Challenges in Infective Endocarditis

Thomas J. Cahill, MBBS; Larry M. Baddour, MD; Gilbert Habib, MD; Bruno Hoen, MD, PHD; Erwan Salaun, MD; Gosta B. Pettersson, MD, PHD; Hans Joachim Schäfers, MD; Bernard D. Prendergast, DM

Disclosures

J Am Coll Cardiol. 2017;69(3):325-344. 

In This Article

Management

Management of patients with IE is both a clinical and logistical challenge. Delivery of optimal care requires an administrative infrastructure and the involvement of multiple hospital specialists, including cardiologists, surgeons, infectious disease physicians, microbiologists, nephrologists, neurologists, and radiologists. Optimizing service delivery and early decision making have the potential to improve clinical outcomes, leading to calls for formation of "IE teams," modeled on the heart team approach to coronary and heart valve disease.[84]

Introduction of a formalized multidisciplinary team approach in Italy, defined by initial evaluation within 12 h, early surgery (within 48 h) if indicated, and weekly review, led to a reduction in in-hospital (28% vs. 13%; p = 0.02) and 3-year (34% vs. 16%; p = 0.0007) mortality, despite patients being older and having more comorbidities.[85] Similarly, a French multidisciplinary team approach to standardizing care, including antibiotic protocols and indications for surgery, reduced 1-year mortality from 18.5% to 8.2%.[86]

Centralized care concentrated in tertiary centers with advanced diagnostic imaging, surgical expertise, and higher throughput clearly has a role in complex cases and may also be universally beneficial. There are arguments against this model, however, such as delays during transfer and loss of local expertise. Reconfiguration toward a system of centralized IE care (or a hub-and-spoke model, with central multidisciplinary review) should therefore be instituted on the basis of evidence. The efficacy of centralized care to improve decision making, time to surgery, cure rates, and short- and long-term outcomes could be readily tested in a before-and-after study.

Antibiotic Therapy

Before the discovery of penicillin, IE was an untreatable disease.[87,88] Effective microbial clearance requires bactericidal antibiotic regimens, usually in combination. Detailed empirical and organism-specific antibiotic protocols are beyond the scope of the present review but are provided in the latest AHA and ESC guidelines.[68,89]

The importance of balancing efficacy of treatment with the overall risk and toxicity of prolonged inpatient therapy is increasingly recognized. Emerging evidence supports short-course or stepped-down antibiotic treatment in selected groups. In patients with uncomplicated IE caused by oral streptococci and normal renal function, a combination of a penicillin or ceftriaxone with an aminoglycoside for a total of 14 days is safe and effective.[90] Similarly, a 2-week course of penicillin monotherapy or penicillin-aminoglycoside in combination is effective for uncomplicated methicillin-sensitive S aureus right-sided IE.[91]

There are increasing data to suggest that the use of aminoglycosides may be causing harm without clear clinical benefit. In a 2006 RCT of daptomycin compared with conventional therapy (penicillin or vancomycin with initial gentamicin) for S aureus bacteremia or right-sided endocarditis, daptomycin was shown to be noninferior. Importantly, renal dysfunction occurred in 11% of those treated with daptomycin compared with 26% of the conventional therapy arm.[92,93] Aminoglycosides have now been removed from the ESC and AHA guidelines for the treatment of methicillin-sensitive S aureus or methicillin-resistant S aureus NVE. Although aminoglycosides have historically been widely used for enterococcal IE, the increasing frequency of resistance (25% to 50% of isolates in recent studies), along with the recognition of potential harm, led the ESC 2015 guideline committee to identify ampicillin and ceftriaxone (Class IB recommendation) as the treatment of choice for aminoglycoside-resistant Enterococcus faecalis. This recommendation is supported by large observational studies showing that ampicillin/ceftriaxone is as effective as ampicillin/gentamicin, with reduced levels of nephrotoxicity.[94,95]

