Antimicrobial therapy of left-sided native valve endocarditis

INTRODUCTION — 

Issues related to the antimicrobial therapy of native valve infective endocarditis (NVE) will be reviewed here; the content reflects American and European guidelines [1,2].

An overview of the management of infective endocarditis (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 NVE, complications of NVE, 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 "Prosthetic valve endocarditis: Surgical management".)

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 native valve infective endocarditis (NVE). 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 NVE should be targeted to the organism isolated from blood cultures. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

Empiric therapy should be administered after at least two (preferably three) sets of blood cultures have been obtained from separate venipunctures, 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 previous antibiotic therapy (with consideration of the potential for antimicrobial resistance) and the setting of acquisition (community versus healthcare-associated). In general, empiric therapy should cover staphylococci (methicillin-susceptible and methicillin-resistant), streptococci, enterococci, and gram-negative bacilli. (See "Native valve endocarditis: Epidemiology, risk factors, and microbiology", section on 'Microbiology'.)

A reasonable empiric regimen for suspected NVE consists of vancomycin plus ceftriaxone. For patients with risk for oral or gastrointestinal sources, ampicillin-sulbactam may be used instead of ceftriaxone; for patients with risk for nosocomial infection with Pseudomonas, cefepime, or piperacillin-tazobactam may be used instead of ceftriaxone.

Assessing clinical response to initial therapy

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

●Surveillance blood cultures – 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].

●Serial examination for complications – 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.

Tailoring therapy — Antibiotic therapy should be tailored to culture and susceptibility data once available. (See 'Specific pathogens' below.)

Duration of therapy

●Clinical approach – 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 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).

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 [3] (see 'Viridans streptococci and S. bovis/S. equinus complex' below)

•Patients with endocarditis due to HACEK (Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) organisms (see 'HACEK organisms' below)

●Role of shortened duration of parenteral therapy – 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. While the 2023 European Society of Cardiology (ESC) guidelines suggest consideration of oral-step down therapy for NVE caused by oral streptococci, Streptococcus gallolyticus, Enterococcus faecalis, S. aureus and coagulase negative staphylococci [2], we favor further study of oral antibiotic therapy for completing treatment of IE, particularly in patients with Methicillin-resistant Staphylococcus aureus (MRSA) and enterococcus.

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".)

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 MSSA (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, the primary composite outcome at five years (death from any cause, unplanned cardiac surgery, embolic events, and relapse of positive blood cultures after 6 months) 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) [5,7]. While these findings are encouraging, the results are difficult to generalize given a number of factors including microbial etiology (streptococci were the most common pathogen among study participants, a low proportion of patients with S. aureus (none of which were methicillin-resistant) and enterococcus, high rate of surgical therapy (which should have a favorable impact on source control), selection bias (only 20 percent of assessed patients were randomly assigned), and referral bias (all patients received care in tertiary centers).

Role of surgery — Indications for surgery in patients with NVE are discussed separately. (See "Surgery for left-sided native valve infective endocarditis".)

Completing therapy

●Outpatient parenteral 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 [1,8]. 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".)

●Monitoring – While on antimicrobial therapy, patients should be monitored for antimicrobial toxicity. Weekly laboratory monitoring (complete blood count, chemistries, liver function tests) and weekly trough levels (for vancomycin and/or aminoglycoside, if applicable) 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 — Patients with NVE require careful regular clinical follow-up including serial physical examinations and follow-up blood cultures to document clearance of bacteremia. With breakthrough bacteremia during therapy, the antimicrobial susceptibility of the breakthrough isolate should be reassessed. Patients should be monitored for development of complications including embolic events and heart failure. Development of complications should prompt evaluation for cardiac surgery.

Issues related to follow up after completion of antibiotic therapy for IE are discussed further 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 native valve endocarditis (NVE) depends on a number of factors, including involvement of right- versus left-sided valvular structures, presence or absence of disseminated extra-cardiac foci of infection, and the susceptibility of the staphylococcal isolate.

Occasional strains of S. aureus are susceptible to penicillin; however, laboratory screening procedures for detecting penicillin susceptibility may not be reliable [9]. Therefore, NVE caused by these organisms should be treated with regimens outlined for methicillin-susceptible S. aureus (MSSA) unless penicillin susceptibility can be confirmed (table 1) [1].

