Antimicrobial therapy of prosthetic valve endocarditis

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

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 prosthetic valve endocarditis, complications of IE, and indications for surgery are discussed separately. (See "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis" and "Complications and outcome of infective endocarditis" and "Surgery for prosthetic valve endocarditis".)

Issues related to management of native valve endocarditis are discussed separately. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Surgery for left-sided native valve infective 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 — Management of prosthetic heart valve infection can be challenging; optimal treatment requires [1]:

●Identification of the causative microorganism and selection of an effective bactericidal antimicrobial regimen

●Monitoring for complications of prosthetic valve endocarditis (PVE) (see "Complications and outcome of infective endocarditis" and "Overview of management of infective endocarditis in adults", section on 'Echo monitoring during therapy')

●Assessing for indications for surgical intervention, particularly when infection has extended beyond the valve to contiguous cardiac tissue, resulting in abscess formation or valve dysfunction (see "Surgery for prosthetic valve endocarditis")

Site of care — Treatment for PVE should be initiated in the hospital, preferably in an institution where cardiac surgery is available. This is important because treatment of PVE with antimicrobial therapy alone often fails, particularly when infection occurs within the initial six months after valve surgery, is caused by a virulent organism, or is complicated by paravalvular extension or by valve dysfunction.

The approach to antibiotic therapy is the same for PVE involving surgically implanted valves and transcatheter implanted aortic valves (TAVI). Among patients with an infected TAVI, 80 percent have one or more clinically evident indications for cardiac surgery; however, only 19 percent of these patients undergo surgical explantation [3]. Most of these patients have not undergone cardiac surgery due to high anticipated surgical mortality; however, as TAVI infections occur in younger patients with fewer comorbidities, surgical intervention will become a more frequent component of management.

Patients should remain hospitalized until fever resolves and it is clear that surgery can be safely avoided (or, if patients have undergone surgery, that they are stable postoperatively). After initial treatment in the hospital (with resolution of fever and bacteremia, imaging assessment to exclude paravalvular infection, and evaluation regarding the potential need for surgical intervention), consideration may be given to completion of antibiotic therapy in the setting of closely supervised outpatient management. (See 'Completing therapy' below.)

Empiric therapy — For hemodynamically stable patients with an indolent clinical course, antibiotic therapy should be delayed pending blood culture results. This delay allows additional blood cultures to be obtained without the confounding effect of antibiotics, which is particularly important for patients who have received recent antimicrobial agents and whose initial blood cultures may be negative.

For patients presenting with hemodynamic instability or acute disease, empiric antibiotics should be initiated promptly after three sets of blood cultures have been obtained from separate venipunctures and ideally spaced over 30 to 60 minutes. While culture results are pending in these acutely ill patients, empiric broad-spectrum antibiotic therapy to cover both gram-positive and gram-negative bacteria should be initiated. An empiric regimen including vancomycin and either cefepime or a carbapenem with antipseudomonal activity (such as imipenem or meropenem) would provide such coverage. In the context of healthcare-associated infection with concern for multidrug-resistant gram-negative bacilli or enterococcal infection, gentamicin could be added after weighing the associated risk of nephrotoxicity.

Clinical response to initial therapy — Most patients with infective endocarditis (IE) become afebrile three to five days after initiation of appropriate antimicrobial therapy. Patients with Staphylococcus aureus endocarditis may respond more slowly, remaining febrile for five to seven days after initiation of therapy. Patients with methicillin resistance in S. aureus (MRSA) infection may experience persistent bacteremia during this period.

The initial microbiologic response to therapy should be assessed by obtaining repeat blood cultures 48 hours after antibiotics are begun; we advise obtaining two sets of blood cultures every 24 to 48 hours until the bloodstream infection has cleared [1].

After initiating antimicrobial therapy, careful serial physical examinations and periodic electrocardiograms (ECGs) should be performed to evaluate for signs of heart failure, emboli, or other complications. This is particularly important if there is persistent bacteremia and/or fever. Patients who develop new complications while on appropriate antimicrobial therapy (such as new emboli, heart failure, conduction disturbances, heart block, or other complications) should have a repeat echocardiogram to assess for worsening valve dysfunction, cardiac abscess, or fistula. (See "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".)

Duration of therapy — The optimal duration of therapy for PVE is uncertain. In general, we agree with treatment guidelines issued by the American Heart Association and the European Society for Cardiology, which recommend that PVE be treated with an agent(s) that is bactericidal for the isolated microorganism for at least six weeks after the last positive blood culture [1,2].

This approach is based on observational studies and expert opinion guided by our understanding of the pathogenesis of vegetation formation and pathogen susceptibility. In general, a minimum duration of six weeks is felt to be important given that organisms deep within vegetations or within biofilm are metabolically relatively inactive (and therefore are less responsive to antibiotics) than organisms near the surface. (See "Pathogenesis of vegetation formation in infective endocarditis" and "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Biofilm'.)

Effective therapy using a shortened duration of parenteral therapy followed by oral therapy was suggested in a study that included patients with PVE [4]; however, this was a single study with a small sample size and with some biases inherent in patient selection. In our opinion, these data do not yet warrant an alteration in the recommended approach to the treatment of PVE. A full course of parenteral 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.

