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 agents alone often fails, particularly when infection occurs within the initial six months after valve surgery and/or is caused by a virulent organism. In addition, invasive infection (with subsequent valve dysfunction) often arises before or during therapy.
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, empiric broad-spectrum antibiotic therapy to cover both gram-positive and gram-negative bacteria should be initiated: vancomycin, gentamicin (for synergy), and either cefepime or a carbapenem with antipseudomonal activity (such as imipenem or meropenem). This regimen covers common PVE pathogens as well as virulent gram-negative bacilli (which could be acquired in the health care setting).
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 S. aureus endocarditis may respond more slowly, remaining febrile for five to seven days after initiation of therapy.
The initial microbiologic response to therapy should be assessed by obtaining repeat blood cultures 48 hours after antibiotics are begun; it is reasonable to obtain at least two sets of blood cultures every 24 to 48 hours until bloodstream infection has cleared [1].
Thereafter, careful serial physical examinations should be performed to evaluate for signs of heart failure, emboli, or other complications. Patients who develop new complications while on appropriate antimicrobial therapy (such as new emboli, heart failure, heart block, or other complications) should have a repeat echocardiogram to assess for worsening valve dysfunction, cardiac abscess, or fistula. (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 cultures first become negative [1,2].
This approach to 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'.)
A shortened duration of parenteral therapy, followed by oral therapy, has been studied in patients with PVE [3]; however, findings from a single study of small sample size and with some biases inherent in patient selection do not yet, in our opinion, 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 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 [1,4]. Patients should be counseled regarding the need for immediate evaluation in the setting of new fever, chills, or other signs of systemic toxicity, including a thorough clinical evaluation and repeat blood cultures [1]. (See "Outpatient parenteral antimicrobial therapy".)
While on antimicrobial therapy, patients should be monitored for antimicrobial toxicity. Weekly laboratory monitoring (complete blood count, chemistries, liver function tests, 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 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 — 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 should be retested carefully for complete antibiotic susceptibility profiles. In addition, such patients should undergo transesophageal echocardiography to assess for extension of infection into paravalvular tissue, which may require surgical intervention. (See "Surgery for prosthetic valve endocarditis".)
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; S. aureus is 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 — 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) [5,6]. The approach to treatment of staphylococcal PVE is not contingent on whether the pathogen is Staphylococcus aureus or coagulase negative (unlike other types of staphylococcal infections).
Antimicrobial treatment of staphylococcal PVE requires combination therapy. 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.
Data to support this antibiotic approach comes from animal models of prosthetic device infection and retrospective clinical series [5,7-10]. 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 [7].
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 and close clinical care alone [11-13]. Issues related to surgery for PVE are discussed further separately. (See "Surgery for prosthetic valve endocarditis", section on 'Microorganisms usually requiring surgery'.)
Primary antistaphylocccal 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, swelling, 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 treatment of PVE due to staphylococcal isolates with reduced vancomycin susceptibility (minimum inhibitory concentration >1 mcg/mL 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) and a beta-lactam (oxacillin, nafcillin, or ceftaroline), which may result in synergy. The ESC suggests combination therapy with daptomycin and a beta-lactam (oxacillin or ceftaroline) or fosfomycin (not available for parenteral use in the United States) [2]. Other approaches include monotherapy with daptomycin, ceftaroline, telavancin, or linezolid [14-18].
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.
If breakthrough bacteremia or microbiologic failure occurs in patients receiving vancomycin, the recovered isolate should be tested for vancomycin and daptomycin resistance as well as rifampin [19]. Daptomycin resistance has emerged during treatment with vancomycin.
The duration of treatment for the primary antistaphylococcal agent is at least six weeks.
Addition of an aminoglycoside
If the organism is resistant to gentamicin, an alternative aminoglycoside should be sought based on antibiotic susceptibilities.
If the organism is resistant to all available aminoglycosides, a fluoroquinolone to which the strain is highly susceptible could be used [20-22].
If the organism is resistant to all aminoglycosides and fluoroquinolones, alternative agents that may be used as a third drug (contingent on in vitro susceptibility) include linezolid, ceftaroline, or trimethoprim-sulfamethoxazole [23]. If this approach is pursued, we continue the three-drug regimen for the entire course of treatment.
Addition of rifampin — 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) for three to five days prior to initiation of rifampin. If the isolate is not sensitive to two other antimicrobial agents, treatment with a single agent should be administered for five days before beginning rifampin.
Rifampin appears to be unique in its ability able to kill staphylococci adherent to foreign material; this is based on in vitro data, evidence from animal model experiments, and clinical observations [5,9,10,20-22,24].
Delayed initiation of rifampin is important because 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 [5,20]. 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 [5].