Methicillin-susceptible S. aureus

●Clinical approach – For patients with NVE due to methicillin-susceptible S. aureus (MSSA), we favor initial treatment with a semisynthetic penicillinase-resistant penicillin (eg, nafcillin, oxacillin, cloxacillin or flucloxacillin) to achieve maximum efficacy in the setting of high inoculum infection. After 4 to 10 days of treatment, with eradication of bacteremia, switching to cefazolin for ease of administration and transition to outpatient therapy is reasonable (table 1) [1,2,10]. Additional considerations regarding use of cefazolin are discussed below.

●Use of cefazolin

•Patients with penicillin allergy – For patients with history of penicillin allergy (in the absence of immediate-type hypersensitivity), cefazolin may be used [1]. Alternatively, penicillin desensitization may be pursued, followed by treatment with an antistaphylococcal penicillin. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

For patients with immediate-type penicillin allergy (documented by formal allergy evaluation), alternative agents include vancomycin or daptomycin (see 'Methicillin-resistant S. aureus' below) [1]. However, these agents should not be used for patients in the absence of a true history of penicillin allergy.

Clinical experience and in vitro studies suggest that vancomycin is a less effective antistaphylococcal agent 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 NVE; relapse is common [1].

•Patients with central nervous system involvement

-Intracerebral septic emboli – Cefazolin may be used for patients with intracerebral septic emboli (in the absence of meningitis or brain abscess) since cefazolin can reach sites of endovascular infection.

-Meningitis and/or brain abscess – For patients with MSSA NVE in the setting of meningitis and/or brain abscess, treatment with nafcillin or oxacillin is preferred over cefazolin because of concerns about limited blood-brain barrier penetrability with cefazolin [1]. Nevertheless, limited clinical series and pharmacokinetic considerations suggest that cefazolin at higher doses and/or continuous infusion may be a reasonable treatment for central nervous system (CNS) infections [11,12]. More clinical studies are needed to clarify this issue.

For patients with MSSA NVE and meningitis or brain abscess who cannot tolerate nafcillin or oxacillin, we treat with vancomycin. For patients who not tolerate vancomycin, alternative considerations include administration of cefazolin at higher doses and/or via continuous infusion [11,12].

•Inoculum effect – Some experts caution against substituting cefazolin for nafcillin in the treatment of staphylococcal endocarditis because of concerns about cleavage of this antibiotic at a high inoculum by certain staphylococcal beta-lactamases [13]. This has been demonstrated in vitro and in a few clinical studies. Two studies have suggested inferiority of cefazolin 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 [14], and another reported relapse in a patient with a retained cardiac device [15]. In a study of 77 patients with MSSA bacteremia (most of whom were treated with cefazolin), increased mortality was observed among patients with increased cefazolin MIC at a high inoculum (n = 42) compared with those with no increase in cefazolin MIC (n = 35), (OR 2.65, 95% CI 1.1 - 6.42]) [16]. Issues related to the inoculum effect are discussed further separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Methicillin-sensitive S. aureus'.)

●No role for addition of an aminoglycoside – Low-dose aminoglycosides should not be combined routinely with antistaphylococcal penicillins or vancomycin for treatment of S. aureus NVE. 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 kidney impairment than those who did not (22 versus 8 percent, respectively) [18,19].

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

Methicillin-resistant S. aureus

●Vancomycin therapy – Treatment of NVE due to methicillin-resistant S. aureus (MRSA) consists of vancomycin for six weeks (table 1) [1,2,20,21]. Vancomycin is preferred over a daptomycin-based regimen given greater clinical experience with vancomycin. In addition, there is greater concern about the emergence of daptomycin non-susceptibility among MRSA isolates during therapy (compared with MSSA isolates) [22,23].  

For cases in which patients are responding poorly to vancomycin or there is concern about reduced vancomycin susceptibility, an alternative approach may be needed. 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 [24-26]. 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").

●Role of daptomycin – For patients with NVE due to MRSA who are unable to tolerate vancomycin, patients infected with an isolate with a vancomycin MIC >1 (by broth microdilution, given high variability among other testing methods), or patients responding poorly to vancomycin, a daptomycin-based regimen may be used [1,2].

•Clinical approach – We are in agreement with 2023 ESC guidelines which favor combination therapy with daptomycin together with an additional antibiotic agent; options include ceftaroline or fosfomycin, if available (table 1) [2]. Combination therapy results in synergy, augmented clearance by immune cells, and may reduce the likelihood of emergence of resistance [27]. If a full treatment course with combination therapy is logistically prohibitive, it may be used initially (eg, until clearance of bacteremia and clinical improvement), followed by transition to daptomycin monotherapy.

