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


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

In This Article


Prevention of IE is better than cure and requires insight into the mechanisms of disease, the patient populations at risk, and an effective preventive intervention. The disease develops in 3 stages. The initiating step is bacteremia, with bacteria commonly entering the bloodstream via the mouth, gastrointestinal and urinary tracts, or the skin, through venous catheters or after an invasive medical or surgical procedure. The second step is adhesion: whereas the normal endothelial lining of the heart is resistant to bacterial adhesion, bacteria (particularly gram-positive species) are able to adhere to abnormal or damaged endothelium via surface adhesins. These specialized proteins mediate attachment to extracellular host matrix proteins, a process which is facilitated by fibrin and platelet microthrombi.[15] Gram-positive bacteria also lack an outer membrane and have a thick surrounding peptidoglycan and are therefore less sensitive to serum-induced killing.

Bacterial adhesion gives rise to colonization, in which cycles of bacterial proliferation occur in addition to thrombosis, monocyte recruitment, and inflammation, leading to formation of a mature vegetation.[16] Many of the microorganisms associated with IE (including staphylococci, streptococci, and enterococci but also less common pathogens, such as Candida species and Pseudomonas aeruginosa) produce biofilms, which allow bacterial populations to embed within an extracellular polysaccharide slime-like matrix, with quorum sensing (chemical cell-to-cell communication) and synchronized gene expression promoting assembly and maturation. Once established, the biofilm protects bacteria from host immune defenses, impedes antimicrobial efficacy, and hides resistant persister organisms.[17] Biofilm-forming capacity is now recognized as an important determinant of virulence in the development of staphylococcal device-related infections.[18]

Antibiotic Prophylaxis

Preventive strategies have historically focused on bacteremia. In 1909, Thomas Horder recognized that the mouth was a major portal for bacterial entry, and, in 1935, streptococcal bacteremia was detected after dental extraction.[19,20] The first trials of penicillin prophylaxis were conducted in the 1940s and showed that antibiotics reduced the incidence of bacteremia after dental extraction.[21,22] Consequently, in 1955, the American Heart Association (AHA) published guidelines recommending antibiotic prophylaxis for patients with rheumatic heart disease and CHD.[23] Maintenance of good oral hygiene and antibiotic prophylaxis for at-risk groups undergoing dental extraction became the standard of care for 50 years.

Between 2007 and 2009, guidelines in the United States and Europe were substantially revised to restrict the use of antibiotic prophylaxis. There were several reasons for these revisions. First, in the era of evidence-based practice, there was (and remains) no randomized controlled trial (RCT) of antibiotic prophylaxis for prevention of infective endocarditis in the context of dental extraction. Second, the efficacy of prophylaxis was questioned on the basis of an apparent failure rate of up to 50%.[24] Third, the importance of widespread antibiotic use as a contributor to emerging resistance was gaining recognition, while the indications for prophylaxis had expanded significantly to encompass groups at moderate risk. Finally, the significance of dental procedures as a cause of IE was questioned due to population studies that did not show dental intervention as a major risk factor.[25,26] In contrast, "everyday" bacteremia, due to tooth brushing, chewing, and inadequate dental hygiene, was recognized as a possible cause of IE. In a cohort awaiting dental extraction (i.e., with dental disease), tooth brushing alone was sufficient to cause bacteremia in 23%.[27] The relative importance of rare and high-magnitude bacteremia (e.g., caused by dental extraction) compared with common, low-level bacteremia in the pathogenesis of IE remained poorly defined. Therefore, in the United States and Europe, antibiotic prophylaxis was restricted to those at highest risk.[28,29] Meanwhile, in the United Kingdom, antibiotic prophylaxis was abandoned entirely in a highly controversial decision by the U.K. National Institute for Health and Care Excellence.[30,31]

Effects of Changing Guidelines on the Incidence of IE

Several studies have now examined the effect of restricting oral antibiotic prophylaxis on the incidence of IE (Table 1). In France, where antibiotic prophylaxis was limited to high-risk groups as early as 2002, a survey approach was used to gather data on all cases of IE across several different regions.[32,33] The incidence of IE in 3 survey years (1991, 1999, and 2008) was found to be stable at 35, 33, and 32 cases per million, suggesting no significant change after restriction of oral antibiotic prophylaxis. Importantly, the number of cases caused by oral streptococci was also stable.

In 2007, the American College of Cardiology (ACC)/AHA restricted antibiotic prophylaxis in the United States to patients with prosthetic valves, CHD, and previous IE, as well as cardiac transplant recipients with valvulopathy.[29] Using data from the Rochester Epidemiology Project, DeSimone et al.[34,35] analyzed the incidence of IE due to viridans group streptococci before and after this change. No increased incidence was identified and, conversely, there was a drop in incidence from 3.6 per 100,000 person-years from 1999 to 2002 to 1.5 per 100,000 person-years from 2011 to 2013. Similarly, 2 population studies from Canada and the United States found no evidence for a change point in the incidence of IE coinciding with the ACC/AHA guideline amendment.[36,37]

In contrast, 2 nationwide epidemiological studies from the United States and the United Kingdom have given cause for concern. Using the Nationwide Inpatient Sample, Pant et al.[2] identified a statistically significant increase in the incidence of IE caused by streptococci, although there was no significant change in the (upward) trend in total hospitalizations or in staphylococcal endocarditis. This study included both non–viridans group streptococci and enterococci in the incidence calculations, however, and did not perform change point analysis to confirm that the change in rate coincided with the ACC/AHA guideline amendment. Furthermore, the investigators had no access to antibiotic prophylaxis prescribing data to confirm that this rate had declined.