Completing therapy — Patients may complete intravenous therapy as outpatients once it is clear that infection has been controlled and that they are hemodynamically stable. The patient (or a caregiver) 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 [1,5]. Patients should be counseled regarding the need for immediate evaluation in the setting of new fever, chills, or other signs of systemic toxicity or symptoms suggesting congestive heart failure or neurologic complications. The assessment should include a thorough clinical evaluation, imaging as indicated by symptoms, 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 and renal function tests, erythrocyte sedimentation rate, and C-reactive protein) 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 events, cardiac conduction disturbances (especially with aortic valve infection in view of the proximity of the valve to the conduction system), and heart failure (see "Complications and outcome of infective endocarditis"). Development of complications should prompt evaluation for cardiac surgery. (See "Surgery for prosthetic valve 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 — In the absence of paravalvular extension of infection, patients with relapse of PVE following completion of appropriate antimicrobial therapy should receive a repeat course of antibiotics as described in the following sections. Bacterial isolates obtained in the context of relapse should be retested carefully for complete antibiotic susceptibility profiles.

In addition, patients with relapse of PVE should undergo transesophageal echocardiography (TEE). If TEE does not demonstrate paravalvular extension, further evaluation for extension of infection into paravalvular tissues should be pursued since this frequently requires surgical intervention; diagnostic modalities include 18-flourodeoxglucose F¹⁸-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT), radiolabeled leukocyte Single-photon emission computed tomography (SPECT)/CT, or cardiac CT angiography (depending upon interval from valve surgery, use of bioadhesive with valve implantation, and available radiographic tools). Patients should also be evaluated for extracardiac sites of infection that may have been inadequately treated.

SPECIFIC PATHOGENS — Antimicrobial therapy should be adjusted based on culture results, as described in the following sections. Selection of antimicrobial therapy for PVE is largely based upon clinical experience; in general, the antimicrobial regimen used to treat a specific pathogen causing PVE is based on the treatment used for that organism when it causes native valve endocarditis; staphylococci are an exception. (See 'Staphylococci' below and "Antimicrobial therapy of left-sided native valve endocarditis".)

If cultures remain negative, therapy for culture-negative PVE should be administered. (See 'Culture negative PVE' below.)

Staphylococci

General principles

●Antimicrobial therapy – The primary consideration in choosing antimicrobial therapy for treatment of staphylococcal PVE hinges upon whether the organism is sensitive to methicillin and other beta-lactam antibiotics (table 1) [6,7].

Combination antimicrobial treatment is advised for treatment of staphylococcal PVE. We agree with the American Heart Association (AHA) and the European Society for Cardiology (ESC), which favor a three-drug regimen consisting of a primary antistaphylococcal agent, gentamicin, and rifampin (if the organism is susceptible to these agents) [1,2]. The antistaphylococcal agent and rifampin should be administered for at least six weeks; gentamicin should be administered for the initial two weeks of treatment to prevent the emergence of rifampin resistance [6].

This antibiotic approach is supported by data from animal models of prosthetic device infection and retrospective clinical series [6,8-11] as well as expert opinion. In one retrospective study including 61 patients with staphylococcal PVE who underwent surgery, valves from patients treated preoperatively with combination therapy were 5.9 times more likely to be culture negative than valves from patients treated with monotherapy; all six patients treated with a triple-drug regimen (including rifampin) had negative valve cultures at surgery [8].

Inclusion of an aminoglycoside and/or rifampin in combination therapy has been questioned by some authors [12,13]; this is discussed further below. (See 'Addition of an aminoglycoside' below and 'Addition of rifampin' below.)

●Role of surgery – In addition to antimicrobial therapy, staphylococcal PVE may require surgical intervention. In the past, S. aureus PVE was an indication for early surgery; however, the benefits of surgical intervention in this setting are more nuanced than previously recognized, and some patients with S. aureus PVE may be successfully treated with medical therapy alone [14-16]. Issues related to surgery for PVE are discussed further separately. (See "Surgery for prosthetic valve endocarditis", section on 'Microorganisms usually requiring surgery'.)

Primary antistaphylococcal agent — For isolates susceptible to methicillin, a semisynthetic penicillinase-resistant penicillin (eg, nafcillin, oxacillin, cloxacillin, or flucloxacillin) is the mainstay of therapy. In patients with penicillin allergy that does not involve anaphylaxis, angioedema, or hives, we are in agreement with the AHA which states that a first-generation cephalosporin (eg, cefazolin) may be substituted for the antistaphylococcal penicillin.

For isolates resistant to methicillin, vancomycin is the agent of choice. For patients with penicillin allergy involving anaphylaxis, angioedema, or hives, vancomycin is also the agent of choice.