If combination therapy is not feasible, daptomycin monotherapy (at high dose: 8 to 10 mg/kg daily) is acceptable. Daptomycin monotherapy should not be used in the setting of concomitant MRSA pneumonia [1,20], but it may be used for patients with septic pulmonary emboli [28,29].

•Supporting evidence

-Daptomycin monotherapy – In a 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 NVE treated with daptomycin or conventional therapy, the median time to clearance of bacteremia among patients treated with daptomycin was shorter (1 versus 5 days) [30].

-Daptomycin combination therapy – The evidence to support daptomycin combination therapy is based on small observational studies suggesting emergence of developing daptomycin non-susceptibility in some S. aureus isolates, particularly with use of lower daptomycin doses and daptomycin monotherapy [31].

One randomized clinical trial including 352 patients with MRSA bacteremia treated with standard therapy (vancomycin or daptomycin monotherapy) or combination therapy (ie, standard therapy plus either flucloxacillin, cloxacillin, or cefazolin) did not show a statistically significant difference in the primary endpoint (mortality, persistent bacteremia, relapse, or treatment failure) [32].

A small trial including 40 patients suggested a benefit with the combination of daptomycin plus ceftaroline for MRSA bacteremia compared with vancomycin or daptomycin monotherapy [33]; however this trial was terminated early and it is difficult to draw conclusions given the small sample size.

●Alternative agents – Thus far, there is insufficient evidence for routine use of agents such as teicoplanin, ceftaroline, telavancin, dalbavancin, oritavancin, linezolid, or tedizolid for treatment of NVE due to MRSA. Agents such as quinupristin-dalfopristin, tigecycline, linezolid, tedizolid, or fluoroquinolones are generally not recommended for treatment of NVE due to MRSA because of lack of sufficient evidence for treating NVE and/or associated adverse effects.

Alternative agents for treatment of MRSA bacteremia are discussed separately (see "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia").

●No role for rifampin or aminoglycosides – We are in agreement with the American Heart Association (AHA) and European Society of Cardiology (ESC) which recommend against addition of rifampin to vancomycin for treatment of NVE due to MRSA, given the risk of rifampin-induced drug interactions and hepatic toxicity [1].

Addition of an aminoglycoside is not recommended for the treatment of NVE due to MRSA given risk of nephrotoxicity and limited clinical benefit [20]. (See 'Methicillin-susceptible S. aureus' above.)

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 NVE should be assumed to be methicillin resistant and treated accordingly [1]. (See 'Methicillin-resistant S. aureus' 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 2). (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 and ESC; the MIC breakpoints are summarized in the tables (table 3 and table 4).

Penicillin-susceptible strains — MIC breakpoints and treatment regimens for NVE due to highly penicillin-susceptible streptococci are summarized in the table (table 3) [1,2].

●Clinical approach – The 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 penicillin G or ceftriaxone for four weeks [1,2].

In the setting of uncomplicated infection in the absence of pre-existing kidney disease, patients who have a prompt response to initial 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, with appropriate monitoring). In choosing between these regimens, one must weigh the risk of longer therapy with the potential risk of kidney toxicity with gentamicin.

In one randomized study including 61 patients with NVE 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 [34].

●Patients with penicillin allergy – Patients with penicillin allergy (in the absence of immediate-type hypersensitivity) may be treated with ceftriaxone. For patients with immediate-type hypersensitivity, we favor desensitization to penicillin if feasible. Alternatively, patients may be treated with vancomycin for four weeks. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Relatively penicillin-resistant strains — MIC breakpoints and treatment regimens for NVE due to relatively penicillin-resistant streptococci are summarized in the table (table 4).

●Clinical approach – 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 [1]. Ceftriaxone monotherapy for four weeks is a reasonable alternative regimen (if the isolate is susceptible) [1].

●Patients with penicillin allergy – If feasible, we favor desensitization to penicillin. If this is not feasible, patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin monotherapy for four weeks [1].

Fully penicillin-resistant strains

●Clinical approach – For treatment of patients with NVE due to fully penicillin-resistant streptococci (defined by the AHA as MIC ≥0.5 mcg/mL), we are in agreement with the ESC which recommends treatment with penicillin G (24 million units per 24 hours IV either continuously or in 4 or 6 divided doses) or ceftriaxone (2 g per 24 hours IV) for four weeks, combined with gentamicin (3 mg/kg per 24 hours IV in 1 dose for first 2 weeks) for the initial two weeks [2].

