Infections of the Cardiovascular System

CHAPTER 86

Infections of the Cardiovascular System Jane E. Sykes and Steven Epstein

Overview of Cardiovascular System Infections Causes: Most often staphylococci, streptococci, and ­Escherichia coli are involved. Gram-negative bacterial etiologies predominate in cats. Culture-negative infections of the bloodstream may be caused by Bartonella spp. or other fastidious bacteria. Anaerobes and mycobacteria are less commonly involved. Rickettsia rickettsii can cause vasculitis and ­myocarditis. Viruses (e.g., parvoviruses), fungi, and protozoal organisms can also infect the bloodstream and myocardium. Geographic Distribution: Worldwide Major Clinical Signs: Highly variable. Fever, inappetence, lethargy, and tachycardia are common. Vomiting and/ or diarrhea can also occur. Additional findings in infective endocarditis include cardiac murmurs, arrhythmias, lameness, and neurologic signs due to thromboembolic disease. Spinal pain, paresis, or paralysis may occur when discospondylitis complicates bacteremia or fungemia. Differential Diagnoses: Noninfectious conditions that can mimic sepsis include pancreatitis, trauma, hypoadrenocorticism, heat stroke, anaphylaxis, pulmonary thromboembolism, hemorrhage, cardiac tamponade, and some toxicities. Dogs with primary immune-mediated disorders may show clinical signs that resemble those of chronic bacteremia and infective endocarditis. For suspected infectious pericarditis, the major differential diagnoses are idiopathic or benign pericardial effusion and neoplastic disorders. Human Health Significance: Dogs and cats with cardiovascular infections may be infected with pathogens that have the potential to cause disease in humans, such as ­Salmonella, Bartonella, and Brucella spp.

Etiologic Agents, Epidemiology, and Clinical Features Bacterial infections of the cardiovascular system include bacteremia, infective endocarditis, myocarditis, and infectious pericarditis. These infections are frequently associated with sepsis, or the host systemic inflammatory response to infection. When sepsis is associated with hypotension and distant organ dysfunction, the terms septic shock and severe sepsis are used, respectively. These terms have been clearly defined in human medicine1 and adapted for use in small animals (Table 86-1).

830

Septicemia is a term that has been used interchangeably with bacteremia by veterinary medical and medical professionals, but it is incompletely defined, and as a result, the use of this term is no longer recommended.

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 immunemediated 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.

CHAPTER 86  Infections of the Cardiovascular System

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TABLE 86-1 Definitions That Apply to Cardiovascular Infections in Dogs and Cats Term

Definition

Bacteremia

The presence of viable or cultivable bacteria in the bloodstream

Uncomplicated bacteremia

Positive blood culture results and exclusion of ­endocarditis; no implants; negative follow-up cultures 2-4 days after the initial set; defervescence within 72 hours of initiation of effective treatment; and no evidence of metastatic sites of infection

Complicated bacteremia

Animals with positive blood culture results that do not meet the criteria for uncomplicated bacteremia

Fungemia

The presence of viable fungi in the bloodstream

Systemic inflammatory response syndrome (SIRS)

The clinical manifestation of systemic inflammation due to both ­noninfectious and infectious etiologies. Criteria for dogs and cats have been adapted from those in human medicine, but these have varied slightly in the cutoff values used. A single definition for dogs or cats has not been widely accepted. SIRS criteria are nonspecific and must be interpreted in light of an underlying disease. Dogs: 2 of 4 of temperature <100°F or >103.0°F (hypothermia or fever), HR > 140 beats/min, nonpanting RR > 30 breaths/min or PCO2 < 32 mm Hg (venous or arterial), WBC <6000 or > 16,000 cells/µL, or >3% band neutrophils Cats: 3 of 4 of temperature <100°F or >103.5°F, HR < 140 or >225 bpm, RR > 40 breaths/min, WBC > 19,500 or <5000 cells/µL, or >5% band neutrophils

Sepsis

SIRS due to a proven or clinically suspected infection

Severe sepsis

Sepsis that is accompanied by dysfunction of organs remote from the site of infection, or sepsisinduced tissue hypoperfusion

Sepsis-induced tissue hypoperfusion

Sepsis that is accompanied with hypotension, an elevated lactate concentration, or oliguria either before or after adequate fluid loading

Septic shock

Sepsis that is accompanied by hypotension (systolic blood pressure < 90 mm Hg or mean arterial pressure < 70 mm Hg) that does not resolve with fluid resuscitation alone (i.e., vasopressor therapy is required)

Multiple organ dysfunction syndrome (MODS)

Dysfunction of two or more organ systems (distant to site of infection) in an animal with SIRS/ sepsis

Infective endocarditis

Infection of one or more endocardial surfaces of the heart; almost always involves a cardiac valve

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.

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SECTION 5  Infections of Selected Organ Systems

TABLE 86-2 Organisms That May Be Cultured Using Routine Blood Culture Methods from the Bloodstream of Dogs and Cats with Bacteremia* Common (>10% of isolates)

Dogs

Cats

• Staphylococcus spp., including S. ­pseudintermedius, S. aureus, and ­coagulase-negative staphylococci • Streptococcus spp., especially S. canis, but also S. bovis complex organisms and rarely other streptococci • Escherichia coli

• Escherichia coli • Other Enterobacteriaceae (Klebsiella pneumoniae, Citrobacter ­freundii, Enterobacter cloacae) • Anaerobes

Uncommon • Enterococcus spp. • Salmonella spp. (1% to 10% • Klebsiella pneumoniae, Serratia spp., Enterobacter cloacae • Non-Enterobacteriaceae of isolates) • Pasteurella canis and Pasteurella dagmatis ­gram-negative bacteria (­Pasteurella multocida, ­Pseudomonas • Pseudomonas aeruginosa • Anaerobes (Clostridium perfringens, Prevotella spp., Bacteroides spp., ­aeruginosa, Acinetobacter ­Fusobacterium spp., Actinomyces spp., P ­ eptostreptococcus spp.) ­baumannii) • Staphylococci • Streptococci Rare (≤1% of isolates)

• Erysipelothrix spp. • Brucella spp. • Citrobacter freundii • Acinetobacter spp. • Salmonella spp. • Mycobacterium spp. • Campylobacter spp. • Other nosocomial pathogens, e.g., ­Ralstonia ­pickettii, Burkholderia cepacia

• Enterococcus spp.

*Not including fastidious organisms such as Bartonella spp.

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, grampositive 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.