For treatment of PVE due to staphylococcal isolates with reduced vancomycin susceptibility (minimum inhibitory concentration >1 mcg/mL by broth microdilution or 1.5 mcg/mL by E-test), and for treatment of PVE with inadequate response to vancomycin therapy, the optimal approach is uncertain and clinical experience is limited. In such cases we favor combination therapy with daptomycin (8 to 10 mg/kg once daily) plus a beta-lactam (ceftaroline, oxacillin, or nafcillin), which may result in synergy. The ESC suggests combination therapy with daptomycin and a beta-lactam (oxacillin, flucloxacillin, or ceftaroline) or fosfomycin (not available for parenteral use in the United States) [2]. Other approaches include monotherapy with daptomycin, ceftaroline, telavancin, or linezolid [17-21].

If breakthrough bacteremia or microbiologic failure (including isolating the causative staphylococcus from an explanted valve or vegetation) occurs in patients receiving vancomycin, the recovered isolate should be retested for susceptibility to vancomycin, daptomycin, and rifampin [22]. Daptomycin resistance has emerged during treatment with vancomycin.

The duration of treatment with the primary antistaphylococcal agent and rifampin is at least six weeks from the time blood cultures become negative. If cultures of an explanted valve or paravalvular abscess are positive, antibiotic therapy should be continued for at least six weeks from the date of surgery. In some patients with persistent bacteremia or slow resolution of fever (suggesting a delayed response to therapy) or in patients treated with a nonstandard regimen, some clinicians continue antibiotic therapy beyond six weeks.

Addition of an aminoglycoside

●Clinical approach – An aminoglycoside is used to enhance the antistaphylococcal activity of the primary antistaphylococcal agent, either by synergy or direct activity. In addition, use of multidrug therapy may prevent emergence of rifampin resistance.

If the organism is resistant to gentamicin, an alternative aminoglycoside (to which the isolate is susceptible) or ceftaroline should be used to prevent emergence of rifampin resistance. Based on data from animal models of endocarditis, a fluoroquinolone to which the strain is highly susceptible could be considered in lieu of gentamicin [23-25].

If the organism is resistant to all aminoglycosides, ceftaroline, and fluoroquinolones, alternative agents that may be used as a third drug (contingent on in vitro susceptibility) include linezolid or trimethoprim-sulfamethoxazole [26]. If this approach is pursued, we continue the three-drug regimen for the entire course of treatment.

Delafloxacin, a newer fluoroquinolone approved by the US Food and Drug Administration for treatment of skin and soft tissue infections, retains activity against many methicillin-resistant staphylococci that have become resistant to other fluoroquinolones. The susceptibility of these staphylococci to delafloxacin is reduced relative to susceptible staphylococci, resulting in concern for selection of resistance during therapy, especially in high inoculum infections. There is no clinical experience in the use of delafloxacin in the treatment of PVE; thus, caution and careful follow-up are required if it is used as part of a PVE regimen.

●Rationale – Use of multidrug therapy may prevent emergence of rifampin resistance; this is supported by in vitro studies as well as clinical reports of emergence of rifampin resistance in the setting of high-inoculum infection treated with a single antistaphylococcal agent plus rifampin.

In a small, randomized trial including patients with methicillin-resistant coagulase-negative staphylococcal PVE, rifampin resistance emerged in 7 of 19 patients (37 percent) treated with vancomycin plus rifampin but in none of 13 patients treated with vancomycin, gentamicin, and rifampin (not significant) [6].

Addition of rifampin

●Clinical approach – The approach to treatment of staphylococcal PVE consists of initial antibiotic therapy with two antimicrobial agents other than rifampin (eg, a primary antistaphylococcal agent and gentamicin, if feasible based on antimicrobial susceptibility and renal function) for three to five days prior to initiation of rifampin. If the susceptibility of the isolate precludes treatment with two antistaphylococcal antimicrobials, treatment with a single agent should be administered for five days before beginning rifampin.

It is important to delay the initiation of rifampin until the bacterial density at the site of infection is significantly reduced. The bacterial gene controlling the site of action for rifampin has a relatively high intrinsic mutation rate; therefore, if large numbers of organisms are exposed to rifampin (either alone or in combination with ineffective antimicrobial agents), a rifampin-resistant subpopulation may emerge rapidly [6,23]. Ideally, delayed initiation of rifampin allows opportunity for reduction in the staphylococcal burden, thereby reducing the likelihood that a rifampin-resistant subpopulation will emerge.

If breakthrough bacteremia or microbiologic failure occurs in patients on a rifampin-containing regimen, rifampin susceptibility should be reassessed [6]. If the isolate has become resistant to rifampin, rifampin should be discontinued.

●Rationale – Rifampin appears to be unique in its ability to kill stationary growth-phase staphylococci embedded in biofilm that is adherent to infected foreign material; this is based on in vitro data, evidence from animal model experiments, and clinical observations [6,10,11,23-25,27].

Use of rifampin is supported by the following studies:

•In a post-hoc analysis of a prospective cohort study including 964 patients with S. aureus bacteremia (including 374 patients with deep-seated infection, of whom 121 had endocarditis), outcomes were compared among those receiving combination antibiotic therapy (most frequently including rifampin) and those not receiving combination therapy. On analysis using a Cox model with a time-dependent covariable, there was no difference between the two groups in 30- or 90-day mortality [28]. However, in the subgroup with implanted foreign bodies treated with a combination regimen that included rifampin, reduced 30-day (hazard ratio [HR] 0.53, 95% CI 0.26-1.07) and 90-day (HR 0.55, 95% CI 0.33-0.91) mortality were observed. In addition, late complications of S. aureus bacteremia, including relapse, were reduced among recipients of combination therapy.

