Bacteremia

Bacteremia can be divided into uncomplicated and complicated bacteremia (see Table 86-1). Transient, low-level (≤10 CFU/mL) subclinical bacteremia follows a variety of procedures such as dental prophylaxis, endoscopy, gastrointestinal surgery, and catheter placement. This is typically cleared rapidly (within 15 to 30 minutes) by a functional mononuclear phagocyte system. However, persistent release of large numbers of bacteria into the bloodstream can overwhelm the host immune response and culminate in clinically significant bacteremia. Overwhelming bacteremia can occur with disorders such as pyelonephritis, pyothorax, severe pyoderma, bacterial peritonitis, pyometra, pneumonia, pancreatitis, a variety of gastrointestinal disorders, bite wounds, orthopedic infections, or catheter-related infections. Underlying immune system dysfunction (such as occurs with diabetes mellitus, malignancy, and neutropenia) also predisposes to clinically significant bacteremia, because bacteria multiply unhindered in the bloodstream.

The most common organisms isolated from the blood of sick, bacteremic dogs are Staphylococcus spp., Streptococcus spp. (especially Streptococcus canis), and Escherichia coli (Table 86-2).² Less than 10% of bacteremic dogs in the author’s hospital are infected with anaerobes, but in a study of critically ill dogs and cats from Colorado, anaerobes were isolated from 31% of 39 dogs and 40% of 10 cats.³ With the exception of Bartonella and hemoplasmas, bacteremia is less commonly recognized in cats than in dogs and usually results from infection with gram-negative bacterial pathogens.² Polymicrobial infections of the blood are common and typically occur in 10% to 20% of dogs and cats with positive blood culture results. Mixed infections with two or more different strains of a single bacterial species can also occur. Polymicrobial infections often occur when anaerobes are involved or when bacteremia develops secondary to compromise of the gastrointestinal tract.

In addition to sepsis and septic shock, bacteremia may be followed by the development of infective endocarditis (IE), discospondylitis, and metastatic abscess formation in a variety of tissues. Chronic bacteremia may trigger secondary immune-mediated disorders, especially immune-mediated polyarthritis or glomerulonephritis, and rarely immune-mediated hemolytic anemia. This can result in erroneous diagnosis of a primary immune-mediated disorder and inappropriate treatment with immunosuppressive drugs, sometimes with a fatal outcome.

Sepsis

Bacteremia does not need to be present for sepsis to occur, but the clinical signs of bacteremia reflect the presence of sepsis (i.e., the host inflammatory response to infection). An understanding of the pathogenesis of sepsis has been critical for the development of drugs to improve survival, but it is complex and not fully understood. In summary, sepsis occurs when components of microbes (known as pathogen-associated molecular pattern molecules, or PAMPs) activate a host inflammatory response when they bind to pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat containing proteins (NLRs).^3a The lipid A portion of bacterial lipopolysaccharide (LPS) is especially well known for its ability to stimulate this response (see Chapter 36), but other molecules, such as peptidoglycan, flagellin, DNA, and viral double-stranded RNA, may also be involved. Superantigens of gram-positive bacteria induce a cytokine cascade through simultaneous activation of large numbers of T cells (see Chapter 34). Bacterial LPS binds to an acute phase reactant protein called LPS binding protein, which transfers the LPS to CD14, a receptor on the surface of phagocytes.⁴ CD14 then transfers the LPS to TLR4, which transmits the signal to the cell interior. This leads to activation of NF-κB and the secretion of cytokines such as TNF-α and Il-1β. The released cytokines induce fever (which may serve to limit bacterial growth), and cause further lymphocyte activation and release of proinflammatory cytokines. Damaged host cells also release molecules (damage-associated molecular pattern molecules, or DAMPs) that bind to TLRs and stimulate cytokine release. Important DAMPs recognized in humans include a chromatin-associated protein known as high mobility group box-1 (HMGB1) and cellular DNA. The cascade of cytokines that is produced in response to DAMPs and PAMPs in turn induces the release and activation of a huge variety of mediators, such as complement, colony stimulating factors, prostacyclin, thromboxane, platelet-activating factor, coagulation factors, histamine, serotonin, nitric oxide, angiotensin II, and endothelin-1. Many of these mediators serve to recruit large numbers of immune cells and trigger fibrin deposition in order to localize, control, and ultimately eliminate the infection. Other molecules, such as cortisol and epinephrine, act to control the inflammatory response. Endothelial cell damage results in increased exposure of tissue factor (which activates the extrinsic coagulation pathway) as well as von Willebrand’s factor. Endothelial cell damage also results in decreased expression of thrombomodulin, an important anticoagulant that normally binds thrombin and prevents it from cleaving fibrinogen. The thrombomodulin-thrombin complex also activates protein C, which binds to protein S; the activated protein C–protein S complex degrades activated coagulation factors Va and VIIIa and prevents coagulation. Recombinant activated protein C has been the subject of much attention and controversy as a specific treatment for sepsis in human patients (see Treatment).

