Canine Bacterial Endocarditis: A Review

Introduction

Infective endocarditis is defined as inflammation of the endocardial surface of the heart from invasion by an infectious agent.^1–7 Bacterial organisms are the pathogens predominantly isolated from lesions in valvular and mural endocardial tissue, and the terms bacterial and vegetative endocarditis are commonly used to describe the disease.^1–6 Endocarditis is uncommon in dogs and rare in cats, but it can result in serious morbidity and often death. Diagnosis of endocarditis is particularly challenging because of its varied clinical presentations, rapid progression, and lack of diagnostic techniques available to definitively confirm the disease in its early stages. The purpose of this paper is to provide a comprehensive review of canine bacterial endocarditis and a concise overview of the disease’s pathophysiology, clinical signs, diagnosis, and treatment.

Epidemiology

The prevalence of bacterial endocarditis in dogs ranges from 0.05% to 6.6%.^1–3,6,8 The Veterinary Medical Teaching Hospital at the University of California–Davis recently reported an increase in the number of cases of endocarditis, but whether this reflects a real increase in the incidence of the disease or simply a heightened awareness, coupled with improved diagnostic capabilities, remains uncertain.⁴ The majority of cases are middle-aged (i.e., ≥4 years old), medium-sized, or large-breed dogs. Most (85% to 90%) affected dogs weigh >15 kg.^1,4,6,9–11 Males are affected more commonly than females, with a male:female ratio of 2:1.^{1,3,4,6,9,11,12} Overrepresented breeds include the German shepherd dog, boxer, golden retriever, and Labrador retriever.^{1,2,4,6,9,11,12} The majority of lesions involve the mitral or aortic valve, or both.^{1–4,7–9,12,13} The tricuspid valve is rarely affected, and the pulmonic valve is almost never affected.^1–6,9–13

Pathogenesis

The pathogenesis of bacterial endocarditis is complex and not completely understood. Most theories have been extrapolated from studies in humans, which suggest a variety of factors are involved, including endothelial integrity, hemostatic function, host immune function, intrinsic microorganismal properties, and peripheral bacteremia.^2,3,7,13 In order for bacteria to colonize the endocardial surface of valve leaflets, formation of a nonbacterial thrombotic vegetation must first develop. The vegetation is an aggregate of platelets, fibrin, red blood cells, mononuclear cells (histiocytes and lymphocytes), and polymorphonuclear leukocytes.^{1–3,7,13,14} Damage to the vascular endothelium is an important step in this process, as normal vascular endothelium is resistant to bacterial adherence and colonization.^7,13,14 Hypercoagulability appears to be a major contributing factor as well.^2,3,7 Bacteremia and bacterial adherence to the vegetation are the events that ultimately lead to colonization of the vegetation and bacterial endocarditis. The precise mechanisms by which adherence and colonization occur are unknown.³ Fibronectin, which is produced by endothelial cells, platelets, and fibroblasts in response to endothelial injury, appears to be important in this adherence process. Many of the pathogenic bacteria causing endocarditis have surface receptors for this glycoprotein. ^2,3,7 Dextran, a polysaccharide produced on the surface of some bacteria known to cause endocarditis, may also facilitate bacterial adherence to platelet-fibrin aggregates. ^2,3,7

Damage to valvular endothelium has traditionally been attributed to trauma secondary to turbulent or high-velocity blood flow.⁷ There is evidence in humans that a direct relationship exists between the normal resting pressure on closed heart valves and the incidence of valvular endocarditis (mitral>aortic>tricuspid>pulmonic).¹⁵ This implies that bacteria may be more easily forced into the endothelium of those valves experiencing higher resting pressures for longer lengths of time, and that these valves may also be at increased risk for scarring.¹⁵ High-velocity flow, on the other hand, may account for the distribution of vegetations, as aortic vegetations are generally seen on the ventricular side of the valve and mitral valve vegetations are usually seen on the atrial side of the valve.^3,13 A significant number of cases of endocarditis occur in people with identifiable predisposing cardiac conditions, such as patent ductus arteriosus, ventricular septal defect, mitral valve prolapse, bicuspid aortic valve, rheumatic heart disease, etc.⁷ In contrast, dogs with these disorders do not appear to be predisposed. ¹ Cases of endocarditis in dogs with mitral valve endocardiosis (i.e., chronic valvular disease) are rare.^1–4 There is some evidence, however, to suggest that an association exists between canine subaortic stenosis and endocarditis. ^4,16

