Statistics from Altmetric.com
Infective endocarditis (IE) is an elusive condition which continues to challenge all those involved in its investigation and management.1 Cardiologists, who often encounter patients with severe complications of the disease destined for complex cardiac surgery or post mortem are naturally fearsome of its consequences and have traditionally maintained the dogma of prevention by antibiotic prophylaxis before invasive procedures. The evidence to support this stance is limited, however, and revision of European and US guidelines in recent years has resulted in a major shift of emphasis in this contentious area. Dramatic guidance from the UK National Institute for Health and Clinical Excellence (NICE) published last month2 now seems set to generate further controversy and confusion in the minds of cardiologists, dentists and their patients. What future therefore for this practice?
CHANGING EPIDEMIOLOGY AND EVIDENCE TO DATE
The clinical profile of valve disease is changing in developed nations with an increasing proportion of elderly patients.3 The past two decades have also witnessed major changes in the demography of IE, with increasing incidence of Staphylococcus aureus (with attendant higher mortality), often acquired as a result of nosocomial infection or intravenous drug abuse, and falling incidence of IE secondary to oral streptococci.4 Furthermore, IE often arises in patients without previously documented cardiac disease (47% in one recent French series) when the question of prophylaxis is irrelevant.5
Even if antibiotic prophylaxis is applied appropriately, the evidence to support its efficacy is limited. Indeed, a recent Cochrane review concluded that there was no evidence to demonstrate whether penicillin prophylaxis is effective or ineffective in preventing IE in patients at risk undergoing an invasive dental procedure.6 Routine daily oral activities (eg, tooth brushing and chewing) cause transient streptococcal bacteraemia, the cumulative result of which is an annual bacteraemic exposure thousands to millions of times greater than that caused by a single tooth extraction.7 Moreover, a direct link between routine dental procedures and IE has never been proved.
The only studies of the efficacy of antibiotic prophylaxis have been case–control analyses. While two small early studies8 9 demonstrated that IE prophylaxis may be effective, a later 2-year study of 275 patients in the Netherlands concluded that most cases of IE are not attributable to an invasive procedure, but to random bacteraemia.10 The authors suggested that even if antibiotic prophylaxis was 100% effective then it would only prevent an extremely small number of cases of IE. A similar French study showed that dental procedures were not associated with an increased risk of IE and that the protective efficacy of antibiotic prophylaxis was only 46% (not significant).11 Finally, a study conducted in 54 Philadelphian hospitals found that preceding dental treatment was no more likely in patients with IE than in controls.12
Even if we conclude that the majority of these studies are negative, the results also fail to demonstrate that antibiotic prophylaxis of IE is ineffective. They do, however, suggest that a huge number of prophylaxis doses are necessary to prevent a very small number of IE cases and that the risk of developing IE after an unprotected at-risk dental procedure is extremely low.13 Although a randomised placebo controlled trial to examine the benefits of antibiotic prophylaxis in preventing IE would be desirable (and has been mooted by the British Cardiovascular Society (BCS) and the European Society of Cardiology (ESC)), such a study would be a massive undertaking, requiring large numbers of patients in each arm to provide adequate statistical power. The heterogeneity of the underlying cardiac conditions and invasive procedures would make stratification extremely difficult and the prospect of such a trial being completed in the near future is remote.