When the inflammatory response to infection is not effectively controlled or localized, the end result is systemic hypotension, tachycardia, increased vascular permeability, leukocytosis, activation of the coagulation cascade, and disordered tissue perfusion as a result of microcirculatory disturbances, volume depletion, and depressed myocardial function. This leads to further damage to host cells, lactic acidosis, and multiple organ dysfunction. Impaired perfusion, tissue hypoxia, and endothelial cell damage may have a wide range of effects on organ function (Table 86-3). Cats may be particularly susceptible to acute lung injury in sepsis, whereas gastrointestinal and/or hepatic dysfunction is often observed in dogs. Clinical signs of severe sepsis in dogs often include fever, obtundation, tachycardia, bounding or weak pulses, bright red mucous membranes, shortened capillary refill time, icterus, and tachypnea. However, many dogs with sepsis are evaluated when in the hypodynamic phase, with tachycardia, poor pulse quality, prolonged capillary refill time, and cold extremities. Cats may show obtundation, pale mucous membranes or icterus, abdominal pain, poor pulse quality, bradycardia, and/or tachypnea and may either be febrile or hypothermic.⁵

Infective Endocarditis

The reported incidence of canine IE has ranged from fewer than 0.1% of cases seen at veterinary teaching hospitals to approximately 1% of cases presenting to veterinary cardiologists.6–9 IE is uncommonly diagnosed in cats. Dogs with IE are typically middle aged to older, large-breed dogs such as German shepherds, golden and Labrador retrievers, Weimaraners, mastiffs, and Rottweilers. For unclear reasons, male dogs are affected approximately twice as often as females. Factors that predispose to IE are similar to those that predispose to continuous bacteremia. However, virulence factors possessed by bacteria subsequently affect whether IE develops, which explains why some bacterial species (especially gram-positive bacteria) are more likely to produce IE than others (gram-negative bacteria). Although valvular heart defects, especially congenital defects such as subaortic stenosis, may predispose young dogs to development of IE, the vast majority of dogs with subaortic stenosis never develop IE, and more than 80% of dogs with IE have no identifiable underlying cardiac abnormality.^8,10 Furthermore, IE is rarely diagnosed in small-breed dogs, which are predisposed to myxomatous mitral valve degeneration. One study also found no association between periodontal disease and IE in dogs.¹⁰

The most commonly reported etiologic agents in canine IE are streptococci, staphylococci, and, to a lesser extent, gram-negative rods, enterococci, and Bartonella spp. (Table 86-4).^7,10–13 Organisms that are less commonly incriminated include fungi, gram-positive rods, mycobacteria, and anaerobes. In dogs, the mitral and/or the aortic valves are most commonly affected (Figure 86-1). The larger, septal leaflet of the mitral valve is more commonly affected than the mural leaflet.⁸ The tricuspid valve and ventricular wall are rarely involved. This distribution correlates with the degree of pressure that rests on each closed valve. Classically, vegetative lesions develop along the line of valve closure.