Use of the combination of ampicillin and ceftriaxone is not an acceptable regimen for treatment of NVE due to penicillin-resistant streptococci given insufficient clinical experience with this approach. (See 'Enterococci' below.)

●Patients with penicillin allergy – For patients with penicillin allergy, intravenous (IV) vancomycin for 4 weeks is warranted [1,2].

No role for daptomycin — Daptomycin should not be used routinely as an alternative to vancomycin for the treatment of NVE 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 [35-37]. In vitro and endocarditis model studies suggest that the likelihood of emergence of daptomycin resistance in streptococci may be reduced if daptomycin is combined with gentamicin or ceftriaxone [38,39].

Streptococcus pneumoniae — Pneumococcal NVE occurs in the context of pneumococcal pneumonia and may be complicated by concurrent meningitis [40].

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. 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".)

Absence of meningitis

●Clinical approach – 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.

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

•For patients with NVE 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 NVE due to penicillin-resistant S. pneumoniae (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 [41].

●Patients with penicillin allergy – Patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin for four weeks [1].

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 [1,2].

●For patients with isolates resistant to cefotaxime or ceftriaxone (MIC ≥2.0 mcg/mL, which is the MIC definition for CNS isolates), treatment with ceftriaxone with addition of vancomycin (table 5), with or without rifampin (900 mg every 24 hours IV or by mouth in three divided doses) may be warranted [1,2].

Pneumococcal NVE is usually fulminant and causes severe valve damage and embolic complications; valve replacement may be necessary [42]. (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 NVE [40,43]. Regimens used to treat NVE due to viridans group streptococci are typically effective since most of these organisms are highly sensitive to penicillin.

●Group A Streptococcus – For treatment of NVE 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 (2g IV every 24 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.

●Streptococcal groups B, C, F, and G – 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, some experts favor adding gentamicin to a penicillin or cephalosporin for the first two weeks of a four- to six-week course of therapy [1].

Streptococcal-like organisms — The treatment of patients with NVE due to streptococcal-like organisms (eg, Abiotrophia defectiva, Granulicatella spp, and Gemella spp) should be selected carefully based on antimicrobial susceptibility data. This is particularly important for Abiotrophia defectiva and Granulicatella spp. Among Granulicatella adiacens, 40 percent are penicillin susceptible, however this does not predict ceftriaxone susceptibility. In contrast, Abiotrophia defectiva is typically susceptible to ceftriaxone, however this does not predict penicillin susceptibility [44].

We are in agreement with the ESC guidelines which suggest treating native valve infective endocarditis (IE) due to Abiotrophia defectiva or Granulicatella spp with penicillin G, ceftriaxone, or vancomycin, choice based on susceptibility results, for 6 weeks.

Enterococci — Most cases of enterococcal NVE are caused by E. faecalis strains [45].

●Antibiotic resistance – 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.

Vancomycin resistance is observed most commonly among Enterococcus faecium strains, which are a less frequent cause of NVE.

Issues related to enterococcal resistance are discussed further separately. (See "Mechanisms of antibiotic resistance in enterococci".)

●Susceptibility testing – 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) [1,2].

Bactericidal synergistic activity against enterococci can be achieved via the combination of two beta-lactam agents (for NVE due to Enterococcus faecalis) or combination of an aminoglycoside with a cell wall agent.

For treatment of NVE due to susceptible strains of E. faecalis, we favor the beta-lactam combination regimen since it avoids the toxicity of aminoglycosides (nephrotoxicity or oto/vestibular toxicity) [46-49].

For patients with NVE due to E. faecium, treatment consists of combination of an aminoglycoside with a cell wall agent; the combination beta-lactam regimen should not be used since most strains of E. faecium are not susceptible to ampicillin.

•Beta-lactam combination regimen – Use of the beta-lactam combination regimen is supported by observational studies. A meta-analysis of eight observational studies demonstrated no significant difference in all-cause mortality, relapse, or treatment failure between patients treated with the beta-lactam combination regimen and patients treated with the aminoglycoside combination regimen; however, more adverse events were observed among those who received aminoglycosides [50].

•One observational study including more than 240 patients (mostly in Spain) with NVE due to E. faecalis were treated with either ampicillin and ceftriaxone or ampicillin and gentamicin [49]. Rates of mortality, treatment failure, and relapse were comparable between the groups; kidney failure occurred more frequently among those treated with gentamicin. Similarly, in a retrospective study including 279 patients in France with NVE due to E. faecalis, the relapse rate was comparable among patients treated with ampicillin and ceftriaxone or ampicillin and gentamicin (13 to 14 percent) [51].