Further research is needed to determine whether additional patient groups may be suitable for shortened courses of antibiotic therapy. For example, in patients who have undergone successful surgery and have negative valve culture findings suggesting successful microbial elimination (after initially positive blood culture results), it may be safe to stop antibiotics after 2 weeks.[96,97] However, current AHA guidelines suggest that the remaining duration of antibiotics be given (including administration before surgery), but this suggestion is indicated on the basis of Level C evidence.[89]

Reduction of in-hospital stays may also be achieved through an early switch to regimens of oral antibiotics with good bioavailability. In IV drug users, there are RCT data supporting the safety and efficacy of oral ciprofloxacin and rifampicin for uncomplicated methicillin-sensitive S aureus NVE, although increasing rates of fluoroquinolone resistance limit applicability.[98] The POET (Partial Oral Treatment of Endocarditis) trial is an ongoing Danish multicenter study designed to address whether step-down to oral treatment is safe after the first 10 days of IV antibiotics in staphylococcal, streptococcal, or enterococcal NVE. Four hundred patients will be randomized to receive 4 to 6 weeks of IV treatment, compared with step-down to oral therapy after a minimum of 10 days, with a primary endpoint of all-cause mortality, unplanned cardiac surgery, embolism, or relapse of positive blood culture findings.[99]

Early hospital discharge is frequently facilitated by the use of outpatient parenteral antibiotic therapy (OPAT). OPAT can be initiated in specific patients after completion of the first 2 weeks of treatment, after which the risk of complications is reduced. OPAT is contraindicated in patients with heart failure, complex infection, high risk of embolism, neurological complications, or renal impairment.[100–102] Facilitated readmission pathways, as well as close nursing and medical monitoring, are necessary.

The major challenges to successful antibiotic therapy are bacterial tolerance and antibiotic resistance. Tolerance occurs when phenotypic variants of bacteria persist despite antibiotic therapy, and they resume growth and infection once antibiotic concentrations fall. There are multiple underlying mechanisms, including the very high bacterial density and poor antibiotic penetration within vegetations, low bacterial metabolic activity, and production of protective biofilms on prosthetic material.[103] The risk of tolerance, combined with relatively slow bactericidal antibiotic effects, underlies the historical requirement for 4 to 6 weeks of parenteral antibiotic therapy.

Novel strategies are required to prevent and treat IE caused by biofilm-forming strains of multidrug-resistant S aureus. These strategies may include the initial inhibition of bacterial adhesion to both living and inert surfaces (thus reducing further biofilm development), disruption of biofilm architecture, and antipathogenic or signal interference approaches involving inhibition of quorum sensing.[18] Prevention of bacterial adhesion at the time of intracardiac device insertion is key and may be achieved by using implants coated with various adhesion inhibitors. However, despite inhibiting biofilm formation in vitro, antibiotic-, silver ion–, and silver nanoparticle–coated implants have proved to be ineffective and poorly tolerated in humans. Disruption of biofilm architecture may be a more promising approach, and several compounds, including human monoclonal antibodies such as TRL1068, are currently being assessed. Treatment of established biofilm using a combination of TRL1068 with daptomycin in an in vivo murine model (in which biofilm was formed by infection with methicillin-resistant S aureus) significantly reduced the adherent bacterial count compared with daptomycin alone.[104]

Surgery

Surgery is performed for the specific indications of progressive valve and tissue damage, uncontrolled infection, and high risk of embolism. The objectives are as follows: to remove infected tissue, foreign material, and hardware; clear and debride paravalvular infection and cavities; restore cardiac integrity and valve function; and remove threatening sources of embolism. Although various surgical techniques have been used (e.g., mitral valve repair, aortic homograft implantation), a clear long-term advantage of one technique has yet to be proven. Regardless of approach, the long-term results are inferior to elective valve surgery: 10-year survival ranges from 40% to 60%.[105,106] It remains unclear whether this late mortality relates to late prosthetic valve complications, extracardiac manifestations of the disease, or persistence of the biofilm complex.