CHAPTER 86  Infections of the Cardiovascular System

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TABLE 86-3

TABLE 86-4

Potential Effects of Sepsis on Organ Function

Causes of Infective Endocarditis in Dogs

Organ

Clinical Abnormalities

Microorganism

Prevalence11

Neurologic system

Obtundation, rarely focal signs and seizures; autonomic dysfunction

Streptococci (primarily S. canis but also S. bovis group organisms)

29%

Heart

Heart rate variability, arrhythmias (ventricular or supraventricular), decreased contractility

Bartonella spp.

20%

Staphylococci (S. pseudintermedius, S. aureus, and coagulase-negative staphylococci)

15%

Gram-negative rods (most commonly E. coli, but also P ­ seudomonas ­aeruginosa, Salmonella spp., ­Citrobacter freundii, ­Klebsiella pneumoniae, Proteus spp., ­Pasteurella spp., Brucella spp.)

15% (7% E. coli; <5% other species)

7% (<5% each species)

Vasculature

Hypotension despite adequate fluid loading

Lungs

Acute lung injury or acute respiratory distress syndrome

Kidneys

Azotemia, oliguria, anuria

Gastrointestinal tract Impaired barrier function and ­bacterial translocation, ­gastrointestinal ulceration, diarrhea, vomiting Pancreas

Pancreatitis

Endocrine system

Adrenal insufficiency, hypoglycemia

Other gram-positive ­bacteria ­(Erysipelothrix spp., G ­ ranulicatella adiacens, ­Actinomyces spp., ­Corynebacterium spp., ­Mycobacterium spp.)

Liver

Cholestatic jaundice

Enterococcus spp.

5%

Immune system

Immunosuppression

Fungi (e.g., Aspergillus spp.)

<5%

Coagulation

Disseminated intravascular ­coagulation with or without ­hemorrhage

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

FIGURE 86-1  Infective endocarditis. Vegetations are attached to the mitral and aortic valves and may be mobile or sessile. 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.

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TABLE 86-5

TABLE 86-6

Physical Examination Findings in 70 Dogs with Infective Endocarditis Seen at the University of California, Davis, Veterinary Medical Teaching Hospital

Infectious Causes of Myocarditis in Dogs and Cats

Physical Examination Finding

Number Affected (%)

Cardiac murmur

41 (59)

Tachycardia

34 (50)

Fever

26 (38)

Tachypnea

24 (35)

Abnormal lung sounds

24 (34)

Recumbency

21 (30)

Mental dullness

19 (27)

Neurologic signs (ataxia, delayed or absent placing reactions, ­strabismus, nystagmus, head tilt, obtundation)

16 (23)

Swollen joints

15 (21)

Stiffness or lameness

13 (19)

Arrhythmias

14 (19)

Dehydration

11 (16)

Bounding pulses

10 (14)

Muscle atrophy

10 (14)

Thin body condition

9 (13)

Weak pulses

8 (11)

Reluctance to stand

8 (11)

Peripheral edema

7 (10)

Spinal pain Abdominal pain, mucosal pallor, red mucous membranes, muscle pain, weakness, cyanosis, cool or cold limbs, oral ulceration, abdominal enlargement, hepatomegaly, icterus, uveitis, petechial or ecchymotic hemorrhages, cutaneous ulceration

7 (10) 6 or fewer (<10)

Modified from Sykes JE, Kittleson MD, Chomel BB, et al. Clinicopathologic findings and outcome in dogs with infective endocarditis: 71 cases (1992-2005). J Am Vet Med Assoc. 2006;228:1735-1747.

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

Pathogen Type Examples

Affected Host Species

Viruses

West Nile virus Canine parvovirus 2 variants Feline panleukopenia virus Pseudorabies virus

D D C D

Bacteria

Gram-negative and ­gram-positive ­bacteria (e.g., extension of ­endocarditis) Bartonella spp. Borrelia burgdorferi Rickettsia rickettsii

D, C

Fungi

Blastomyces dermatitidis Candida albicans Cryptococcus neoformans Aspergillus spp. Paecilomyces variotii

D D D D D

Algae

Prototheca spp.

D

Protozoa

Trypanosoma cruzi Sarcocystis felis Leishmania Neospora caninum Hepatozoon americanum Toxoplasma gondii

D C D D D D, C

D, C D D

C, Cat; D, dog.

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.

CHAPTER 86  Infections of the Cardiovascular System

BOX 86-1

TABLE 86-7

Reasons to Consider Blood Culture in Dogs and Cats

Modified Duke Criteria Used for Diagnosis of Infective Endocarditis in Dogs and Cats8,20

Fever (especially when viral infection is not likely or underlying immunosuppression or barrier disruption is present) Unexplained peripheral edema in dogs Evidence of thromboembolism in dogs (e.g., organ infarction, cold limbs) Neutrophilic polyarthritis in dogs Discospondylitis in dogs Echocardiographic evidence of infective endocarditis or new heart murmur Neutrophilic lymphadenitis Severe pneumonia or pyothorax Peritonitis Development of leukopenia, bandemia, or leukocytosis in association with immunosuppression, catheters, or other devices Thrombophlebitis in association with an indwelling catheter Sepsis in a patient in which a culture cannot be obtained from the suspected source (e.g., pneumonia in a severely hypoxemic patient, gastrointestinal bacterial translocation) Immune-mediated hemolytic anemia or thrombocytopenia

Diagnosis Antemortem diagnosis of bacteremia is based on culture of bacteria from the bloodstream. Reasons to consider blood culture are shown in Box 86-1. The diagnosis of sepsis is based on the presence of the systemic inflammatory response syndrome (SIRS) together with suspected or proven infection (see Table 86-1). A number of biomarkers have been investigated for discrimination of sepsis from SIRS in dogs,16-18 but as yet, highly sensitive and specific biomarkers for sepsis have not been identified. The diagnosis of IE is based on a set of criteria modified from the Duke criteria used for diagnosis of IE in human patients, which consider the results of blood culture and echocardiography as major criteria, and other clinical manifestations of IE as minor criteria (Table 86-7).8,19,20 Diagnosis of infective pericarditis relies on echocardiography and the results of cytologic examination and culture of pericardial fluid, or alternatively, histopathologic examination and culture of pericardial biopsies obtained during thoracotomy or thoracoscopy. In dogs and cats, infectious myocarditis is usually a necropsy diagnosis because myocardial biopsy is rarely performed. However, bacterial myocarditis may be suspected based on echocardiographic abnormalities, the presence of arrhythmias, and positive blood cultures.