If the isolate is resistant to rifampin, rifampin should be omitted; an antistaphylococcal antibiotic combined with gentamicin (or an alternative to gentamicin) should be used for the duration of therapy.
Streptococci
Viridans streptococci and S. bovis/S. equinus complex — For treatment of PVE in the United States, the 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) parameters (table 3 and table 4) [2,25]. In the United States, 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) [26].
Penicillin-susceptible strains — The preferred regimen for streptococcal PVE due to penicillin-susceptible strains consists of combination therapy with a beta-lactam antibiotic (eg, penicillin, ampicillin, or ceftriaxone) for six weeks and an aminoglycoside (eg, gentamicin) for two weeks. If aminoglycoside therapy is relatively contraindicated (eg, in the setting of renal insufficiency), monotherapy with a beta-lactam antibiotic may be given [5]. An alternative regimen 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 the organism [27]. This approach is based on in vitro studies, in vivo studies using experimental endocarditis models, clinical series, and clinical experience [6,28]. 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 [29-32].
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 risk of enhanced aminoglycoside nephrotoxicity 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 the strain is gentamicin resistant, monotherapy with a beta-lactam antibiotic may be given [5]. 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) and for patients with streptococcal-like organisms with penicillin resistance (eg, Abiotrophia defective, Granulicatella spp, and Gemella spp), 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).
If the patient is intolerant of penicillin and ceftriaxone or 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, and Granulicatella species [33-35]. 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 [36,37].
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 (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 4).
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). (See "Initial therapy and prognosis of bacterial meningitis in adults".)
Enterococci — Bactericidal activity against enterococci requires the synergistic interaction of a cell wall active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamicin or streptomycin) [27]. The cell wall agent is bacteriostatic against enterococci, and the aminoglycoside produces bactericidal synergy.
To achieve this interaction, the organism 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 independently acquired genes; therefore, organisms should be tested for high-level resistance to each of these drugs. At the above concentrations, growth in the presence of the aminoglycoside indicates high-level resistance and precludes synergistic use of the aminoglycoside. In addition, gentamicin resistance at the above concentration indicates that synergy cannot be achieved with netilmicin, tobramycin, amikacin, or kanamycin.
Antibiotic resistance among enterococci has become significantly more common, necessitating careful testing of each strain causing endocarditis to select a synergistic regimen [38,39].
Susceptible strains
General approach — For treatment of PVE caused by susceptible enterococci, we are in agreement with the AHA and the ESC guidelines, which recommend combination therapy with a cell wall active agent (penicillin, ampicillin, or vancomycin) plus an aminoglycoside (usually 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 [40],
For patients whose nephrotoxicity risk precludes aminoglycoside therapy, an alternative regimen for treatment of PVE due to Enterococcus faecalis consists of a beta-lactam combination regimen of ceftriaxone (2 g intravenously [IV] every 12 hours) and ampicillin (2 g IV every 4 hours); this regimen achieves a bactericidal effect by facilitating expanded binding to the cell membrane penicillin-binding proteins (PBPs) [41-43]. However, dual beta-lactam therapy may not provide synergistic bactericidal activity against Enterococcus faecium and has not be shown effective for treatment of endocarditis due to this organism [44,45]. If nephrotoxicity or oto/vestibular toxicity are a concern or emerge during therapy, gentamicin should be discontinued and the dual beta-lactam regimen should be used. (See 'Emergence of nephrotoxicity during therapy' below.)
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'.)
Emergence of nephrotoxicity during therapy — In the setting of progressive nephrotoxicity during treatment, the duration of aminoglycoside administration may be reduced or, in the setting of PVE due to E. faecalis, beta-lactam combination regimen may be used. (See 'General approach' above.)
Use of an abbreviated aminoglycoside course is supported by a prospective study including 27 cases of enterococcal PVE; clinical cure was achieved in 78 percent of cases [46]. Among cured patients, a cell wall active agent was given for a median of 42 days and a synergistic aminoglycoside was added for a median of 15 days. Similarly, the efficacy of an abbreviated course of the aminoglycoside component of therapy was affirmed in a Danish study [47].
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. 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 — Treatment regimens for PVE due to enterococcal strains susceptible to penicillin, vancomycin, and streptomycin but resistant to gentamicin, options include a beta-lactam combination regimen (ceftriaxone plus ampicillin for six weeks) or an aminoglycoside combination regimen (penicillin or ampicillin plus streptomycin, both for four to six weeks) provided that the patient does not have pre-existing renal dysfunction or cranial nerve VIII dysfunction. Dosing is summarized in the table (table 7).