Surgery is currently performed in 50% to 60% of patients, and 6-month survival rates are >80%.[107,108] The indications for surgery have been predominantly derived from historical observational studies that show benefit in patients with valve dysfunction causing heart failure, uncontrolled infection (defined as paravalvular extension, abscess, or persistent bacteremia), or recurrent embolism. For a specific patient, there is often debate, for example, in cases of mild heart failure or regarding the definition of persistent bacteremia.[109] Current indications for surgery, as defined in the AHA and ESC guidelines, are shown in Table 3.

In real-world situations, a significant number of patients with a guideline indication for intervention still do not undergo surgery (i.e., 24% [202 of 863] of patients with left-sided IE and a guideline indication for intervention in the ICE-PCS [International Collaboration on Endocarditis–Prospective Cohort Study] registry).[108] Predictors of nonsurgical treatment were liver disease (odds ratio [OR] for surgery: 0.16; 95% CI: 0.04 to 0.64), stroke before surgical decision (OR: 0.54; 95% CI: 0.32 to 0.90), and S aureus infection (OR: 0.50; 95% CI: 0.30 to 0.85). In contrast, severe aortic regurgitation, abscess, and embolization were associated with surgery. Reasons for avoiding surgery in 181 patients included an anticipated poor prognosis regardless of treatment (34%), hemodynamic instability (20%), death before surgery (23%), stroke (23%), sepsis (21%), and surgeon declined to operate (26%). Ultimately, the perceived risk of the operation determines the threshold for surgery; operations for active IE present high risk, with an overall in-hospital mortality of 20% (and higher still in many centers).

Improved risk-scoring models for IE would help to clarify the decision-making process. Gaca et al.[110] used the Society of Thoracic Surgeons' database to derive an IE surgical risk score, identifying 13 risk factors for mortality, including emergency status, cardiogenic shock, hemodialysis, and "active endocarditis." Other, smaller cohorts have incorporated more detailed parameters of infection, including valve type and organism.[111,112] The PALSUSE score includes age ≥70 years, substantial intracardiac destruction, staphylococcal infection, urgent surgery, female sex, and EuroSCORE (European System for Cardiac Operative Risk Evaluation) ≥10 as predictors of in-hospital mortality, with in-hospital mortality ranging from 0% in patients with a score of 0, to 45% in patients with a score >3.[112]

The optimal timing of surgical intervention is also contentious. Delaying surgery may allow a longer duration of antibiotic therapy and hemodynamic stabilization but incurs the risk of disease progression with valve destruction, abscess formation, heart block, embolic complications, and even death. Indeed, for some outcomes (e.g., embolism) the potential gains from surgery are reduced with time.[56] In 2012, the first RCT of surgery for IE compared early surgery (undertaken within 48 h of randomization) with conventional care in patients with NVE, severe valve regurgitation, and large vegetations.[126] The South Korean study cohort was young (mean age 47 years), with little comorbidity and predominantly streptococcal infection. Early surgery was associated with a significant reduction in the composite endpoint of in-hospital death or embolism (entirely driven by a reduction in embolism). Furthermore, >90% of patients in the conventional care group eventually required surgery, thereby validating present indications for intervention. This study is a landmark achievement for research in IE and has encouraged a trend toward early surgery, but its findings are of uncertain applicability in older populations with multiple comorbidities and staphylococcal infection. Studies from the ICE-PCS registry, which define early surgery as that undertaken "within the course of the initial hospitalization for IE," have shown conflicting results. Although early surgery for NVE is associated with reduced mortality, this scenario does not hold true for PVE after adjustment for confounding variables, including survivor bias (i.e., the increased likelihood of patients who survive to undergo surgery).[113–115]

The emphasis on "early surgery" differs significantly between European and U.S. guidelines. The ESC guidelines distinguish emergency surgery (performed within 24 h), urgent surgery (within a few days), and elective surgery (after 1 to 2 weeks of antibiotic therapy), with surgery advised on an urgent basis for the majority of cases.[68] In contrast, the AHA guidelines define early surgery as "during initial hospitalization and before completion of a full course of antibiotics." Our conclusion at this time is that there is no proven benefit in delaying surgery once an indication for intervention has been established. Whether this surgery is undertaken the same day or within 48 h depends on the individual clinical circumstances and availability of appropriate surgical expertise. Current series show that very low mortality can be achieved in centers of excellence with high-level experience of the management of complex patients and concentrated expertise in cardiology, microbiology, and surgery.[106,116]