Laboratory Abnormalities Complete Blood Count

Common CBC findings in dogs and cats with bloodstream infections are mild nonregenerative anemia, neutrophilia with a left shift and neutrophil toxicity, lymphopenia, and/or monocytosis. Degenerative left shifts may be present, and dogs and cats with disseminated intravascular coagulation (DIC) may be thrombocytopenic

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Major Criteria

Minor Criteria

Identification of a typical ­organism using blood culture • Streptococcus spp. • Staphylococcus spp. • Escherichia coli All 3, or most of 4, separate blood cultures positive, with first and last specimens drawn at least 1 hour apart Two positive blood cultures for any microorganism, when blood cultures are drawn more than 12 hours apart Findings on ­echocardiogram positive for infective ­endocarditis

Predisposing heart ­condition (congenital valvular ­malformation) New or worsening heart ­murmur Fever (≥103°F [39.4°C]) Presence of vascular/embolic phenomena Immunologic ­phenomena: ­nondegenerate ­neutrophilic polyarthritis, ­ glomerulonephritis, ­immune-mediated hemolytic anemia Microbiologic phenomena: positive blood culture not meeting major criteria, or ­serologic evidence of ­infection with a typical organism, or detection of a typical organism using PCR technology

Definite endocarditis: 2 major criteria, or histopathologic confirmation of endocarditis. Possible endocarditis: Positive echocardiographic findings and 1 minor criterion, or 1 major and 3 minor criteria, or 5 minor criteria. In recent human guidelines, 1 major and 3 minor criteria, or 5 minor criteria, are considered sufficient evidence for diagnosis of definitive endocarditis.19

or have evidence of schistocytosis. Rarely, bacteria are seen within circulating leukocytes on blood smear examination.

Serum Biochemical Tests

The serum chemistry profile in dogs and cats with bloodstream infection may show evidence of organ dysfunction as a result of severe sepsis or bacterial embolization and infarction. Abnormalities include azotemia, increased activities of liver enzymes, mild to moderate hyperbilirubinemia (usually <5 mg/dL), and electrolyte and acid-base abnormalities (such as a high anion gap metabolic acidosis due to azotemia or lactic acidosis). Hyperglycemia may be present early in septic shock. Hypoglycemia can also be present as a result of decreased hepatic gluconeogenesis or upregulation of non–insulin dependent glucose transporters. Hypoalbuminemia occurs in most dogs with IE, ranges from mild to severe, and may result from decreased hepatic production, from increased vascular permeability, or as part of the inflammatory response (albumin is a negative acute-phase reactant protein). Dogs with thromboemboli to skeletal muscle may have markedly increased activity of serum creatine kinase.

Urinalysis

Urinalysis findings in dogs and cats with bacteremia or IE include proteinuria, pyuria, cylindruria, microscopic hematuria, and/or bacteriuria. Severe proteinuria (urine protein:creatinine

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SECTION 5  Infections of Selected Organ Systems

A

B FIGURE 86-2  A, Parasternal (left) and short-axis (right) views of the mitral valve of a 7-year-old male neutered Weimaraner with Enterococcus faecium endocarditis that was diagnosed after a perineal urethrostomy procedure. There is a large vegetative lesion attached to the mitral valve (arrow). A smaller lesion is attached to the septal leaflet of the valve. B, Parasternal (left) and short-axis (right) views of the aortic valve of a 4-year-old intact male Doberman with culture-negative endocarditis. The aortic valve cusps are thickened and a hyperechoic nodule is evident (arrow). (Images courtesy University of California, Davis Veterinary Cardiology Service.)

ratio >5) may occur as a result of glomerular damage in dogs with IE.

Coagulation Profile

Dogs and cats with sepsis and DIC may have prolonged APTT and PT, increased concentrations of fibrin degradation products or D-dimers, and/or decreased concentrations of plasma fibrinogen and antithrombin. If thromboelastography is used, either hyper- or hypocoagulability may be documented in dogs.21 In dogs with IE, PT is often shortened, and fibrinogen concentration is often increased.8

Diagnostic Imaging Plain Radiography

Thoracic radiographs in dogs with IE often show no detectable abnormalities. When present, abnormal findings include pulmonary infiltrates as a result of pneumonia, acute respiratory distress syndrome (ARDS), or CHF; generalized cardiomegaly; left atrial enlargement; pulmonary venous distention; mild pleural effusion; and, occasionally, even microcardia or vascular attenuation (see Figure 52-4). Infectious pericarditis may be associated with radiographic evidence of pleural effusion or cardiomegaly. Changes to the intervertebral disc spaces that suggest discospondylitis may also be detected in dogs with bacteremia or IE (see Chapter 85).

Echocardiography

Echocardiography is indicated when infective endocarditis, myocarditis, or pericarditis is suspected based on the history and physical examination findings (such as fever, arrhythmias, a new murmur, or signs of left- or right-sided CHF). It is also indicated for all dogs and cats with bacteremia, even in the absence of a cardiac murmur or arrhythmia; for dogs with neutrophilic polyarthritis; and for dogs and cats with evidence of systemic thromboembolic disease. Echocardiographic findings in IE can include valvular hyperechogenicity, thickening and irregularity of the valves, and valvular vegetations, which may be nodular, discrete, or have a shaggy or moth-eaten appearance (Figure 86-2 and see Figure 52-5). Large vegetations can oscillate or vibrate, and follow-up echocardiography sometimes reveals sudden disappearance of a vegetative lesion in association with thromboembolism. Mild or severe valvular regurgitation or insufficiency may be present in association with the lesions. Other echocardiographic findings include left ventricular eccentric hypertrophy, chamber dilation, mural hyperechogenicity, ruptured chordae tendineae, acquired defects in the valves or myocardium, and mild pericardial effusion. Echocardiography is a sensitive tool for diagnosis of IE (in one study, its sensitivity was 88% when necropsy was used as the gold standard),8 but negative results do not completely rule out the

CHAPTER 86  Infections of the Cardiovascular System

A

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B

FIGURE 86-3  Long-axis (A) and short-axis (B) echocardiographic images that show pericarditis in a 4-year-old male neutered Weimaraner with disseminated coccidioidomycosis. The epicardium is adhered to the pericardium (arrow), and a moderate quantity of anechoic pericardial fluid (F) can be appreciated. The cardiac chambers are distorted. (Images courtesy University of California, Davis Veterinary Cardiology Service.)

A

B

FIGURE 86-4  A, Abdominal ultrasound image that shows a splenic infarct (arrow) in a 6-year-old female spayed bouvier des Flandres with Staphylococcus aureus infective endocarditis. B, Splenic infarct at necropsy. (Image courtesy University of California, Davis Veterinary Anatomic Pathology Service.) possibility of IE. Echocardiography is also useful for monitoring treatment of IE. Echocardiographic findings in infectious pericarditis include pericardial effusion, adhesions of the pericardium to the epicardium, and sometimes focal or diffuse pericardial thickening and hyperechogenicity (Figure 86-3). Restrictive disease is characterized by impairment of diastole, with decreased left ventricular internal dimensions during diastole, and variation of blood flow velocity across the mitral valve with the respiratory cycle (increased with expiration and decreased with inspiration). In addition, deviation of the interventricular septum into the left ventricle can occur during inspiration and into the right ventricle during expiration.

