Advances in Adult Infective Endocarditis

Infective endocarditis (IE) is a serious disease, one that was universally fatal prior to the introduction of the sulfonamide agents in the late 1930s and especially penicillin in the mid-1940s, and it remains a very important cause of morbidity and mortality. IE still causes the loss of an estimated 1.58 million disability-adjusted life years or years of healthy life globally.¹ The American Heart Association (AHA) has played an important role for about 60 years (since 1955) in making recommendations for the prevention of IE, and it expanded that role in 1981 to make treatment recommendations only for viridans streptococcal IE and then in 1995 to provide periodically updated recommendations for the diagnosis and management of various forms of IE as well. The last iteration prior to the current one of 2015 was in 2005.² The 2015 AHA scientific statement regarding IE in adults includes very considerably expanded and updated detailed recommendations by a highly distinguished group of experts in this field working on behalf of the AHA Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council.

The new recommendations are very specific and comprehensive, and they reflect the evolution of diagnostic modalities and medical and surgical treatment over the decade since the previous recommendations. The 64 recommendations in the 2005 version have grown to 149 recommendations in 2015, an increase of 130%! They again incorporate the evidence-based system for diagnostic and treatment recommendations that is used by the American College of Cardiology and the American Heart Association, first included in the 2005 recommendations, which enables the readership to assess the strength of the evidence upon which recommendations are based.

In the past decade, many changes have occurred in the epidemiology of IE and in patient characteristics, including the emergence of Staphylococcus aureus as the leading etiologic agent of IE, the increasing importance of health-care--associated IE (much of it due to S. aureus), the increasing median patient age, the diminishing proportion of patients with rheumatic heart disease and increasing proportion of those with prosthetic valves and other cardiac devices among patients developing IE, and the increasing proportion (to about 50%) of IE patients undergoing cardiac surgery during their course of therapy.^3-5 Technologic advances have also contributed to the evolving recommendations related both to diagnosis and treatment, with generally better outcomes for IE patients. Improved techniques for identifying the infectious agent in “culture-negative” IE are discussed, including detection of 16S and 18S rRNA by polymerase chain reaction (PCR) to detect bacteria and fungi, respectively. Newer imaging modalities that have improved both diagnosis and therapy of IE, including three-dimensional echocardiography, magnetic resonance imaging (MRI) of the heart and brain, magnetic resonance angiography (MRA), and multi-slice computed tomography (CT) are also reviewed. Additional areas in which progress has been made include the timing of valve surgery in IE, risk stratification for quantifying IE morbidity and mortality and the role of surgery, and defining the niches for daptomycin in treatment of S. aureus and enterococcal IE, and these are all reviewed in the 2015 document.

More than previous AHA recommendations for therapy of IE have done, the 2015 version presents quite specific and detailed recommendations, for example, IE caused by three discrete categories of viridans streptococci based upon their penicillin minimum inhibitory concentrations (MICs) and for four distinct categories of enterococci distinguished by their various antibiotic susceptibility patterns. As with most clinical guidelines and recommendations, the complexity and variability of IE are so great that recommendations of the kind included in the 2015 statement can support but not replace clinical decisions for the management of individual patients.

A detailed statement on the unique features of IE in children is also available from the AHA Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease.⁶

A new section in the 2015 statement provides valuable advice related to antibiotic pharmacokinetics/pharmacodynamics (PK/PD) in IE with dosing implications. This emphasizes that antibiotics can be divided into whether they possess concentration-dependent (aminoglycosides, fluoroquinolones, vancomycin, and daptomycin) or time-dependent (penicillins, cephalosporins) effects upon bacteria. Additional pharmacologic issues that are included relate to the microbial inoculum effect, the importance of bactericidal antibiotics in treatment of IE, duration of therapy, and penetrability of drugs into the vegetations of IE.

Daptomycin is considered a reasonable alternative to vancomycin or to an anti-staphylococcal penicillin together with low-dose, short course gentamicin in adults with S. aureus native valve endocarditis (NVE), whether right-sided or left-sided. Daptomycin is approved at 6 mg/kg IV daily, but higher doses (~9 mg/kg IV daily) may be important for some indications. The therapy of NVE due to methicillin-resistant S. aureus (MRSA) is evolving, with high-dose daptomycin (~9 mg/kg/dose) becoming a reasonable alternative to vancomycin, and the potential role of ceftaroline not yet clearly defined. Daptomycin also appears to be a reasonable choice for NVE due to methicillin-susceptible S. aureus (MSSA) in those with ß-lactam allergy or intolerance.

This statement includes many recommendations related to the complex problem of enterococcal IE, including whether aminoglycoside-containing regimens should continue to be considered the cornerstone of therapy, appropriate dosing recommendations for aminoglycosides, duration of aminoglycoside therapy, and the possible role of non-aminoglycoside--containing regimens for E. faecalis IE. Even though cephalosporins and anti-staphylococcal penicillin (e.g., oxacillin, nafcillin) have minimal or no activity against enterococci in vitro, the combination of ampicillin with ceftriaxone (“double beta-lactam therapy”) appears as effective as ampicillin and aminoglycoside therapy for E. faecalis IE in several reports and is free of the significant nephrotoxicity associated with aminoglycosides.

The complicated issue of the role of valve surgery in the management of IE (with the proportion of patients with native valve [NVE] and prosthetic valve [PVE] undergoing surgery rising about 7% per decade over the last 30 years⁷) is discussed extensively. Seven specific recommendations regarding early valve surgery for left-sided NVE, 7 recommendations regarding early valve surgery in PVE, and 4 recommendations regarding right-sided IE are included. Two more recommendations relate to the complex issue of valve surgery in patients with prior cerebral emboli/hemorrhage/stroke.

In summary, the 2015 AHA statement on the diagnosis and management of infective endocarditis is the definitive work at this time and is an invaluable asset to the clinician treating patients with this life-threatening infection.