Resolving the controversy of early surgery requires robust evidence to move the field forward. RCT-level data are required to drive practice change, which is harder to progress on the basis of observational data alone. In the last 20 years, only 7 RCTs involving patients with IE have been published, the majority of which have focused on antibiotic therapy (Table 4). The first stage is to carefully define the priorities for new RCTs that are reasonable and acceptable to the medical community. Multicenter studies are challenging, as experience and outcomes vary greatly between centers, whereas few have the volume to perform such studies in isolation. Furthermore, unresolved issues, such as early surgery, may be left behind as competing research priorities emerge. For example, should PVE be considered as a uniformly surgical disease? Should all patients with IE and severe valve dysfunction have surgery, even if they are not in heart failure? San Román et al.[109] have proposed a trial of patients with left-sided IE and high-risk features (but not classical surgical indications) randomized to undergo surgery within 48 h or receive conventional care, with mortality as the primary endpoint. Although logistically challenging, this study would be extremely valuable and may herald a long-awaited shift from observational studies to RCT-level research.

Contemporary Management Challenges in IE

IE After TAVR. TAVR has transformed the outlook for patients with aortic stenosis who were previously deemed inoperable or at high risk for surgery. Although the technology looks set to expand to intermediate-risk populations over time, current TAVR patients are often frail, undergoing multiple health care interventions, and may therefore be at high risk of bacteremia and IE. The TAVR-endocarditis population represents a common challenge to cardiologists and surgeons managing contemporary IE, namely, how should we manage PVE in patients who are elderly and at high risk of surgery but with expected poor outcome if managed medically?

Small numbers of cases of TAVR-endocarditis were reported in the seminal PARTNER (Placement of Aortic Transcatheter Valve) trials,[117,118] and real-world cohorts are now starting to shed light on incidence and outcomes (Table 5). Amat-Santos et al.[12] described 53 patients with TAVR-endocarditis in a multicenter U.S. registry, representing an overall incidence of 0.67% at a mean follow-up of 1.1 years. The incidence of TAVR-endocarditis was 0.5% in the first year post-procedure, occurring at a median time point of 6 months. More than 70% of patients presented with fever, and 77% had an identifiable vegetation on echocardiography. An antecedent procedure was identified as the likely cause of bacteremia in approximately one-half of patients, and antibiotic prophylaxis had been used in 59% of cases. Infection was most commonly due to staphylococci (CoNS 25%; S aureus 21%; and enterococci 21%). Although the self-expanding CoreValve system (Medtronic, Minneapolis, Minnesota) was an independent risk factor for IE (hazard ratio [HR]: 3.1; 95% CI: 1.37 to 7.14), this finding requires validation in other series.

Mangner et al.[13] described 55 patients with TAVR-endocarditis from a single center in Germany, representing a cumulative incidence of 3.02% (1.82% per patient-year); 42% of the cases (23 of 55) were health care acquired. On multivariate analysis, chronic hemodialysis and peripheral arterial disease were significant risk factors for the development of subsequent TAVR-endocarditis (chronic hemodialysis—HR: 8.37; 95% CI: 2.54 to 27.63; p < 0.001; peripheral arterial disease—HR: 3.77; 95% CI: 1.88 to 7.58; p < 0.001). Infection was caused by S aureus in 38% of cases, enterococci in 31%, CoNS in 9%, and streptococci in 9.1% of cases. In 7 patients, a valve other than the TAVR prosthesis was infected.