Abdominal Sonographic Findings

Sonographic abnormalities can be present in a variety of organs in dogs with IE and may reflect underlying disease processes (such as neoplasia or bacterial peritonitis) or septic thromboembolism. Infarction and hemorrhage secondary to thromboembolism can result in focal cavitary or hypoechoic lesions in the spleen (Figure 86-4) or focal hyperechoic or hypoechoic lesions in the kidney. Thrombi may be found in the iliac arteries or aorta.

Microbiologic Tests Culture

Routine blood cultures assist in identification of infecting pathogens and permit susceptibility testing. Ideally, at least three blood cultures should be obtained from separate sites within a 24-hour period. A suggested protocol for blood cultures is outlined in Chapter 3 (see Box 3-2). The use of separate venipuncture sites has been suggested but is not considered essential for diagnosis of human IE, although collection of specimens from indwelling catheters should be avoided.19 If a catheter-related bloodstream infection is suspected, collection of paired specimens has been recommended in humans, with one specimen collected from the catheter before removal and the other collected from a peripheral site.22 The skin should be prepared in the same manner used for surgery, and utmost care should be taken to avoid contamination with commensal bacteria. Because IE is generally associated with continuous bacteremia, positive results in only one of multiple bottles should be interpreted with caution. Positive results for Bacillus spp. or coagulase-negative staphylococci in a single bottle generally reflect contamination. The decision to perform anaerobic blood culture should be considered in light of the animal’s underlying disease process and client financial constraints. For example, anaerobic culture

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SECTION 5  Infections of Selected Organ Systems

may not be cost effective in dogs with IE, given the rare involvement of anaerobes in this condition. Anaerobes are more likely to be present in dogs with histories that suggest involvement of plant awn foreign bodies, bite wounds, or gastrointestinal compromise. False-negative blood cultures may occur as a result of lowlevel bacteremia or fungemia, the presence of fastidious or unculturable organisms such as Bartonella or anaerobes, insufficient specimen size, suboptimal specimen transport conditions, or recent antimicrobial treatment. Nevertheless, blood culture is still indicated in animals with a history of antimicrobial treatment, especially if antimicrobials have only been administered for 2 to 3 days. If an animal with IE is in stable condition, discontinuation of existing antibiotic treatment for several days (ideally 7 to 10 days) could be considered before blood cultures are obtained. Specific culture and serology for Bartonella is also indicated in dogs and cats with IE or suspected myocarditis (see Chapter 52). This should be considered even if routine blood cultures are positive, because polymicrobial infections that include Bartonella spp. and other bacteria can occur.11 Special media used to isolate Bartonella spp. (Bartonella α-Proteobacteria growth medium [BAPGM]) may also yield other fastidious bacteria such as Sphingomonas spp., the clinical significance of which requires further study.23 Serologic testing for Aspergillus antigen and Brucella antibody could also be considered for dogs with culture-negative IE (see Chapters 53 and 65). Attempts should also be made to isolate causative organism(s) from other sites that are suspected to be a source of infection based on the history and clinical findings. Appropriate specimens could include transtracheal or bronchoalveolar lavage specimens, urine, ascites fluid, wounds, or pleural effusion. Urinary tract infections may reflect ascending pyelonephritis or spread of bacteria from the blood into the urine. However, bacteria cultured from the urine do not always reflect those present in the bloodstream,11 so blood cultures should always be performed even when urine cultures are positive. Isolation of the same organism from the blood as well as an additional site facilitates interpretation of the significance of a single positive blood culture and aids decisions regarding appropriate antimicrobial drug treatment.

There are no specific pathologic findings in sepsis or bacteremia, but underlying causes such as pneumonia, pyometra, or peritonitis may be apparent. Microabscesses may be present in multiple tissues. Isolation of the same bacterial species from multiple different tissues supports a diagnosis of bacteremia. Pathologic findings in IE include valvular vegetations; avulsion or perforation of valvular structures; and gross and histopathologic evidence of infarction, widespread thrombosis, and CHF (Figure 86-5). The inflammatory process may be chronic, with lymphoplasmacytic and histiocytic cell infiltrates and fibrosis; or acute, suppurative, and fibrinous, with or without microscopically visible intralesional bacteria (see Figure 34-6). Bartonella IE is characterized by chronic inflammation and may be associated with valvular mineralization (Figure 52-6), whereas IE due to other microorganisms may be acute or chronic and is rarely associated with mineralization.11 Use of tissue gram stains and silver stains can reveal organisms within valvular vegetations. Necrotizing vasculitis may also be present in the lungs, myocardium, kidney, spleen, liver, and/or brain. Erythrophagocytosis has been described in reticuloendothelial tissues of dogs with IE due to gram-positive cocci. Membranoproliferative, membranous, or necrosuppurative glomerulonephritis may also be identified.8 Gross examination of the heart in animals with myocarditis may reveal focal or multifocal areas of myocardial pallor and/ or friability. The pericardium of dogs and cats with pericarditis may be thickened and discolored, and pericardial effusion may be present. Histopathology reveals acute or chronic inflammatory infiltrates, depending on the underlying cause, sometimes with intralesional bacteria, protozoa, or fungi.

Molecular Diagnosis Using the Polymerase Chain Reaction

Treatment and Prognosis

PCR assays have been used to rapidly detect bacterial DNA within whole blood and especially valvular tissue (obtained at necropsy) of animals with IE and are especially useful for detection of fastidious bacteria such as Bartonella spp. within heart valves (see Chapter 52). These assays use broad-range primers that target bacterial 16S ribosomal subunit DNA, and the identity of the organism is determined by sequence analysis of resulting PCR products. In one prospective study that examined the performance of a conventional broad-range bacterial PCR assay on whole blood for diagnosis of the etiology of IE in 18 dogs, there was no difference in the overall sensitivity of the PCR assay and culture, but the combined use of the PCR assay and blood culture was more sensitive than the use of either assay alone.20 This was because the PCR assay detected several fastidious organisms, which included Bartonella vinsonii, Brucella, and Granulicatella adiacens, but appeared less sensitive than culture for detection of less fastidious organisms such as streptococci. Studies that include larger numbers of dogs and cats and that examine the performance of other PCR assays such as real-time PCR assays

are required before broad-range bacterial PCR can be recommended for routine diagnosis of bacteremia and IE in dogs and cats, but PCR assays show promise when used in conjunction with blood cultures. Of major concern is the possibility of false positives with highly sensitive PCR assays due to detection of contaminating bacteria. Even in human medicine, evidence is considered insufficient to recommend the routine use of whole blood or serum real-time PCR assays for the diagnosis of culturenegative IE.19