•In a randomized trial including more than 750 patients with S. aureus bacteremia treated with an antistaphylococcal regimen and randomly assigned to addition of rifampin or placebo, a small reduction in clinical and microbiologic recurrence of infection was observed in patients who received a rifampin-containing regimen [29].

However, a retrospective study [12] and a systematic literature review [13] have questioned the benefit of combination antibiotic regimens for treatment of staphylococcal PVE:

•The retrospective study included 180 PVE cases, of which 114 were caused by S. aureus and 66 by coagulase negative staphylococci; methicillin resistance was noted in 17 and 39 patients in these groups, respectively [12]. Overall, in-hospital and one-year mortality rates were 23 and 35 percent, respectively. In comparing the outcome of 101 patients treated with a rifampin-containing regimen (median rifampin duration 33 days [interquartile range 12.5 to 41.2]) to 79 patients not receiving rifampin, the in-hospital and one-year mortality and relapse rates in the two groups were not significantly different. Details of the primary antistaphylococcal therapy were not provided for either study arm. The treatment groups appeared comparable; however, the study was retrospective and thus limited by undetected selection bias.

•The literature review stated that the ESC and AHA recommendation for a combination antimicrobial regimen including rifampin was not based on sufficient clinical data, but largely on expert opinion combined with animal model studies [13]. In view of the potential toxicities associated with combination therapy, the authors suggested that gentamicin and rifampin for treatment of PVE be used primarily within the context of clinical trials.

Nonetheless, given the high mortality rates for staphylococcal PVE (25 percent in-hospital and 35 percent at one year), we continue to prefer the combination regimens recommended by the AHA and ESC. The potential benefits support its use, particularly in patients treated medically (in whom infected biofilm may pose a unique challenge). The potential for adverse events and drug-drug interactions must be managed with careful monitoring [28].

Streptococci

Viridans streptococci and S. bovis/S. equinus complex — For treatment of streptococcal PVE in the United States, the penicillin susceptibility of viridans group streptococci and Streptococcus bovis/Streptococcus equinus complex (table 2) are defined in the AHA treatment guidelines [1]; the British Society for Antimicrobial Chemotherapy guidelines and the ESC guidelines use different minimum inhibitory concentration (MIC) susceptibility parameters (table 3 and table 4) [2,30]. In the United States, most streptococci that cause endocarditis are highly penicillin susceptible (MIC ≤0.12 mcg/mL); occasional strains are relatively resistant to penicillin (MIC >0.12 mcg/mL and <0.5 mcg/mL), and rare strains are fully resistant to penicillin (MIC ≥0.5 mcg/mL) [31].

Penicillin-susceptible strains — For treatment of streptococcal PVE due to penicillin-susceptible strains, we are in agreement with the AHA, which recommends a beta-lactam antibiotic (eg, penicillin, ampicillin, or ceftriaxone) for six weeks, with the option to add an aminoglycoside (eg, gentamicin) for the initial two weeks. The addition of an aminoglycoside is relatively contraindicated in the setting of renal insufficiency and cranial nerve VIII dysfunction [6]. An alternative regimen for beta-lactam intolerant patients consists of vancomycin monotherapy for six weeks. Antibiotic dosing is summarized in the table (table 3).

Combination beta-lactam-aminoglycoside therapy is used to achieve synergistic killing of streptococci [32]. This approach is based on in vitro studies, in vivo studies using experimental endocarditis models, clinical series, and clinical experience [7,33]. However, there are no studies demonstrating the superiority of combination therapy over penicillin monotherapy. In addition, studies have demonstrated that various genetic pathways mediate high-level resistance to streptomycin (and less frequently to gentamicin) in a small percentage of streptococci that cause endocarditis; in these isolates, the presence of high-level aminoglycoside resistance abrogates the bactericidal synergy of combination therapy [34-37].

To avoid the potential exposure to aminoglycoside toxicity in the absence of therapeutic benefit, laboratory testing for high-level gentamicin resistance should be performed prior to initiation of combination therapy, if possible. However, the optimal approach to screening streptococci for high-level aminoglycoside resistance is uncertain, and there is no Clinical and Laboratory Standards Institute guidance. Bacterial growth on brain-heart infusion agar plates (which are commercially available for screening enterococci) in the face of high aminoglycoside concentrations is suggestive of high-level resistance and loss of bactericidal synergy with combination therapy.

Relatively penicillin-resistant strains — The preferred regimen for streptococcal PVE due to relatively penicillin-resistant strains (MIC >0.12 mcg/mL and <0.5 mcg/mL) consists of combination therapy with a beta-lactam antibiotic (eg, penicillin, ampicillin, or ceftriaxone) for six weeks and an aminoglycoside (eg, gentamicin). Antibiotic dosing is summarized in the table (table 4).