Bacteremias are induced by physical manipulation or traumatization of bacteria-laden mucosal surfaces, such as oral/pharyngeal surfaces and the gastrointestinal and urinary tracts.^1–3,6 Development of bacterial endocarditis as a result of bacteremias produced by periodontal disease or dental procedures has long been a controversial issue in humans.^14,17–22 For many years, antibiotic prophylaxis for patients considered at risk from these procedures (i.e., patients with underlying mitral valve abnormalities) has been a standard of practice.^7,17–22 Despite insufficient evidence linking dental disease to endocarditis, antibiotic prophylaxis has remained standard for medical and legal reasons.^7,17–22 Other predisposing factors for development of endocarditis may include immunosuppression from previous illness or corticosteroid therapy, bacterial infections within body tissues or cavities, implanted hardware (e.g., pacemakers), and hypercoagulable disorders.^1–6

Etiological Agents

The organisms most commonly recognized and identified as the causative agents of bacterial endocarditis in dogs include coagulase-positive Staphylococcus spp., Streptococcus spp., Escherichia coli, Pseudomonas aeruginosa, Corynebacterium spp., and Erysipelothrix rhusiopathiae. ^1–6,12,23 Recently, Bartonella (B.) spp. (i.e., B. vinsonii berkhoffii, B. clarridgeiae, B. washoensis) have been identified as causative agents in cases of endocarditis that grew no bacteria on blood culture. The diagnosis of bartonellosis was made using antemortem serology and postmortem polymerase chain reaction assays.^{1,2,4,23–25} Interestingly, five of six dogs that were positive for Bartonella spp. in one study had aortic valve involvement only, while the sixth had both aortic and mitral valve involvement.²⁵

Clinical Presentation

Dogs that develop endocarditis rarely are presented with a history of an obvious predisposing infection, surgical or dental procedure, trauma, intravenous or urinary catheterization, or immunosuppressive drug therapy.¹ They more commonly have a combination of nonspecific signs of systemic illness (often extracardiac) such as depression, weakness, lethargy, weight loss, anorexia, intermittent or shifting lameness, and/or encephalopathy.^{1–6,23,27,28} Tachypnea, dyspnea, and coughing may be noted and reflect left-sided congestive heart failure.^1–6,27 Many dogs will have a fever and/or leukocytosis, although fevers may be masked by concurrent anti-inflammatory drugs.^1–5

A febrile dog with a new heart murmur (or change in quality of an existent murmur) is classically regarded as suspicious for endocarditis, although these findings may be overemphasized.^1,3,6 In one study, only 41% of dogs had a new or previously undiagnosed heart murmur.⁶ Cardiac abnormalities associated with endocarditis usually result from damage to valvular structure and altered function, as the vegetative lesions lead to poor coaptation of valve leaflets and regurgitation. This regurgitation may cause volume overload and signs of left-sided congestive heart failure, which is a common sequela.^1–6,12,13

Mitral valve lesions resulting in mitral regurgitation are detected on physical examination as systolic murmurs that are loudest at the left apex. Vegetative lesions on the aortic valve can result in stenosis of the aortic valve, resulting in a systolic murmur at the left heart base. Aortic valve vegetations may also lead to poor valve coaptation, possibly valve perforation, and leakage of blood back into the ventricle during diastole. The latter is more common and manifests as a diastolic murmur heard loudest over the left heart base.^1,2 Occasionally, both abnormalities are present and result in systolic and diastolic murmurs (a “to and fro” murmur). “To and fro” murmurs also occur with ventricular septal defects with concurrent aortic regurgitation, and they can potentially be confused with the continuous murmur of a patent ductus arteriosus.²⁹ The “to and fro” murmur of bacterial endocarditis is acquired and not congenital, however. In dogs, auscultation of a diastolic murmur is generally helpful in the diagnosis of endocarditis, because only a limited number of etiologies are known to cause aortic insufficiency. ^1,3 Dogs with aortic valve lesions commonly are presented with bounding peripheral pulses from a wider-than-normal pulse pressure. The widened pulse pressure occurs from both increased systolic pressure that arises secondary to volume overload of the left ventricle (i.e., the Frank-Starling mechanism) and decreased diastolic pressure from leakage across the aortic valve into the ventricle during diastole. Sinus tachycardia or ventricular dysrhythmias may also be detected.^{1–6,12,13,27}