The development of IE begins with colonization of a heart valve by bacteria and deposition of fibrin, platelets, leukocytes, and erythrocytes. Colonization may be facilitated by changes in the valve surface as a result of turbulent blood flow, which results in the deposition of platelets, fibrin, and fibronectin; the end result is a sterile vegetation, or nonbacterial thrombotic endocarditis. Bacteria then adhere to this matrix, induce inflammatory cytokine and tissue factor release, and become covered with additional layers of platelets and fibrin, which promote bacterial growth to extremely high densities in an environment that is protected from the immune system. Properties of bacteria known to promote valve colonization include adhesins such as fimA in streptococci and clumping factor and fibronectin-binding proteins in staphylococci,14,15 as well as factors that cause platelet aggregation. Portions of the vegetation can then dislodge and embolize in a variety of different tissues, especially the kidneys, spleen, brain, joints, and muscles, with an enormous spectrum of associated clinical manifestations. Thromboembolic complications are more likely to occur in dogs with mitral valve involvement than in those with aortic valve IE.⁸ Regardless of the valve affected, valvular dysfunction can lead to impaired cardiac output and congestive heart failure (CHF).

As in humans, IE in dogs may be best classified on the basis of the etiologic agent involved, because the etiologic agent often determines the clinical course of disease, disease manifestations, prognosis, and the most appropriate antimicrobial drugs for treatment. For example, Bartonella IE is more likely to involve the aortic valve than the mitral valve, often occurs in the absence of fever, has a high prevalence of CHF when compared with IE caused by other bacterial pathogens, and is negatively correlated with survival (see Figure 52-3). In contrast, Streptococcus canis IE usually involves the mitral valve and is often associated with secondary polyarthritis. Dogs with gram-negative IE may be less likely to develop CHF than those with IE caused by other pathogens.¹¹

The clinical signs and physical examination abnormalities that occur with IE are extremely variable and depend not only on the causative organism, but also on the valve affected, the presence or absence of thromboembolic complications, and the sites and extent of thromboembolism. Common historical findings include lethargy; inappetence; locomotory problems such as lameness, shifting lameness, joint pain, stiffness, reluctance to move, and inability to walk; and vomiting, weight loss, respiratory difficulty, and/or cough. Locomotory abnormalities can result from peripheral arterial thromboembolism, embolic or immune-mediated polyarthritis, neurologic abnormalities, and rarely, hypertrophic osteopathy. The most common initial physical examination findings are fever, tachycardia, and a cardiac murmur (Table 86-5).⁸ In one study of dogs with IE, fever was present in the history or serial physical examinations of only 41 (60%) of 68 dogs with IE, and a cardiac murmur in only 53 (76%) of 70 dogs with IE, so an absence of fever or cardiac murmur does not rule out IE.⁸ Although diastolic murmurs are suggestive of IE, more than 90% of dogs with murmurs due to IE have systolic murmurs.

Infectious Myocarditis

Infectious myocarditis in dogs and cats usually results from hematogenous spread of microorganisms to the myocardium or extension of endocarditis lesions to the myocardium. Viruses, bacteria, protozoa, or fungi may be involved. Some organisms have a particular tropism for the myocardium (Table 86-6). Infectious myocarditis is rare in cats.

Myocarditis may be subclinical or result in arrhythmias, CHF, or sudden death. Simultaneous infection of a variety of other organs is frequent for most pathogens that cause myocarditis, so clinical signs of systemic infection (fever, lethargy) and other organ dysfunction are often present.

Infectious Pericarditis

Infectious pericarditis may result from direct inoculation of organisms into the pericardium (such as occurs with penetrating wounds), extension of infection from adjacent organs such as the pleural space or lungs, or hematogenous dissemination of viral, bacterial, or fungal pathogens to the pericardium. Bite wounds or grass awn migration usually result in mixed aerobic-anaerobic infections that involve organisms such as Actinomyces spp. (see Chapter 42). Infectious pericarditis as a result of hematogenous spread of pathogens is rare; idiopathic pericardial effusion and heart-base neoplasia are the most common causes of inflammatory or hemorrhagic pericardial effusion in dogs. Pathogens with particular tropism for the pericardial sac include feline infectious peritonitis virus and Coccidioides spp. (see Chapters 20 and 63). Pericarditis results in diastolic cardiac dysfunction with subsequent development of right-sided heart failure, which is manifested as weak pulses, tachycardia, jugular venous distention, ascites, and pleural effusion. Muffled heart sounds may be detected on cardiac auscultation as a result of pericardial and/or pleural effusion.

Laboratory Abnormalities