The optimal approach to administration of gentamicin (dosing and duration) is uncertain; our approach differs from that suggested by the AHA and ESC. We administer gentamicin 3 mg/kg/day in three divided doses (rather than a single daily dose, as favored by the AHA and ESC) for a minimum of two weeks (rather than six weeks, as favored by the AHA and ESC). We favor divided dosing to maintain a bactericidal level throughout the day, given that the cell wall agent may be bacteriostatic (rather than bactericidal) for relatively resistant streptococci. We favor a two-week duration based on limited data from treatment of native valve endocarditis with these organisms and the increased risk of aminoglycoside nephrotoxicity and cranial nerve VIII toxicity with longer courses of therapy.

Prior to initiation of combination therapy, laboratory testing for high-level gentamicin resistance should be performed, if possible. (See 'Penicillin-susceptible strains' above.)

If aminoglycoside therapy is relatively contraindicated (eg, in the setting of renal insufficiency or cranial nerve VIII dysfunction), or the strain is gentamicin resistant, monotherapy with a beta-lactam antibiotic may be given [6]. An alternative regimen consists of vancomycin monotherapy for six weeks.

Fully penicillin-resistant strains — For patients with PVE due to fully penicillin-resistant streptococci (defined by the AHA as MIC ≥0.5 mcg/mL), management consists of combination therapy with a beta-lactam antibiotic (eg, penicillin, ampicillin, or ceftriaxone) for six weeks and, in the absence of high-level resistance, an aminoglycoside (eg, gentamicin). In such cases we administer gentamicin (3 mg/kg/day in three divided doses) for six weeks. Antibiotic dosing is summarized in the table (table 4).

A similar approach is used to treat PVE caused by streptococci-like organisms: Abiotrophia defectiva, Granulicatella spp, and Gemella spp. While a regimen of high-dose penicillin or ampicillin plus gentamicin may be used initially, confirming the antimicrobial susceptibility of the isolate is important in the selection of optimal treatment. Notably, among Granulicatella adiacens, penicillin susceptibility does not predict ceftriaxone susceptibility (in contrast to Abiotrophia defectiva); this must be tested specifically.

If the patient is intolerant of penicillin and ceftriaxone, or if gentamicin cannot be used, vancomycin monotherapy should be used; we do not give gentamicin with vancomycin because of the increased risk of nephrotoxicity with coadministration of these agents.

Penicillin allergy — For patients with immediate-type reactions (urticaria or anaphylaxis) to penicillin, vancomycin is an acceptable alternative regimen. For patients with non-immediate type reactions, cefotaxime or ceftriaxone may be used. (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)

Daptomycin should not be used routinely as an alternative to vancomycin for treatment of endocarditis caused by non-speciated viridans streptococci; emergence of stable high-level resistance to daptomycin has been noted in at least 25 percent of the Streptococcus mitis group isolates (S. mitis, Streptococcus oralis, and Streptococcus sanguinis) with exposure to daptomycin in vitro and in experimental endocarditis models. Resistance has also emerged in Streptococcus parasanguinis, Abiotrophia spp, and Granulicatella adiacens [38-40]. In vitro and endocarditis model studies suggest that the likelihood of emergence of daptomycin resistance in streptococci may be diminished when daptomycin is combined with gentamicin or ceftriaxone, although this approach would not be recommended therapy [41,42].

Other streptococci — For treatment of PVE due to penicillin-susceptible Streptococcus pneumoniae (in the absence of meningitis) or a Streptococcus belonging to serogroups A, B, C, F, and G, the regimen consists of penicillin or ceftriaxone, as for penicillin-susceptible viridans streptococci for six weeks (table 3). For serogroups B, C, F, and G, gentamicin may be administered for the initial two weeks; gentamicin is not used for serogroup A because these strains are highly susceptible to penicillin.

For treatment of PVE due to S. pneumoniae with relative or full penicillin resistance (MIC ≥0.12 mcg/mL) in the absence of meningitis, the regimens in the table may be used (table 3). In such cases, adding an aminoglycoside is not recommended.

For treatment of PVE due to penicillin-resistant pneumococci complicated by meningitis, the regimen must be adjusted to ensure adequate antimicrobial penetration into the cerebrospinal fluid (with meningeal doses of ceftriaxone, vancomycin, or both, contingent on susceptibility). (See "Initial therapy and prognosis of community-acquired bacterial meningitis in adults".)

Enterococci — Bactericidal activity against enterococci can be achieved with the synergistic interaction of a cell wall active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamicin or streptomycin). The cell wall agent is bacteriostatic against enterococci but promotes entry of the aminoglycoside into the cell, where it is bactericidal [43].

To achieve this interaction, the organism (E. faecalis or E. faecium) must be susceptible to the cell wall active agent at achievable serum concentrations and must be susceptible to gentamicin (at 500 mcg/mL) or streptomycin (at 1000 mcg/mL in broth or at 2000 mcg/mL on agar culture). High-level resistance to gentamicin and streptomycin is mediated by two independent genes; therefore, organisms could be tested for high-level resistance to each of these drugs. Growth in the presence of the aminoglycoside at the above concentrations indicates high-level resistance and precludes a synergistic bactericidal effect when that aminoglycoside is combined with a cell wall active agent. In addition, gentamicin resistance at the above concentration indicates that synergy cannot be achieved with netilmicin, tobramycin, amikacin, or kanamycin.