Most recently, 250 cases from the Infective Endocarditis after TAVR International Registry were reported from 47 centers worldwide.[119] The overall incidence was 1.1% per person-year, presenting at a median time of 5.3 months' post-procedure. On multivariate analysis, predictive factors were younger age (HR: 0.97 per year; 95% CI: 0.94 to 0.99), male sex (HR: 1.69; 95% CI: 1.13 to 2.52), diabetes mellitus (HR: 1.52; 95% CI: 1.02 to 2.29), and moderate-to-severe aortic regurgitation (HR: 2.05; 95% CI: 1.28 to 3.28). Infective organisms were enterococci in 24.6% and S aureus in 23.3%. The in-hospital mortality rate was 36%, and 2-year mortality was 67%. Additional patient- and device-related factors contributing to increased risk of endocarditis are likely to be identified and may also teach us more about the nature of endocarditis. The apparently high incidence may also be due to front-loaded risk in the early months after the procedure, and longer follow-up will be required to compare outcomes with surgical valve replacement.

Management of TAVR-endocarditis is highly challenging. It remains to be shown whether transcatheter techniques can be used successfully in its management without removal of the infected implant. Many of these patients were considered high risk or very high risk for surgery before undergoing TAVR. Indeed, <20% of patients underwent either open-heart surgery or a transcatheter valve-in-valve procedure in the studies to date. Meanwhile, outcomes with antibiotic therapy alone are extremely poor, with in-hospital and 1-year mortality ranging from 47% to 64% and 66% to 75%, respectively. These data underscore the importance of developing better preventive strategies in terms of valve design and prevention of bacteremia.

Stroke and IE

IE is complicated by stroke in 20% to 40% of cases.[120,121] In addition to causing variable neurological disability, stroke is an independent adverse prognostic factor for survival.[120,122] The risk of stroke is highest at diagnosis and decreases rapidly after the initiation of antibiotic therapy (incidence drops from 4.82 per 1,000 patient-days in the first week of therapy to 1.71 per 1,000 patient-days in the second week).[56] Identified risk factors for embolism are vegetation size (>10 to 15 mm), mitral valve involvement, vegetation mobility, and S aureus infection.[123–125]

A key unresolved challenge in the contemporary management of IE is the role of surgery in prevention of stroke/embolism and selection of patients for such surgical intervention. The 2015 update to the AHA/ACC guidelines provided a Class IIa indication for surgery to prevent recurrent embolism in patients with ≥1 previous emboli and ongoing high risk of further embolism (defined as persistent or enlarging vegetations).[89] Similarly, the ESC guidelines provide a Class I recommendation for surgery to prevent recurrent emboli in patients with a persisting vegetation >10 mm in size.[68] On the basis of RCT evidence, both guidelines indicate a Class IIa recommendation for surgery in patients at risk of first embolism (vegetation >10 mm in size) when associated with severe valvular regurgitation or stenosis.[126] Surgery for prevention of embolism (in the absence of valve dysfunction) may be considered in patients at highest risk (e.g., vegetations >15 mm) but is rarely undertaken in most institutions for this indication alone.

The optimal timing of surgical intervention in patients who have already had a stroke is contentious, with a number of older studies suggesting poor outcomes from early surgery.[107] There is a risk of hemorrhagic transformation caused by anticoagulation therapy for cardiopulmonary bypass, and hypotension during surgery might theoretically worsen cerebral ischemia. Observational studies have typically been small and inadequately controlled for confounding variables.[120,121] In the largest study from the ICE-PCS collaboration, the outcome from 58 patients with an ischemic stroke undergoing early surgery (<7 days) was compared with late surgery. After risk adjustment, surgery was associated with a nonsignificant increase in the risk of in-hospital mortality (OR: 2.3; 95% CI: 0.94 to 5.65).[121] This finding has been interpreted by both the AHA and ESC to suggest that surgery can be undertaken safely if required, although stroke remains a common reason for lack of surgical intervention in everyday practice.[108] In contrast, transient ischemic attack or silent embolism should not delay surgery that is indicated for other reasons.[120] Conversely, patients with cerebral hemorrhage or complex stroke (causing coma) have significantly higher surgical mortality, and surgery should be deferred for at least 4 weeks if indicated in these patients.[125,127] The plan of action for patients with minor bleeding or minor hemorrhagic conversion of an ischemic stroke remains open to clinical judgment. Clinical scenarios are often complex, and the risk and benefit equation often challenges any rigid recommendation.