In the United Kingdom, where national guidance advised against use of antibiotic prophylaxis in March 2008, early analyses signaled no rise in the incidence of IE.[38] In 2015, however, Dayer et al.[5] published an extended analysis looking at National Health Service hospital discharge diagnoses up to 2013. Antibiotic prophylaxis dropped from 10,900 prescriptions per month to 2,236 prescriptions per month after introduction of the U.K. National Institute for Health and Care Excellence guidelines. In parallel, there was a significant rise (above the projected trend) in the number of IE cases, by 0.11 case per 10 million persons (or an additional 35 cases in England) per month. Statistical analysis identified June 2008 (3 months after implementation of the new guidelines for the use of antibiotic prophylaxis) as the point of change, but it was not possible to confirm that these cases were due to oral streptococci because microbiological data were unavailable.

These data are observational and cannot establish a causal link between restriction of antibiotic prophylaxis and incidence of IE. They are subject to confounding, for example, by increasing numbers of device implants, although this factor has been adjusted for in some studies. Despite the longstanding controversy and difficulty with observational data, a randomized trial is highly unlikely due to cost, logistics, and ethical debate as to whether true equipoise exists to allow conduct of a placebo-controlled trial. The current pragmatic approach (endorsed by the ACC/AHA and the European Society of Cardiology [ESC]) (Table 2) is to limit prophylaxis to individuals at highest risk on the basis of the underlying cardiac condition. In our view, this approach correctly balances the risks and benefits of individual and population antibiotic use. Importantly, this classification omits patients who have noncardiac risk factors (e.g., those who are immunocompromised) and who may be at increased risk of both IE and poor outcome if the disease develops. There are few data to guide specific practice in these groups, and a tailored approach for individual patients remains appropriate, according to clinical circumstances.[39,40]

Prevention of Health Care–Associated IE

Health care–associated IE accounts for an increasing proportion of cases and requires specific strategies for prevention. The affected patient demographic is older, and most have either degenerative valve disease or no intrinsic cardiac risk factors. Instead, the most frequent risk factors are hemodialysis, cancer, diabetes mellitus, and the presence of a CIED.[9,41] Staphylococcus aureus is the causative organism in approximately one-third of cases, and the overall proportion of IE due to S aureus in the United States rose from 24% to 32% between 1998 and 2009.[3]S aureus is consistently an independent risk factor for in-hospital death.[42] In keeping with the affected patient population and underlying microbiology, the in-hospital mortality for patients with health care–associated IE is significantly higher than for community-acquired infection (31.1% vs. 20.3%; p < 0.01).[9]

Reduction of health care–acquired bacteremia is thus a logical target. Longitudinal studies from Denmark found that an increase in S aureus bacteremia occurred from 3 to 20 per 100,000 person-years between 1957 and 1990, mirroring increasing rates of hospital admission and invasive medical procedures (although rates have now plateaued in the developed world).[43,44] In the United States, 10% to 20% of the population are persistent carriers of S aureus.[45] For central line–associated bloodstream infection, practice-changing interventions to improve adherence to sterile practice (hand hygiene, barrier precautions, and antisepsis) have already significantly reduced rates of bacteremia.[46,47] Bundled interventions to reduce catheter-related bloodstream infection in high-risk groups, such as those undergoing hemodialysis, could translate into a major impact on the incidence of IE.[48,49]

Novel approaches to prevention of bacteremia and strategies to target adherence are urgently required.[50] Innovative material technologies, which prevent interaction of bacteria with prosthetic surfaces (so-called low-fouling coats) or contain long-lasting bactericidal coatings, hold promise but have so far failed to translate into clinical practice. Indeed, enthusiasm for antibacterial coatings has been tempered by experience with the Silzone valve (St. Jude Medical, St. Paul, Minnesota), which had a silver-coated sewing ring, but had to be recalled within 3 years of its release in 1997 due to an increased risk of thrombosis and paravalvular leak.[51,52] Furthermore, this outcome was seen as a failure of regulatory approval processes for modification of existing valves. A vaccine targeted at bacterial components has long been seen as attractive for patients at high risk of bacteremia. However, 2 candidate S aureus vaccines failed to demonstrate efficacy in Phase III clinical studies, with 1 failing to reach an efficacy endpoint (prevention of S aureus bacteremia in patients undergoing hemodialysis) and another leading to increased mortality in patients undergoing median sternotomy who developed staphylococcal infection.[53,54] More positively, a new composite vaccine targeting 5 components of S aureus has recently been shown to be highly protective in mouse models.[55]