Bactericidal synergy against Enterococcus faecalis (but not Enterococcus faecium) also can be achieved by combining two beta-lactam antibiotics. Exposure of E. faecalis to high concentrations of ampicillin plus ceftriaxone results in bactericidal synergy through the saturation of penicillin binding proteins 2, 3, 4, and 5; this synergy is achieved irrespective of high-level resistance to aminoglycosides. In animal models of E. faecalis endocarditis, treatment with ampicillin plus ceftriaxone was comparable to ampicillin plus gentamicin and was also effective against E. faecalis with high-level gentamicin resistance [43-46]. These observations have led to use of a double beta-lactam regimen (ampicillin plus ceftriaxone) for treatment of E. faecalis endocarditis. However, dual beta-lactam therapy may not provide synergistic bactericidal activity against E. faecium and has not been shown effective for treatment of endocarditis due to this species [47,48].

Antibiotic resistance among enterococci has become significantly more common, necessitating careful testing of each strain causing endocarditis to select a synergistic regimen [49,50]. Ideally all enterococci causing IE should be speciated; for resistant strains, speciation is essential.

Susceptible strains

General approach — The AHA and the ESC guidelines recommend two types of regimens for treatment of PVE caused by susceptible enterococci:

●Beta-lactam combination regimen – This regimen for treatment of PVE caused by Enterococcus faecalis (but not E. faecium) combines treatment with ceftriaxone and ampicillin. In three retrospective studies, the efficacy of this regimen has been comparable in efficacy to the above regimen and has been associated with significantly less frequent nephrotoxicity [44-46,51]. Accordingly, this regimen is being used increasingly, particularly in patients with pre-existing renal dysfunction or in whom the risk of nephrotoxicity or oto/vestibular toxicity is a concern [46].

Data supporting use of a beta-lactam combination regimen are discussed further separately. (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'General approach' and "Treatment of enterococcal infections", section on 'Bacteremia'.)

●Aminoglycoside combination regimen – This regimen combines a cell wall active agent (penicillin, ampicillin, or vancomycin) with gentamicin [1,2]. Gentamicin is administered with divided dosing (three times daily) to maintain a bactericidal level throughout the day for bactericidal synergy (table 5). This approach is based on in vitro studies, animal models, and clinical series [43,51].

Emergence of nephrotoxicity during therapy — If nephrotoxicity or oto/vestibular toxicity emerge while using a gentamicin-containing regimen, we discontinue gentamicin and switch to the dual beta-lactam regimen. (See 'General approach' above.)

An alternative approach to mitigate potential nephrotoxicity during treatment with the aminoglycoside combination regimen is to reduce the duration of aminoglycoside treatment [52,53]. This approach is supported by a prospective study including 27 cases of enterococcal PVE; clinical cure was achieved in 78 percent of cases [52]. Among cured patients, a cell wall active agent was given for a median of 42 days, and a synergistic aminoglycoside was given for a median of 15 days.

Penicillin allergy — Patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin plus gentamicin for six weeks (table 6). If the risk of nephrotoxicity with this regimen is unacceptable, patients should be desensitized to penicillin to allow treatment with penicillin or ampicillin plus an aminoglycoside or ampicillin plus ceftriaxone. Patients with a less definitive history of beta-lactam allergy should be evaluated by an allergy consultant in an effort to clarify the history and facilitate use of the preferred beta-lactam based therapies if feasible.

Gentamicin resistance — For PVE caused by E. faecalis strains susceptible to penicillin, vancomycin, and streptomycin but with high-level resistance to gentamicin, we favor treatment with a beta-lactam combination regimen (ceftriaxone plus ampicillin for six weeks). For strains that do not exhibit high-level resistance to streptomycin, the combination of penicillin or ampicillin plus streptomycin will provide bactericidal synergy and may be used, provided that the patient does not have pre-existing renal dysfunction or cranial nerve VIII dysfunction. Dosing is summarized in the table (table 7).

If the enterococcus exhibits high-level resistance to both streptomycin and gentamicin, no available aminoglycoside will provide bactericidal synergy; thus, an aminoglycoside should not be administered. If the isolate is E. faecalis, the beta-lactam combination regimen should remain effective (see 'General approach' above) [44-46]. Prolonged treatment with a cell wall active agent alone (eg, ampicillin for 8 to 12 weeks) may be effective, but the risk of relapse is high [54].

E. faecium is a relatively infrequent cause of PVE; but when this species does cause infection, it is typically resistant to multiple antibiotics, and optimal treatment is not certain. (See 'Resistance to penicillins, aminoglycosides, and vancomycin' below.)

Penicillin resistance — Intrinsic high-level penicillin resistance in enterococci is usually due to alterations in penicillin-binding proteins. For patients with PVE due to enterococcal strains with intrinsic high-level penicillin resistance, we are in agreement with the AHA which recommends combination therapy with vancomycin plus gentamicin for six weeks. Dosing is summarized in the table (table 6).