Pathologic Findings

The mainstay of treatment of bacteremia, IE, sepsis, and bacterial myocarditis or pericarditis is early antimicrobial drug treatment. The initial choice of antimicrobial drugs should be based on knowledge of the prevalent bacterial species and their antimicrobial drug susceptibilities for each hospital and/or ­geographic region, as well as the likely source of infection (which can provide information about the likely bacterial species involved) (Tables 86-8 and 86-9). The presence or absence of IE and/or severe sepsis also affects treatment recommendations. In addition to antimicrobial drug therapy, the underlying cause of infection or chronic bacteremia should be identified and removed if possible. All catheters or devices should be removed and replaced at new sites if they are still needed. An attempt should be made to locate foreign bodies such as grass awns with imaging techniques and surgically remove them. Surgery may be required to resolve gastrointestinal compromise, such as occurs with foreign bodies, intestinal neoplasia, or torsion. Underlying immunosuppressive disease such as neoplasia or diabetes mellitus should be identified and treated if possible.

CHAPTER 86  Infections of the Cardiovascular System

A

B

C FIGURE 86-5  Gross pathology findings in a 12-year-old male neutered Irish water spaniel with Enterococcus durans infective endocarditis and widespread thromboembolic disease. A, Mitral valve. The leaflets are thickened and nodular. B, Left kidney. Multiple, variably sized, well-demarcated red foci with dark red rims and numerous well-­ demarcated tan slightly depressed foci are present. On cut surface, these foci extend to and beyond the corticomedullary junction as wedge-shaped lesions (white arrow). On one pole there is a 2.0 cm × 1.5 cm × 1.4 cm tan to brown-green abscess (white arrowhead). C, Spleen. Several well-demarcated lesions that measured 0.3 to 0.5 cm in diameter are present. (Courtesy the University of California, Davis, Veterinary Anatomic Pathology Service.)

839

Maintenance of optimal oxygen delivery to tissues and adequate tissue perfusion is essential for effective treatment of severe sepsis and septic shock. The use of goal-directed therapy for the management of severe sepsis/septic shock in the emergency room during the first 6 hours of hospitalization reduces mortality in humans.24 The first priority is to rapidly correct blood volume deficits. Liberal administration of IV crystalloids is a critical treatment for dogs and cats with sepsis. Colloids could also be used, but studies of human patients with septic shock have shown either no additional benefit of synthetic colloids such as hetastarch and the possibility of increased mortality25 or increased risk of development of acute kidney injury.26 Because hypoalbuminemia is common and affected animals often have increased vascular endothelial permeability, fresh frozen plasma may be needed to maintain appropriate intravascular volume. Excessive fluid administration may be associated with increased mortality, so careful monitoring of central venous pressure (CVP) is optimal. The endpoints of fluid resuscitation should be mean arterial pressure (MAP) of at least 65 mm Hg, adequate perfusion on physical examination, and a lactate clearance of at least 10% or a plasma lactate concentration less than 2 mmol/L.27 Fluid support is provided until a maximal target CVP of 8 to 12 mm Hg is reached or the listed goals are met. Tight glycemic control (targeting a blood glucose of <150 mg/dL) has been shown to increase the risk of serious adverse effects in humans and is not recommended at this time.26 However, blood glucose concentrations must be monitored and hypoglycemia avoided by the addition of supplemental dextrose to IV fluids. Bicarbonate therapy is not recommended to treat metabolic acidosis associated with tissue hypoperfusion because acidosis may be protective. Animals that develop acute lung injury (ALI) or ARDS (bilateral pulmonary interstitial to alveolar infiltrates that are not due to left-sided congestive heart failure with a PaO2/FiO2 ratio less than 300 [ALI] or less than 200 [ARDS]) may benefit from mechanical ventilation. For less severely affected animals, supplemental oxygen to maintain a SpO2 of at least 95% or PaO2 of at least 80 mm Hg is indicated. Arterial blood pressure must be monitored either by direct (arterial catheter) or indirect (oscillometric) means and maintained through treatment at or above 65 mm Hg. If hypotension persists despite adequate fluid loading as described previously, a diagnosis of septic shock is made and treatment with vasopressors such as dopamine, norepinephrine, or vasopressin may be indicated. The decision to use inotropes (such as dobutamine) first is based on echocardiographic evidence of impaired myocardial contractility (decreased fractional shortening on echocardiogram, or direct measurement of cardiac output via pulmonary artery catheter or other techniques). If inotropes are not indicated, then vasopressors should be prescribed to achieve an adequate blood pressure. Often treatment with dopamine (5-15 µg/kg/min) is attempted first. If an adequate MAP cannot be obtained, then norepinephrine (0.1-1 µg/kg/min), or vasopressin (0.5-4 mU/kg/min) can be added; additional vasopressors are always added and not substituted. If MAP cannot be maintained with norepinephrine, then vasopressin is added (or vice versa). Treatment of severe sepsis and septic shock with hydrocortisone has been controversial in human medicine. High doses of hydrocortisone increase mortality and should not be used.28,29 Relative adrenal insufficiency has been identified in dogs and cats30 with an apparent reversal of signs of shock

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SECTION 5  Infections of Selected Organ Systems

TABLE 86-8 Suggested Empiric Antimicrobial Drug Choices for IV Use in Dogs and Cats with Severe Sepsis or Septic Shock Pending the Results of Blood Culture and Susceptibility* Antimicrobial Drug

Spectrum

Ampicillin or clindamycin Activity against most and ­gram-negative ­bacteria, an aminoglycoside† ­methicillin-resistant ­staphylococci, ­streptococci, ­enterococci, and most ­anaerobes

Suspected Source of Infection Urinary tract, abdomen

Lung, urinary tract, Ampicillin or clindamycin Active against most abdomen, ­anaerobes, streptococci, and pyothorax a fluoroquinolone ­susceptible ­staphylococci, and ­aerobic gram-negative rods. Not active against some ­methicillin-resistant ­staphylococci, ­enterococci, and MDR gram-negative bacteria.

Comments Good first choice for most infections, ­except when the respiratory tract is involved. ­Consider use of ­ampicillin-sulbactam instead of ampicillin or addition of metronidazole if infection with ­penicillinase-producing ­anaerobes is ­possible (e.g., gastrointestinal compromise or plant foreign body, IE absent). Consider when MDR gram-negative ­bacteria, enterococci, or methicillin-resistant ­staphylococci are unlikely based on local ­resistance patterns and ­aminoglycosides are contraindicated because of toxicity or ­concerns related to drug penetration. ­Consider use of ­ampicillin-sulbactam instead of ­ampicillin or addition of m ­ etronidazole if ­infection with ­penicillinase-producing ­anaerobes is likely.