Cardiac Device Infection

CIEDs include permanent pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy devices. The number of CDIs in the United States has increased out of proportion to the increase in implantation rates.[128] Overall, the incidence of CDI after first implantation is 1 to 10 per 1,000 device-years (approximately 1 per 1,000 device years for pacemakers and 8 to 9 per 1,000 device-years for complex devices).[129–131] Patients with CDIs have increased short- and long-term morbidity and mortality, and the incremental cost of management is estimated at more than $15,000 per patient.[132,133]

CDI may involve the generator pocket, device leads, or endocardial (valve or nonvalve) surfaces (or any combination of these locations). Pocket infections are characterized by cellulitis, erythema, wound discharge, and pain, and there may be incipient or overt erosion of the skin overlying the pocket. Infection involving CIED leads or the endocardial surface (CIED-IE) is characterized by systemic features (e.g., fevers, rigors), and frequently coexists with pocket infection. IE may originate from a pocket infection or occur by seeding of infection to the leads via the bloodstream. Staphylococci (particularly CoNS) account for 60% to 80% of cases.[134]

Risk factors for CDIs may be patient-, procedure-, or device-related factors.[135] Patient-specific risk factors include corticosteroid use, diabetes mellitus, end-stage kidney disease, previous device infection, chronic obstructive pulmonary disease, malignancy, and heart failure. Procedural risk factors are the development of a post-operative hematoma (OR: 8.46; 95% CI: 4.01 to 17.86), reintervention for lead displacement, long procedure times, and implantation of ≥2 leads. Need for a revision procedure is associated with a 2- to 5-fold higher risk of infection than the initial implantation. Use of antibiotic prophylaxis has been shown to protect against CDI in both RCTs and observational studies.[136]

Diagnosis of CIED-IE is made on the basis of echocardiography and blood culture results, with TEE having better sensitivity and specificity than TTE for detection of lead vegetations.[137] Importantly, sterile clots are seen in a high percentage of CIED patients without infection, and these lesions are indistinguishable from infected vegetations.[138] In cases in which echocardiography is negative or equivocal, radiolabeled leukocyte scintigraphy or 18FDG-PET/CT scans are highly valuable, and they may become the definitive investigation on the basis of a number of studies demonstrating high sensitivity and specificity for infection (Figure 3).[139–141] However, there is evidence that 18FDG-PET/CT imaging may yield a false-negative result for CIED-IE (i.e., lead involvement) if patients have received previous antibiotic therapy. In 1 study, 9 of 13 patients had a false-negative scan for CIED-IE (sensitivity 30.8%).[141] Further studies are required to assess the time course over which the diagnostic value of 18FDG-PET/CT imaging is preserved.

Figure 3.

Cardiac CT and 18FDG-PET/CT Imaging in the Diagnosis of CDI
Pacemaker lead IE in a young man with congenital atrioventricular block. On TEE, vegetations were seen on the pacemaker leads (A and B, white arrow). On CT imaging, vegetations were seen on the pacemaker lead (C, white arrow) with an accompanying pulmonary embolism (D, red arrow). Confirmation of active pacemaker endocarditis was provided by 18FDG-PET/CT imaging, with uptake seen on the pacemaker lead (E, white arrow) and within the pulmonary vascular tree (F, red arrow). CDI = cardiac device infection; RA = right atrium; SVC = superior vena cava; other abbreviations as in Figures 1 and 2.

Strategies for the prevention and management of CDI are beyond the scope of the present review but are covered in detail by recent guidelines.[142] If CIED-IE is confirmed, complete removal of the infected system is indicated because medical therapy alone is associated with increased risk of recurrence and mortality.[142,143] Percutaneous extraction is usually feasible but associated with a major complication rate of 1.9%.[144] Prolonged antibiotic therapy is advised, and blood culture findings should be negative for at least 72 h before reimplantation if a new device is essential.

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