Occasionally, E. faecalis may be resistant to penicillin and ampicillin by virtue of beta-lactamase production; if this is suspected, confirmation by testing for beta-lactamase can be requested. In such cases, vancomycin or ampicillin-sulbactam or amoxicillin-clavulanate could be used as the cell wall active agent in a combination regimen with an aminoglycoside, contingent on absence of high-level resistance.

Resistance to penicillins, aminoglycosides, and vancomycin — For PVE caused by vancomycin-resistant E. faecium (VRE) organisms (which often are also resistant to penicillin and ampicillin and highly resistant to gentamicin and streptomycin), the optimal approach is uncertain (table 8). A full evaluation of the isolate's resistance profile is required for selection of therapy. Occasionally, a standard regimen is available. Infectious disease consultation is advised.

In general, daptomycin is active against enterococci, including VRE [31]. Clinical experience with daptomycin treatment of enterococcal endocarditis is limited, raising important concerns regarding reporting bias [55]. In general, if daptomycin is used, it should be administered in high doses (10 to 12 mg/kg IV once daily) and combined with either ampicillin or ceftaroline. While combination with either of these beta-lactam agents may enhance the bactericidal activity of daptomycin (even against daptomycin-resistant enterococci), this effect is related to gene mutations that regulate the cell membrane and is difficult to predict [56-58].

Linezolid is often active against E. faecium and E. faecalis, but its effectiveness in the treatment of PVE caused by VRE is not fully established [1,59]. Quinupristin-dalfopristin is active against E. faecium but causes unacceptable infusion-related toxicity that usually precludes routine use.

Patients with PVE caused by extensively antibiotic-resistant enterococci should be managed with the assistance of infectious disease consultation [43];

For patients with PVE due to highly resistant enterococci, consultation regarding surgical intervention during suppressive bacteriostatic therapy is warranted; in addition, surgery may be warranted for patients not responsive to antimicrobial therapy. (See "Surgery for prosthetic valve endocarditis".)

HACEK organisms — The fastidious gram-negative bacilli, Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella (HACEK organisms), are highly susceptible to third-generation cephalosporins; some are ampicillin-resistant due to the production of beta-lactamase. For treatment of HACEK PVE, we are in agreement with the AHA, which recommends treatment with ceftriaxone (or a comparable third- or fourth-generation cephalosporin, such as cefotaxime or cefepime, respectively) for six weeks. Ampicillin (or ampicillin-sulbactam/amoxicillin-clavulanate) should be used only if growth in vitro is sufficiently vigorous to allow reliable susceptibility testing and confirms susceptibility. For patients unable to tolerate a cephalosporin or ampicillin, ciprofloxacin or another fluoroquinolone may be used (table 9) [1].

The ESC recommends ceftriaxone for six weeks. If the isolate does not produce beta-lactamase and is ampicillin susceptible, ampicillin in combination with gentamicin is an option. The ESC cites ciprofloxacin as another possible therapy, although it is less extensively studied for this indication [2]. Use of ampicillin-gentamicin combination therapy is not well established, and aminoglycoside exposure may expose patients to nephrotoxicity risks.

Patients with HACEK PVE who do not have valvular dysfunction can often be cured with antibiotics alone [60].

Other gram-negative organisms — Treatment of PVE caused by non-HACEK gram-negative bacilli should be based upon the 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 [1,2]. Maximal doses of the selected antimicrobials (eg, rather than the low doses used for synergy) should be used in an attempt to expose a potentially high bacterial inoculum deep in vegetations to high antimicrobial concentrations. The rationale for combination therapy is to minimize the likelihood of antibiotic resistance in the setting of a potentially large bacterial burden within the protected environment of vegetation. These patients should be treated in conjunction with an infectious disease consultant.

Surgery to excise the infected valve is often required in PVE due to gram-negative bacilli, especially that caused by Pseudomonas aeruginosa or when infection involves the left-sided heart valves.

Corynebacteria (diphtheroids) — For PVE due to organisms susceptible to gentamicin (MIC <4.0 mcg/mL), treatment consists of penicillin plus gentamicin, which will result in synergistic bactericidal activity.

Gentamicin resistance precludes bactericidal synergy [61]. For gentamicin-resistant strains, treatment for six weeks with vancomycin, which is bactericidal against diphtheroids, is warranted. Vancomycin is also appropriate in the setting of penicillin allergy or concern for aminoglycoside nephrotoxicity.

Fungi — Treatment of fungal endocarditis consists of antifungal therapy and generally 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 PVE — Culture-negative infective endocarditis (IE) 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 obtaining blood cultures

●Inadequate microbiologic techniques

●Infection with fastidious bacteria or nonbacterial pathogens

In the absence of prior antibiotic exposure, the most common causes of culture-negative IE are fastidious organisms (eg, fastidious bacteria, zoonotic agents and fungi); in the setting of prior antibiotic exposure, the most common causes are Streptococcus spp. Additional diagnostic evaluations (such as next-generation sequencing of plasma for pathogen DNA, polymerase chain reaction testing of vegetation, vegetation microscopy, or serology) can be used to pursue identification of the etiologic agent. (See "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis", section on 'Culture-negative endocarditis'.)