A carbapenem or Active against aerobic ­piperacillin-tazobactam ­gram-negative rods or ­including Pseudomonas, ­ticarcillin-clavulanate ­anaerobes, ­streptococci. Not ­active against ­methicillin-resistant ­staphylococci and some ­enterococci.

Abdomen, aspiration Use when infection with MDR ­gram-negative pneumonia bacteria and anaerobes is likely but ­aminoglycosides are contraindicated ­because of toxicity or concerns ­related to drug ­penetration (e.g., airway ­involvement). Consultation with a ­veterinary clinical specialist with a focused interest in infectious disease or antimicrobial pharmacology recommended before use.

Vancomycin and a carbapenem

Skin/soft tissue, ­urinary tract, abdomen

Active against methicillinresistant ­staphylococci, ­streptococci, MDR ­aerobic gram-negative bacilli, and anaerobes.

Last line for treatment of life-threatening mixed ­infection with MDR gram-negative ­bacteria, MDR ­enterococci, anaerobes, and ­methicillin-resistant staphylococci when aminoglycosides are ­contraindicated because of toxicity or ­concerns related to inadequate drug penetration. ­Consultation with a ­veterinary clinical specialist with a focused interest in infectious disease or antimicrobial pharmacology ­recommended before use.

Dosages for IV administration (normal renal function). See Chapter 8 for precautions. Amikacin, 15 mg/kg q24h (dogs), 10 mg/kg q24h (cats) Ampicillin sodium, 20 mg/kg q6h Ampicillin-sulbactam, 20 mg/kg q6-8h (dose based on ampicillin component) Clindamycin phosphate, 10 mg/kg q12h (dilute 1:10 in sterile saline and give slowly over 30 min) Gentamicin sulfate, 14 mg/kg q24h (dogs), 8 mg/kg q24h (cats) Ciprofloxacin hydrochloride, 10 mg/kg q24h Enrofloxacin, 5-20 mg/kg q24h (dogs); avoid in cats and never exceed 5 mg/kg, see important cautionary notes in Chapter 8 Imipenem-cilastatin, 5 mg/kg q6h (dilute in 100 mL sterile saline and give slowly over 30 min) Meropenem, 25 mg/kg q8h Piperacillin-tazobactam, 40 mg/kg q6h Ticarcillin-clavulanate, 50 mg/kg q6h Vancomycin, 15 mg/kg q8h (dilute in sterile saline and give slowly over 30 min) MDR, Multidrug-resistant. *Spectrum should be reduced once culture and susceptibility results become available. †In human patients, amikacin is less nephrotoxic than gentamicin and may be preferable for treatment of dogs and cats with severe sepsis or septic shock.

CHAPTER 86  Infections of the Cardiovascular System

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TABLE 86-9 Suggested Empiric Antimicrobial Drug Treatment for IV Use in Dogs and Cats with Infective Endocarditis Pending the Results of Blood Culture and Susceptibility* Antimicrobial Drug

Spectrum

Comments

Ampicillin and gentamicin

Covers all major causes of IE including most MDR Streptococci, Bartonella, ­methicillin-resistant staphylococci, ­gram-negative rods. Consider substitution of gentamicin enterococci, aerobic gram-negative with a fluoroquinolone if impairment of renal function is rods present.

Vancomycin and a carbapenem

Methicillin-resistant ­staphylococci, enterococci, gram-negative ­aerobes

Use only when infection with methicillin-resistant ­staphylococci is likely, local susceptibility patterns ­preclude use of other ­antimicrobials, and aminoglycosides are ­contraindicated because of toxicity (e.g., refractory ­pyoderma; ­history of ­orthopedic surgery, antimicrobial treatment, or ­hospitalization in the last year; or contact with other animals or humans known to have methicillin-resistant ­staphylococcal infections). Consultation with a ­veterinary clinical specialist with a focused interest in infectious disease or antimicrobial pharmacology ­recommended before use.

For drug doses, see bottom of Table 86-8. *Spectrum should be reduced once culture and susceptibility results become available.

with the treatment of hydrocortisone in one reported case.31 Current recommendations for human patients are to consider hydrocortisone therapy when hypotension responds poorly to adequate fluid resuscitation and vasopressors. Hydrocortisone is preferred to dexamethasone and dosed at 1 mg/kg IV q6h. Other supportive treatments could include the H2 blocker famotidine or proton pump inhibitors to manage gastrointestinal ulceration. The use of red blood cell transfusions to maintain a hemoglobin concentration above 7.0 g/dL may be beneficial. Recombinant activated protein C (drotrecogin alfa) was the only approved drug specifically indicated to treat severe sepsis in human patients, but was withdrawn from the market after a worldwide trial showed that it failed to improve outcome for severe sepsis and septic shock.32 An anti-TLR4 receptor compound, eritoran tetrasodium, also failed to improve outcome. Human intravenous immunoglobulin has been used to treat humans with sepsis, with improved survival. Whether this also translates to dogs and cats is not known.33,34

Bacteremia and Septic Shock It is well established in human patients that the earlier appropriate antimicrobial drug treatment is initiated in sepsis, the lower the mortality. With every hour that antimicrobial drug therapy is delayed after documented hypotension, mortality in affected people increases by 8%.35 Because of the urgent need to initiate antimicrobial drug treatment, initial treatment should be intravenous, bacteriocidal and broad spectrum, and should occur within an hour of diagnosis of severe sepsis and septic shock, pending the results of culture and susceptibility. Reasonable initial choices for septic shock in dogs and cats are outlined in Table 86-8. In order to avoid overuse of antimicrobial drugs reserved for treatment of resistant bacterial infections, the drug spectrum should be reduced according to the results of culture and susceptibility as soon as those results are available. Treatment should be continued for at least 2 weeks, although the optimum duration of treatment may vary depending on the underlying cause. Repeat blood cultures

could be considered if fever or clinical abnormalities that suggest ongoing infection persist after 7 days of treatment, but the need for and timing of follow-up blood cultures in animals that are responding adequately to treatment requires further study.