Many nonspecific clinical signs occur as a result of septic embolization to blood vessels and organs.^1,7,13 Septic emboli are common findings at necropsy in dogs that have died from endocarditis, with the kidney being the most common organ to suffer ischemic insult.^1,2,4,13 The spleen, left ventricle, liver, brain, intestines, and iliac artery are other sites where emboli are seen at necropsy.^1,4,13 Infarcts of these organs often account for clinical deterioration of affected dogs prior to their death.^1–3,5 Immune-complex glomerulonephritis, with or without embolization, may result in renal disease; this is also a common necropsy finding.^1–5,13

The pathophysiology of lameness and manifestations of joint pain in dogs with endocarditis vary. Septic emboli lodging in vascular branches to appendicular skeletal muscle, as well as sepsis in a joint, can lead to a focal lameness. A common site of embolization is downstream to the right subclavian artery, which causes right thoracic limb lameness. ^1,3 Generalized, shifting lameness or other joint pain is believed to result from arthritis secondary to immune complex deposition in joints following antigenic stimulation by bacteremia.^1–5,13

Diagnosis

Prior to the era of echocardiography, the diagnosis of bacterial endocarditis in dogs relied on clinical presentation with abnormalities such as fever, leukocytosis with a left shift, a new heart murmur, and positive blood cultures.^1–6 In many cases, monocytosis (>90% of cases), anemia, and thrombocytopenia (immune-mediated or consumptive) are supportive hematological findings.^1,2,4,6 Serum biochemical abnormalities (e.g., azotemia or hypoalbuminemia) may arise secondary to embolization or result from bacteremia (e.g., hypoglycemia).^1,2,4 Urinalysis may reveal proteinuria, casts, and an active sediment secondary to glomerulonephritis. ^2,4,5

Echocardiography is helpful in diagnosing endocarditis through detection of vegetative lesions on valvular surfaces [see Video loop; http://www.jaaha.org/cgi/content/full/43/5/256/DC1]. Most vegetative lesions have a characteristic appearance on echocardiography. They can be irregular, echogenic thickenings or mobile, pedunculated masses [Figure 1]. Sensitivities as high as 90% have been reported for echocardiography, but echocardiographic diagnosis greatly depends on the experience and skill of the operator and quality of the equipment used.¹

Endocardiosis of the mitral valve can appear echocardiographically similar to, or indistinguishable from, mitral valve endocarditis; it is responsible for most false-positive diagnoses [Figures 2A, 2B]. Lack of detection of a vegetative lesion does not rule out endocarditis, as small, vegetative lesions may not be detected via echocardiography.³ Thus, the clinical presentation and progression of clinical signs remain the most important tools in diagnosis. Echocardiographic evidence of myocardial remodeling and failure allows grading of the severity or chronicity of the endocarditis, and Doppler echocardiography is useful in determining the nature and severity of regurgitant flow.^1–4

Blood cultures can be misleading because of contamination; however, they are highly supportive of endocarditis if they are positive.^1,3 Sensitivity testing is used to guide antibiotic selection. Three blood culture samples are obtained over a 24-hour period, at least 1 hour apart from each other. In critically ill dogs, these samples may be taken over a 3-hour period. Blood samples (≥10 mL) are collected in commercial vacuum bottles; care must be taken not to withdraw excessive amounts from small dogs. It is important to collect adequate volumes, as the concentration of bacterial organisms within blood is usually very small (<5 to 10 bacteria/mL). Historically, both aerobic (vented) and anaerobic (unvented) cultures have been recommended, but the small number of cases caused by anaerobes suggests that aerobic cultures alone may be sufficient.^1–3 A urine culture may also be informative.

Cultures are preferably obtained at a time when the dog is not on antibiotic therapy. If the dog is already receiving antibiotics, samples are ideally collected when the drug is at trough levels.^2,3 Blood collections are done from separate venipuncture sites that are prepared aseptically; samples are only taken from indwelling catheters if they are jugular catheters that have been recently placed.^1–3 Sampling from multiple sites is more supportive of true infection if the same organism is grown from these sites, and it reduces the likelihood that contamination has occurred.