Other pathogens for consideration include:

●Coxiella burnetii is a relatively common cause of culture-negative endocarditis; the frequency varies in different geographic locations. Further information regarding Q fever can be found on the United States Centers for Disease Control and Prevention website [62,63].

●Fungal endocarditis should be considered, especially in patients with a complex perioperative course. (See 'Fungi' above.)

●Rarely, culture-negative PVE due to atypical mycobacteria has been described. Reports have described valve contamination during manufacture. Mycobacterium chimaera has caused culture-negative PVE, although this organism can be recovered from blood when cultures are placed in special media. This infection has occurred as a consequence of intraoperative wound contamination by aerosol from contaminated heater-cooler machines used during cardiopulmonary bypass. These cases can have an indolent, markedly delayed onset (eg, years after valve replacement surgery) and can present with multiple foci of infection [64]. (See "Overview of nontuberculous mycobacterial infections", section on 'M. chimaera associated with cardiac surgery'.)

Empiric treatment of patients with culture-negative PVE should be pursued in consultation with an infectious disease specialist. We are in agreement with the AHA, which favors the following initial approach while awaiting results from an expanded diagnostic evaluation [1]:

●Onset ≤1 year after surgery – Patients with culture-negative PVE with onset ≤1 year after surgery should receive antimicrobial therapy for coverage of infection due to staphylococci, enterococci, and aerobic gram-negative bacilli. Broad coverage can be achieved using an empiric regimen with vancomycin as well as cefepime or a carbapenem with activity against P. aeruginosa. With an acute septic onset, gentamicin can be added to further enhance coverage, with care to avoid nephrotoxicity. Addition of rifampin can be delayed at least three to five days after start of therapy.

●Onset >1 year after surgery – Patients with culture-negative PVE onset >1 year after surgery should receive antimicrobial therapy for coverage of infection due to staphylococci, viridans group streptococci, enterococci, and HACEK organisms. Empiric therapy could be initiated with vancomycin and ceftriaxone; this regimen provides initial empiric coverage but is not adequate treatment for enterococcal infection.

Patients with nosocomial or hospital-associated culture-negative PVE should be treated empirically as outlined above for patients with onset ≤1 year after valve implantation.

If additional diagnostic evaluations identify the etiologic agent, antibiotic therapy should be targeted accordingly. If negative blood cultures may be attributable to prior antimicrobial exposure, consideration should be given to the prior antimicrobial's spectrum of activity and the patient's relevant epidemiology to select empiric therapy.

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".)

SUMMARY AND RECOMMENDATIONS

●General considerations − Management of prosthetic valve endocarditis (PVE) requires bactericidal antimicrobial therapy, monitoring for complications, and assessment of indications for surgical intervention. Specific recommendations provided are based upon clinical experience and in vitro studies, rather than on clinical trial data showing a benefit for clinical outcomes. (See 'General considerations' above.)

●Empiric therapy − Empiric therapy prior to a microbiologic diagnosis is not always necessary. (See 'Empiric therapy' above.)

•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).

Empiric antibiotic therapy may be initiated after three sets of blood cultures have been obtained. We suggest an empiric regimen that covers gram-positive and gram-negative bacteria, such as vancomycin, gentamicin (for synergy), and either cefepime or a carbapenem with antipseudomonal activity (Grade 2C).

•For patients with suspected PVE who are hemodynamically stable with an indolent clinical course, therapy can be delayed briefly while awaiting blood culture results. In patients with prior antibiotic exposure, the delay allows obtaining repeat cultures with reduced confounding by prior therapy.

●Targeted therapy − Therapy for PVE should be targeted to the organism isolated from blood cultures, along with the in vitro susceptibility results. The approach is summarized in the tables and is discussed in the sections above:

•Staphylococci (table 1) − For treatment of staphylococcal PVE, we suggest combination therapy with a three-drug regimen which includes a primary antistaphylococcal agent, gentamicin, and rifampin, rather than one- or two-drug regimens (Grade 2C). The antistaphylococcal agent and rifampin should be administered for at least six weeks; gentamicin should be administered for the initial two weeks of treatment. Alternative regimens are suggested for resistant organisms. (See 'Staphylococci' above.)

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

-Viridans streptococci and Streptococcus bovis/Streptococcus equinus complex (table 3 and table 4)  

-Streptococcus pneumoniae

-Streptococcal groups A, B, C, F, and G

-Enterococci (table 5 and table 6 and table 7 and table 8)

-HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella) organisms (table 9)

-Other non-HACEK gram-negative organisms

-Corynebacteria (diphtheroids)

-Fungi

-Culture-negative endocarditis

●Treatment duration − We suggest that patients with PVE be treated with parenteral antibiotics for at least six weeks rather than for shorter durations (Grade 2C). 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. 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. (See 'Duration of therapy' above.)

●Monitoring during treatment − Patients with PVE require careful regular clinical follow-up including serial physical examinations and obtaining follow-up blood cultures to document clearance of bacteremia. Patients should be monitored for development of complications including embolic events and heart failure. Development of complications should prompt evaluation for cardiac surgery. (See 'Clinical response to initial therapy' above and 'Completing therapy' above.)