Infective Endocarditis Guidelines for the treatment of IE in humans have been published and updated.19,36 However, many factors considered for treatment of human patients do not apply to dogs and cats, including the availability of valve replacement; penicillin allergy in some patients; the higher incidence of infections with ­methicillin-resistant staphylococci and vancomycin-resistant enterococci; evidence that supports use of specific antimicrobial drugs or drug combinations; and the possibility of long hospitalization times for parenteral antimicrobial drug therapy. Indications for cardiac surgery in humans include severe acute regurgitation or valve obstruction with refractory pulmonary edema; uncontrolled infection with enlarging vegetations; persistent fever and positive blood culture for at least 10 days after appropriate antimicrobial drug treatment is commenced; ­infection caused by fungi or multidrug-resistant bacteria; large vegetations (>10 mm) in association with embolic episodes or other complications; and isolated large vegetations (>15 mm).19 For dogs and cats, valve replacement is not generally possible, so treatment must rely on antimicrobial drugs and resolution of any predisposing factors. Where the local prevalence of multiresistant gram-negative bacteria and methicillin-resistant staphylococci is low, a combination of ampicillin and an aminoglycoside is a good choice for empiric treatment of IE pending the results of culture and susceptibility. Where bloodstream infections with multiresistant gram-negative bacteria and methicillin-resistant staphylococci are locally prevalent, empiric recommendations made for human patients could be considered for dogs and cats pending the results of culture and susceptibility, provided there is a chance of treatment success in the absence of valve replacement. When severe sepsis is absent and IE follows an indolent

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SECTION 5  Infections of Selected Organ Systems

TABLE 86-10 Suggested Antimicrobial Drugs for Treatment of Major Causes of Infective Endocarditis in Dogs and Cats Once Cause is Known* Cause

Preferred Treatment

Oral Equivalent

Methicillin-susceptible ­Staphylococcus spp.

Ampicillin IV Flucloxacillin IV (β-lactamase producer) Ampicillin-sulbactam IV (β-lactamase producer)

Amoxicillin PO Flucloxacillin PO Clavulanic acid–amoxicillin PO

Methicillin-resistant but ­rifampin-susceptible ­Staphylococcus spp.

Gentamicin IV and rifampin PO or Vancomycin IV* and rifampin; IV ­ trimethoprim-sulfas, chloramphenicol or ­doxycycline with or without rifampin could also be considered if tolerated and the ­organism is susceptible.

None

Streptococcus spp.

Benzylpenicillin IV Ampicillin IV

Amoxicillin PO

Penicillin-susceptible enterococci

Ampicillin IV

Amoxicillin PO

Penicillin-resistant enterococci

Vancomycin IV* and gentamicin IV. If possible, consider other options based on culture and susceptibility.

None. Linezolid could be considered as an oral alternative.*

Aerobic gram-negative rods

Base on susceptibility Ampicillin IV and gentamicin IV Ampicillin IV and fluoroquinolone IV Imipenem-cilastatin or meropenem IV* Or base on susceptibility (other options, such as injectable cephalosporines, ­piperacillin-tazobactam, or ­ticarcillin-clavulanate may be effective)

Bartonella spp.

Ampicillin IV and gentamicin IV Doxycycline IV and rifampin PO

Doxycycline PO and rifampin PO

Aspergillus spp.

Voriconazole or posaconazole

Voriconazole or posaconazole

*In part based on recommendations for treatment of human IE. The reader is referred to the text for precautionary statements on the use of vancomycin, linezolid, and carbapenems such as meropenem in animals.

course, it is recommended in human patients that antimicrobial treatment be withheld pending the results of culture and susceptibility, or a combination of penicillin with or without low-dose gentamicin (1 mg/kg IV q12h) be administered until results are available. Aminoglycosides are used at this low dose, twice daily for their synergistic activity with penicillin against enterococci and viridans streptococci, which are uncommon causes of IE in dogs. Empiric treatment protocols that have activity against drugresistant bacteria are used in human patients pending results of culture and susceptibility when severe sepsis is present, such as vancomycin and low-dose gentamicin (no risk factors present for gram-negative bacterial infection), or vancomycin and meropenem (risk factors present for multiresistant Enterobacteriaceae and Pseudomonas infection). However, the use of vancomycin and meropenem in dogs and cats has been controversial and may not be permitted or feasible in some geographic locations. Recommendations for treatment of IE in dogs once the microbial etiology is known are shown in Table 86-10. Intravenous antimicrobial drugs should be continued in the hospital for as long as possible (ideally at least 7 to 10 days). A switch to oral medications is not recommended for human IE patients because of poor activity when compared with intravenous medications.19 However, oral antibiotic treatment has been used with success to treat some dogs with IE and may be the only viable option. At-home treatment with intravenous drugs through peripheral indwelling catheters, vascular access ports,

or subcutaneous injections may be possible for some dogs, but dog, owner, and drug factors should be considered very carefully and proper client education is critical. If oral antimicrobial drugs are used, bacteriocidal drugs with good and reliable oral bioavailability are preferable. Medical treatment should be continued for at least 4 to 6 weeks, until the underlying disease process has resolved and valvular lesions have also resolved based on echocardiographic examinations. Echocardiography should be repeated after 4 weeks, or earlier if there is evidence of complications (CHF, embolic disease) or inadequate treatment response. Successful resolution of IE is associated with reduction in size and consolidation of valvular vegetations and increase in valvular echogenicity. With unsuccessful treatment, lesions enlarge or remain unchanged, and/or new lesions may appear on other valves.8

Infective Pericarditis In addition to specific antimicrobial drug treatment, surgery may be required in dogs with infective pericarditis in order to debride the pericardium and restore cardiac diastolic function. This carries a significant risk of mortality; if feasible, referral to an experienced cardiac surgeon is recommended.

Prognosis The prognosis for dogs and cats that develop septic shock, severe sepsis, IE, myocarditis, or pericarditis is guarded, and depends

CHAPTER 86  Infections of the Cardiovascular System on underlying disease processes, the severity of organ damage, and the etiologic agent or agents. In a study of 114 dogs seen at a veterinary teaching hospital with sepsis secondary to gastrointestinal tract leakage, overall mortality rate was 47.4%.37 The mortality rate was 40/57 (70%) for dogs with MODS and 14/57 (25%) for dogs without MODS; 50% of the dogs in the study had MODS. In another study, mortality rate in dogs due to IE was at least 40/71 (56%), and median survival time was only 54 days.8 Factors strongly associated with negative outcome in dogs with IE were thrombocytopenia, increased serum creatinine concentration, renal complications, thromboembolic complications, and Bartonella infection.