GUIDELINES AND PHILOSOPHY
The original “treat all” philosophy was based upon an understandable fear of the condition and its complications. As we have seen, however, the number needed to treat for effective prevention is exceedingly high and routine antibiotic administration is not risk free. Thus, anaphylaxis to β-lactam antibiotics occurs in 15–40 of 100 000 uses (being potentially fatal in 1–3 of 100 000 uses),14 15 and there are legitimate broader concerns about the problem of community-derived antibiotic resistance. In this overall context, the cost effectiveness of routine antibiotic prophylaxis is questionable.16
In an attempt to answer these questions, recently revised European and US guidelines have advocated the “number needed to treat” or “bang for your buck” philosophy, restricting use of antibiotic prophylaxis to patients at the highest risk of IE undergoing the highest-risk procedures (table 1).17
Thus, innovative French guidelines18 published in 2002 challenged accepted practice, emphasising the importance of general and oral hygiene in populations at risk and suggesting restriction of prophylaxis to patients with the highest ratio of benefit to individual and collective risk. Prophylaxis was considered optional in lower-risk groups, based upon composite clinical assessment of the patient and procedural risk. The 2006 guidelines of the British Society for Antimicrobial Chemotherapy19 also recommended prophylaxis only for those at high risk and for whom IE would result in high mortality. Although the committee acknowledged that many clinicians would be reluctant to withhold antibiotic prophylaxis despite the absence of evidence to support its use, this publication was met with anger by the British cardiological community.20
However, a global shift in practice was stimulated by the 2007 American Heart Association (AHA) guidelines.21 These suggested prophylaxis only for those patients with high-risk cardiac disorders and indicated that antibiotic prophylaxis was no longer recommended for patients with native valve disease or for any gastrointestinal or genitourinary procedures. These guidelines have been subsequently replicated in German speaking nations22 and seem likely to be echoed in a forthcoming revision of ESC guidance.
Finally, the most recent (and potentially most controversial) guidelines, published in 2008 by NICE, espouse the “proof of principle” philosophy and suggest an end to the practice of antibiotic prophylaxis altogether.2 23 Although NICE identify patients at increased risk of developing IE, they no longer advocate prophylaxis for dental or respiratory procedures, even for traditionally held high-risk groups. Departing from this bold principle, however, and reflecting the virulence of enterococcal IE, they recommend that patients at risk undergoing gastrointestinal or genitourinary procedures at a site where there is suspected pre-existing infection receive an antibiotic that covers IE-causative organisms. The BCS and British Heart Foundation contributed to the development of these guidelines and support their conclusions.
CONCERNS, QUESTIONS AND CONSENSUS
These varied recommendations have encountered distinctly mixed reactions—many in the dental profession, confused by increasingly complicated and ambiguous guidelines have praised them as “a victory for science and common sense”.24 On the other hand, many cardiologists maintain that they are a potentially dangerous departure from established (albeit non-evidence-based) practice which will unnecessarily expose patients to the devastating risks of IE.25–28 At the 2007 BCS Annual Scientific Congress, 70% of participants attending a debate on this topic expressed concern about the safety of the revised AHA guidelines and their reluctance to change current practice. Their reaction to the more recent NICE declaration is likely to be even more pronounced—outrage, debate or even denial. Fear of litigation is a factor,29 though unnecessarily so since adherence to recognised guidelines affords robust legal protection.30 A genuine concern for the welfare of patients is admirable, however, and careful monitoring of the incidence and presentation of IE (particularly in high-risk groups) in the wake of any change in practice will be essential. The means to achieve this will not be straightforward, however, and national monitoring through local databases, disease registers and, conceivably, the Department of Health requires exploration.
Notwithstanding the current paucity of evidence, it is clear that the efficiency of current practice is restricted owing to the exorbitant number needed to treat to prevent a single case of IE, with potential for overall harm. A shift of the fundamental question from “Who is at risk?” to “Who might benefit?” therefore seems appropriate. National or international registries may provide useful information and ironically, previous ethical concerns obstructing the required randomised controlled trial have now been removed. Whether there will be sufficient political imperative and enthusiasm to undertake such a major endeavour remains to be seen. In the immediate term, unanimous interpretation and direction from the relevant professional societies (representing cardiologists, cardiothoracic surgeons, microbiologists and dental practitioners) and an open-minded attitude of individual clinicians are required to stem further confusion and debate.
Competing interests: None.
Funding: The work of BDP is supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.
BDP and CKN are both contributors to forthcoming revised ESC guidelines for the management of infective endocarditis. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. BDP was an independent expert advisor to the NICE guidelines committee.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.