cardiac risk factors or other predisposing conditions), we suggest administration of empiric antibiotic therapy (Grade 2C). For patients who present without acute symptoms, empiric therapy is not always necessary; initiation of treatment can await blood culture results.

Collecting blood cultures prior to antibiotics − Empiric therapy may be administered after at least two (preferably three) sets of blood cultures have been obtained from separate venipunctures and ideally spaced over 30 to 60 minutes. (See 'Empiric therapy' above.)

Antibiotic selection − In general, empiric therapy should cover staphylococci (methicillin susceptible and resistant), streptococci, and enterococci. Vancomycin is an appropriate choice for initial therapy in most patients. (See 'Empiric therapy' above.)

Tailoring treatment − The optimal antibiotic regimen depends upon the causative organism and in vitro susceptibility results. The approach is summarized in the tables and is discussed in the sections above:

Staphylococci (table 2) (see 'Staphylococci' above)

Streptococci:

-Viridans streptococci and S. bovis/S. equinus complex (table 3 and table 4 and table 5) (see 'Viridans streptococci and S. bovis/S. equinus complex' above)

-S. pneumoniae (see 'Streptococcus pneumoniae' above)

-Streptococcal groups A, B, C, F, and G (see 'Streptococcal groups A, B, C, F, and G' above)

Enterococci (table 6 and table 7 and table 8 and table 9) (see 'Enterococci' above)

HACEK organisms (table 10) (see 'HACEK organisms' above)

Other gram-negative organisms (see 'Other gram-negative organisms' above)

Culture-negative endocarditis (see 'Culture-negative endocarditis' above)

Duration (see 'Duration of therapy' above)

The suggested duration of therapy in patients with NVE depends on the pathogen and site of valvular infection. In general, the suggested duration of therapy in patients with NVE ranges up to six weeks (with the exception of NVE due to highly resistant enterococcus, for which the duration is at least six weeks).

Some data suggest that a shortened duration of intravenous therapy may be sufficient in some cases; however, thus far, the weight of this evidence has been insufficient to change practice. A full course of therapy is particularly important for patients with virulent or relatively resistant pathogens, secondary cardiac or extracardiac complications, and in the setting of prolonged infection prior to diagnosis.

Follow-up − Patients with endocarditis require careful regular clinical follow-up that includes serial physical examinations and obtaining follow-up blood cultures to document clearance of bacteremia. (See 'Follow up' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel J Sexton, MD, who contributed to earlier versions of this topic review.

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