Treatment

Treatment of bacterial endocarditis aims to destroy offending bacteria via strong bactericidal therapy. Selection of an appropriate antibiotic is ideally based on blood culture and sensitivity results. In most cases, however, antimicrobial therapy is begun prior to definitive culture. In cases with negative cultures or cases that are acutely ill, antibiotic choices may be made empirically. If a primary focus of infection is known or suspected, antimicrobial selection can be made based on the organisms most likely to be the source of bacteremia. When gram-positive infections are suspected, use of a penicillin-type agent (e.g., ampicillin, amoxicillin), potentiated-penicillin drug (e.g., ticarcillin plus clavulanate), or first- (e.g., cefazolin) or second-generation cephalosporin is indicated.^1,3,30 If gram-negative organisms are believed to be responsible, use of an aminoglycoside (e.g., amikacin, gentamicin) or fluoroquinolone (e.g., enrofloxacin) may be appropriate.^1,3,30

For acutely ill dogs with no evidence of infection elsewhere in the body, use of antibiotic combinations to achieve full-spectrum coverage is warranted. Such combinations may include a penicillin-type drug and an aminoglycoside or fluoroquinolone. Use of an aminoglycoside in dogs with renal compromise is contraindicated, and a fluoroquinolone or cephalosporin is a viable alternative.^1–5 The addition of clindamycin or metronidazole for anaerobes is also valid.² Doxycycline or azithromycin is a reasonable selection in cases of suspected Bartonella spp. endocarditis, although no studies in dogs have evaluated antibiotic efficacy against Bartonella spp.^24,30 The Table provides a comprehensive summary of antimicrobial recommendations for treatment of endocarditis based on common sources of bacteremia and the most likely offending organism(s).

One of the key features of this disease is that bacteria colonizing the valvular vegetations are shielded from standard antibiotic treatment regimens.^1–3 Parenteral therapy must be instituted that achieves very high serum levels of bactericidal agents. Ideally, therapy is continued for many weeks, but prolonged therapy in dogs may not be a realistic option. Intravenous therapy is usually administered for 1 to 2 weeks until the dog stabilizes clinically, at which time therapy is either continued as subcutaneous or oral treatments.^1–5

In addition to antimicrobials, treatment of congestive heart failure, acid-base imbalances, and fluid and electrolyte imbalances is important. In dogs suffering left-sided congestive heart failure (the most common cause of death in endocarditis), combination therapy with a diuretic (e.g., furosemide), angiotensin-converting enzyme inhibitor (e.g., enalapril, benazepril), and digoxin is usually successful at resolving edema and maximizing cardiac output.^1–3,12 Use of an additional afterload reducer, such as amlodipine, nitroprusside, or hydralazine, helps to minimize regurgitant flow into the heart chambers through the aortic or mitral valves.^1–3 Blood pressure monitoring is essential, particularly when combining afterload-reducing agents.^1–3

Management and control of underlying medical conditions are crucial to provide the best chance of recovery. Equally as important is reduction of potential avenues for continued or new infection via wound/abscess management. Limiting the use of multiple or prolonged intravenous and urinary catheters is important.

Dogs suffering from undiagnosed endocarditis are sometimes mistakenly treated with corticosteroids, because they are believed to be suffering from a primary immune-mediated disease. Corticosteroids may result in clinical improvement for the first 1 to 2 days, then clinical signs worsen. Corticosteroids adversely affect prognosis and are contraindicated. ^1,3,6 Use of anticoagulant therapy to prevent embolic events has been explored, but it does not appear to be beneficial and may increase the risk of hemorrhage.^2,5 Reduction of vegetation bacterial density to allow better antibiotic penetration is another theoretical benefit to the use of anticoagulant therapy. As further studies are completed, recommendations regarding anticoagulant therapies may change in the future.

Prognosis

Prognosis for dogs with bacterial endocarditis is poor to grave.^1–3,13 Studies from the early 1980s showed survival rates of 20%, while a recent retrospective case series reported a mortality rate of 56%.^4,6,8 One reason for poor survival is the difficulty in sterilizing the infected vegetation.^1,2,7 Even if valve sterilization is achieved, valve scarring often results in significant regurgitation, volume overload, and congestive heart failure; the resultant long-term prognosis is poor.^1–3,5,7,13 Development of noncardiac sequelae, such as renal complications and thromboembolic disease, also contributes to a poor prognosis.

Conclusion

Bacterial endocarditis is a disease that primarily affects middle-aged to older, large-breed dogs; but it can occur in any age, sex, or breed of dog. The varied and often nonspecific clinical signs and course of the disease make diagnosis difficult. The disease is best recognized by reviewing the overall clinical picture and laboratory findings and performing echocardiography and blood cultures. Bacterial endocarditis in dogs is often fatal, and treatment must be aggressive and immediate to maximize chances for survival.