•Aminoglycoside combination regimen

-Beta-lactam selection and duration – 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 symptom duration <3 months may be treated successfully with four weeks of penicillin or ampicillin [52]; for patients with symptom duration >3 months and patients with relapsed infection, six weeks of penicillin or ampicillin therapy is preferred.

-Gentamicin duration – To minimize the risk of nephrotoxicity, we are in agreement with the ESC 2023 guidelines which favor limiting the duration of gentamicin to the first two weeks of treatment, using single daily dosing [2]. This approach is in contrast to the AHA 2015 guidelines which favor treatment for four to six weeks using divided dosing [1].

A longer duration of gentamicin therapy has been associated with increased likelihood for decline in kidney function. In one nonrandomized study including 84 patients with enterococcal NVE with symptom duration <3 months treated with gentamicin for two weeks or four to six weeks, those treated with a shorter duration of gentamicin had a higher estimated glomerular filtration rate at discharge; rates of event-free survival at one year were comparable [53].

●Penicillin allergy – For patients with immediate-type hypersensitivity to beta-lactams, options include:

•Desensitization to penicillin, to allow treatment with ampicillin plus ceftriaxone (or a beta-lactam plus an aminoglycoside) (table 6); this is preferred if feasible. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

•Treatment with vancomycin for six weeks plus gentamicin for two weeks (table 7).

A six-week duration of vancomycin should be administered (rather than four weeks), since 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) [1,2].

●Preferred approach – 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].

●Alternative approach – An aminoglycoside combination regimen (penicillin or ampicillin for six weeks plus streptomycin for the initial two weeks) is an alternative regimen, provided that the patient does not have pre-existing kidney 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 'Susceptible strains' above.)

●Penicillin allergy – Issues related to management of patients with immediate-type hypersensitivity to beta-lactams are discussed above. (See 'Susceptible strains' above.)

For treatment of NVE 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) [1,2].

For patients with NVE due to enterococcal strains with intrinsic high-level penicillin resistance (MIC ≥16 mcg/mL), we are in agreement with the ESC which recommends combination therapy with vancomycin for six weeks plus gentamicin for the initial two weeks (table 7) [2].

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 NVE due to enterococci with high-level aminoglycoside and/or vancomycin resistance is uncertain. We favor treatment with daptomycin 10 to 12 mg/kg/day, in combination with an additional agent such as ampicillin, ceftaroline, or ertapenem [2,54].

Data on management of vancomycin-resistant enterococcal NVE are limited; the approach is guided by limited data in patients with bacteremia. In one retrospective cohort study including more than 600 patients with bacteremia 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) [55].

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 species (including H. parainfluenzae, the most likely cause of endocarditis among HACEK organisms)

●Aggregatibacter species (including Aggregatibacter actinomycetemcomitans [previously called Actinobacillus actinomycetemcomitans], Aggregatibacter aphrophilus [previously called Haemophilus aphrophilus], and Aggregatibacter paraphrophilus [previously called Haemophilus aphrophilus])

●Cardiobacterium species (including Cardiobacterium hominis)

●Eikenella corrodens

●Kingella species (including Kingella kingae)

HACEK organisms are isolated readily when incubated for five days with automated blood culture systems. However, because these organisms can be fastidious, it may be difficult to obtain susceptibility results in the clinical setting. (See "Blood culture-negative endocarditis: Epidemiology, microbiology, and diagnosis".)

Virtually all HACEK organisms are highly susceptible to third-generation cephalosporins such as ceftriaxone (even strains that produce beta-lactamase), as well as fluoroquinolones [56]. We are in agreement with the AHA and ESC which recommend treatment with ceftriaxone for four weeks (table 10) [1,2]. Ciprofloxacin is an alternative regimen.

Another alternative regimen in the ESC guidelines consists of ampicillin for four weeks in combination with gentamicin for the initial two weeks [2]. This regimen should be used only if growth in vitro is adequate for reliable beta-lactam susceptibility testing, confirmation of ampicillin susceptibility, and absence of beta-lactamase production. In addition, the potential for aminoglycoside nephrotoxicity should be considered carefully.

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 [57].

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, fluoroquinolone, or trimethoprim-sulfamethoxazole for six weeks is reasonable [1,2].

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 careful consideration of 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 'Role of surgery' and "Treatment and prevention of invasive aspergillosis".)

CULTURE-NEGATIVE ENDOCARDITIS

●Etiology and approach – 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 five days) [1].