In the setting of high-level resistance to both streptomycin and gentamicin, an aminoglycoside should not be administered. Under such circumstances, synergy is not feasible and aminoglycoside resistance precludes bactericidal therapy. In such cases, possible approaches include a beta-lactam combination regimen of ampicillin plus ceftriaxone (in the setting of PVE due to E. faecalis) (see 'General approach' above) [41-43] or a prolonged course of a cell wall active agent (eg, 8 to 12 weeks) [48].
Penicillin resistance — 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).
Resistance to penicillin and ampicillin is usually due to alterations in PBPs. In the setting of PVE due to such isolates, vancomycin is the cell wall active agent of choice. Occasionally, E. faecalis may be resistant to penicillin and ampicillin by virtue of beta-lactamase production; if this is suspected, testing for beta-lactamase can be requested. In such cases, vancomycin or ampicillin-sulbactam could be used as the cell wall active agent.
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 and expert consultations is advised.
In general, daptomycin is active against enterococci, including VRE [26]. Clinical experience with daptomycin treatment of endocarditis is limited, raising important concerns regarding reporting bias [49]. 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 daptomycin-resistant enterococci), this effect is related to gene mutations that regulate the cell membrane and is difficult to predict [50-52].
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 [1,53]. Quinupristin-dalfopristin is active against E. faecium but causes unacceptable infusion-related toxicity that precludes routine use.
In the setting of PVE due to highly resistant enterococci, surgical intervention during suppressive bacteriostatic therapy should be strongly considered; in addition, surgery may be warranted for patients not responsive to antimicrobial therapy. (See "Surgery for prosthetic valve endocarditis".)
HACEK organisms — For treatment of Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella (HACEK) PVE, we are in agreement with the AHA which recommends treatment with ceftriaxone (or comparable third-generation cephalosporin such as cefotaxime or fourth-generation cephalosporin such as cefepime) for six weeks. Ampicillin (or ampicillin-sulbactam) should only be used if in vitro susceptibility tests confirm susceptibility. All HACEK organisms are highly susceptible to third-generation cephalosporins; some are ampicillin resistant due to the production of beta-lactamase. For patients unable to tolerate a cephalosporin or ampicillin, ciprofloxacin or another fluoroquinolone may be used (table 9) [1].
The ESC recommends ceftriaxone, ampicillin (if the organism is susceptible) in combination with gentamicin, or ciprofloxacin [2]. Use of combination therapy is not well established and aminoglycoside exposure is likely not necessary.
Patients with HACEK PVE who do not have valvular dysfunction can often be cured with antibiotics alone [54].
Other gram-negative organisms — Treatment of PVE caused by 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]. 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.
Surgery to excise the infected valve is often required in gram-negative bacillus endocarditis, 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 [55]. For gentamicin-resistant strains, treatment consists of vancomycin which is bactericidal against diphtheroids. Vancomycin is also appropriate in the setting of penicillin allergy or concern for aminoglycoside nephrotoxicity.
The duration of treatment is six weeks.
Fungi — Treatment of fungal endocarditis consists of antifungal therapy and valve replacement.
Issues related to Candida endocarditis are discussed separately. (See "Candida endocarditis and suppurative thrombophlebitis".)
Issues related to endocarditis caused by Aspergillus are discussed separately. (See "Treatment and prevention of invasive aspergillosis", section on 'Antifungal therapy' and "Treatment and prevention of invasive aspergillosis", section on 'Duration' and "Treatment and prevention of invasive aspergillosis", section on 'Role of surgery'.)
CULTURE NEGATIVE 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 blood culture incubation
●Inadequate microbiologic techniques
●Infection with fastidious bacteria or nonbacterial pathogens
The most common causes of culture-negative IE are fastidious organisms (eg, zoonotic agents and fungi) and Streptococcus spp in patients who have received previous antibiotic treatment.
Other pathogenic considerations 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 [56,57].
●The possibility of fungal endocarditis should be considered, especially in patients with a complex perioperative course. (See 'Fungi' above.)
●Rarely, culture-negative PVE due to atypical mycobacteria have been described. Mycobacterium chimaera may present as blood culture-negative PVE unless cultures are placed in special media; it occurs 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). (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 American Heart Association, which favors the following initial approach [1]:
●Patients with culture-negative PVE onset ≤1 year after surgery should receive antimicrobial therapy for coverage of infection due to staphylococci, enterococci, and aerobic gram-negative bacilli. An empiric regimen with vancomycin, gentamicin, cefepime, and delayed addition of rifampin (after three to five days of therapy) provides broad therapy.
●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.
If additional diagnostic evaluation (such as polymerase chain reaction, vegetation microscopy, or serology) identify the etiologic agent, antibiotic therapy should be targeted accordingly.
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 hemodynamically stable with an indolent clinical course, therapy can await blood culture results.
●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 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.)