Cultures are negative in native valve endocarditis (NVE) for three major reasons:

•Administration of antimicrobial agents prior to blood culture incubation

•Inadequate microbiologic techniques

•Infection with fastidious bacteria or nonbacterial pathogens

In the absence of prior antibiotic exposure, the most common causes of culture-negative NVE are fastidious or non-culturable organisms (eg, fastidious bacteria, zoonotic agents, and fungi); in the setting of prior antibiotic exposure, the most common causes are Streptococcus spp, staphylococci, and enterococci.

Additional diagnostic evaluations (such as next-generation sequencing of plasma for pathogen DNA, polymerase chain reaction [PCR] testing of vegetation, vegetation microscopy, or serology) can be used to pursue identification of the etiologic agent. (See "Blood culture-negative endocarditis: Epidemiology, microbiology, and diagnosis".)

●Management – 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 (AHA) suggests the following approach [1]:

•Acute presentation – For patients with acute clinical presentation (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].

•Subacute presentation – For patients with a subacute clinical presentation (symptomatic for weeks), antimicrobial therapy for coverage of infection due to S. aureus, viridans group streptococci, HACEK (Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) organisms, and enterococci is reasonable. Empiric coverage could include vancomycin and either ceftriaxone or 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 culture collection, the type and duration of antecedent 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 plus cefepime (to cover healthcare-associated pathogens) 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 serologies or other diagnostic tests identify the etiologic agent.

For patients with NVE 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 5^th to 6^th 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 10^th to 12^th 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 native valve endocarditis (NVE) 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

•Collecting blood cultures prior to antibiotics – In order to increase the likelihood of identifying the infecting pathogen and therefore optimizing treatment, 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 for NVE should cover staphylococci (methicillin-susceptible and methicillin-resistant), streptococci, enterococci, and gram-negative bacilli. For empiric treatment of NVE, we suggest vancomycin plus ceftriaxone (Grade 2C); other regimens with comparable spectrum of activity are also acceptable. (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 1) (See 'Staphylococci' above.)

-Methicillin-susceptible S. aureus (MSSA) – For patients with NVE due to MSSA we favor initial treatment with a semisynthetic penicillinase-resistant penicillin (eg, nafcillin, oxacillin, or flucloxacillin) to achieve maximum efficacy in the setting of high inoculum infection (table 1). After 4 to 10 days of treatment, with eradication of bacteremia, switching to cefazolin for ease of administration and transition to outpatient therapy is reasonable.

-Methicillin-resistant S. aureus (MRSA) – For patients with NVE due to MRSA, we favor treatment with vancomycin over a daptomycin-based regimen, given greater clinical experience with vancomycin, as well as concern about the potential for emergence of daptomycin non-susceptibility during therapy.

For patients with NVE due to MRSA who are unable to tolerate vancomycin, patients infected with an isolate with vancomycin MIC >1, or patients responding poorly to vancomycin, we suggest combination therapy with daptomycin plus ceftaroline (or fosfomycin, if available) (Grade 2C), rather than daptomycin monotherapy. Combination therapy results in synergy, augmented clearance by immune cells, and may reduce the likelihood of emergence of resistance.

•Enterococci (table 6 and table 7 and table 8 and table 9) (See 'Enterococci' above.)

-For treatment of NVE due to susceptible strains of Enterococcus faecalis, we suggest beta-lactam combination therapy (ampicillin plus ceftriaxone) since it avoids the toxicity of aminoglycosides (Grade 2C).

Use of an aminoglycoside combination regimen (including ampicillin, penicillin, or vancomycin combined with a synergistically active aminoglycoside) is an alternative approach. In such cases, we favor administration of gentamicin for two weeks (rather than longer durations) as a single daily dose, to minimize the risk of nephrotoxicity and oto/vestibular toxicity.

•Other pathogens - Suggested regimens are provided for the following pathogens in the relevant sections and tables above:

-Viridans streptococci and S. bovis/S. equinus complex (table 2 and table 3 and table 4) (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)

-Streptococcal-like organisms (see 'Streptococcal-like organisms' above)

-HACEK (Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) 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 NVE require careful regular clinical follow-up including serial physical examinations and follow-up blood cultures to document clearance of bacteremia. If breakthrough bacteremia develops, the antimicrobial susceptibility of the breakthrough isolate should be reassessed. Patients should be monitored for development of complications including embolic events and heart failure; these should prompt evaluation for cardiac surgery. (See 'Follow up' above.)

ACKNOWLEDGMENT — 

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