Prevention Methods to prevent bloodstream infections and sepsis include limiting the use of invasive devices and catheters unless absolutely necessary and attention to routine hygiene in the hospital to minimize nosocomial infections. Other measures include management of immunosuppressive disorders such as diabetes mellitus, minimizing use of immunosuppressive drugs such as glucocorticoids, and prompt attention to wounds or other underlying infections that have the potential to spread to the bloodstream. The role of prophylactic antimicrobial drugs to prevent bacteremia and sepsis has been controversial. Beneficial outcomes have been reported when antimicrobials are used to prevent infection after chemotherapy. In one study, the use of a 14-day course of trimethoprim-sulfadiazine reduced morbidity in dogs

CASE EXAMPLE Signalment: “Betsy,” a 6-year-old female spayed bouvier des Flandres from Fallon, NV

History: Betsy was seen at the UC, Davis, VMTH emergency

service for treatment of possible sepsis. One week before she was evaluated she had been lethargic and reluctant to stand while on a camping trip. Over the next 2 days she lost interest in food and water and seemed disoriented and unable to see, then developed dark, liquid diarrhea. She was taken to the local veterinary clinic 3 days later where her temperature was 106.3°F (41.3°C), she was unable to stand, and blood work showed moderate thrombocytopenia and hypoglycemia. An injection of ceftiofur (unknown dose), cephalexin (15.4 mg/kg PO q8h), and cimetidine (4.5 mg/kg PO q12h) were prescribed and she was referred for further evaluation. Betsy was up to date on vaccinations for distemper, canine adenovirus, parvovirus, and rabies.

Physical Examination:

Body Weight: 64 kg. General: Obtunded, laterally recumbent, T = 106.2°F (41.2°C), HR = 170 beats/min, RR = 50 breaths/min, mucous membranes dark red, CRT <1 s. Eyes, Ears, Nose, and Throat: Hypopyon and conjunctivitis were present in both eyes, and there was marked mucopurulent ocular discharge bilaterally. Serous nasal

843

with osteosarcoma or lymphoma during the first 14 days after treatment with doxorubicin.38 In human patients a 7-day course of a fluoroquinolone during the expected neutropenic period after chemotherapy for solid tumors and lymphomas reduced the incidence of fever, probable infection, and hospitalization.39 Prophylactic treatment with antimicrobial drugs could be considered for animals with severe neutropenia (<500 cells/µL), although more studies are required that examine the prevalence of bacteremia in neutropenic animals and the benefits of prophylactic antimicrobial drug treatment. Finally, prophylactic antimicrobial drug treatment has been suggested for dogs and cats with congenital heart defects that undergo dental procedures, but evidence to support the need for this practice is lacking.

Public Health Aspects Dogs with bloodstream infections may harbor bacteria such as methicillin-resistant Staphylococcus aureus that have the potential to colonize humans; these bacteria may not only be present in the bloodstream, but also at other anatomic sites of colonization such as the gastrointestinal tract or nasal cavity. Therefore, routine precautions should be taken when these dogs are handled, with special attention to hand hygiene and fomite disinfection. Dogs and cats with signs of cardiovascular infection may also be infected with important human pathogens such as Salmonella spp., Bartonella spp., Brucella spp., and Rickettsia rickettsii, so caution should be taken when handling blood from animals with cardiovascular infections, and needle-stick injuries should be avoided.

discharge was present bilaterally. There was moderate dental calculus and gingivitis. Several small gingival ulcerations were present. Integument: Generalized cutaneous petechiation was noted. Musculoskeletal: The dog was nonambulatory and unable to stand. Body condition score was 7/9. Cardiovascular: No arrhythmias or murmurs were auscultated. Very strong, synchronous femoral pulses were palpated bilaterally. Respiratory: Increased bronchovesicular sounds were present in all fields. Abdominal Palpation: Moderate abdominal distention was noted. Palpation was difficult because of recumbency and the large size of the patient. All Other Systems: No abnormalities detected.

Laboratory Findings:

Venous Blood Gas: pH 7.351, pCO2 31 mm Hg, pO2 41.4 mm

Hg, base deficit 7.8 mmol/L, ionized calcium 1.14 mmol/L, bicarbonate 16.3 mmol/L, lactate 4.2 mmol/L, glucose 59 mg/dL.

CBC:

HCT 47.8% (40%-55%) MCV 68.5 fL (65-75 fL) MCHC 36.2 g/dL (33-36 g/dL) WBC 25,250 cells/µL (6000-13,000 cells/µL) Neutrophils 17,675 cells/µL (3000-10,500 cells/µL) Band neutrophils 3030 cells/µL Lymphocytes 505 cells/µL (1000-4000 cells/µL)

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SECTION 5  Infections of Selected Organ Systems

Monocytes 3788 cells/µL (150-1200 cells/µL) Platelets 23,000 platelets/µL (150,000-400,000 platelets/µL) Marked neutrophil toxicity was evident.

Serum Chemistry Profile:

Anion gap 25 mmol/L (10-24 mmol/L) Sodium 146 mmol/L (145-154 mmol/L) Potassium 3.8 mmol/L (3.6-5.3 mmol/L) Chloride 113 mmol/L (108-118 mmol/L) Bicarbonate 12 mmol/L (16-26 mmol/L) Phosphorus 2.9 mg/dL (3.0-6.2 mg/dL) Calcium 10.3 mg/dL (9.7-11.5 mg/dL) BUN 34 mg/dL (5-21 mg/dL) Creatinine 1.6 mg/dL (0.3-1.2 mg/dL) Glucose 59 mg/dL (64-123 mg/dL) Total protein 5.9 g/dL (5.4-7.6 g/dL) Albumin 3.0 g/dL (3.0-4.4 g/dL) Globulin 2.9 g/dL (1.8-3.9 g/dL) ALT 58 U/L (19-67 U/L) AST 130 U/L (19-42 U/L) ALP 356 U/L (21-170 U/L) Cholesterol 377 mg/dL (135-361 mg/dL) Total bilirubin 0.7 mg/dL (0-0.2 mg/dL) Urinalysis: SGr 1.028; pH 8.0, 3+ protein (SSA), 1+ bilirubin, 2+ hemoprotein, no glucose or ketones, 1-3 WBC/HPF, 4-10 RBC/HPF, 0-2 granular casts, few triple phosphate crystals, no bacteria seen. Coagulation Panel: PT 8.3 s (7.5-10.5 s), PTT 19.3 s (9.0-12.0 s), fibrinogen 506 mg/dL (90-255 mg/dL), D-dimer >2.0 µg/mL (0-0.25 µg/mL). Arterial Blood Gas (Post–Fluid Bolus)(FiO2 65%): pH 7.278, pCO2 40 mm Hg, pO2 62.7 mm Hg, oxygen saturation 82.3%, ionized calcium 1.36 mmol/L, bicarbonate 17.6 mmol/L, base deficit 7.5 mmol/L, lactate 2.8 mmol/L.

Imaging Findings:

Abdominal Ultrasound: The liver was hypoechoic and

enlarged. The gallbladder wall was edematous. Bright mesentery surrounded the left limb of the pancreas. There was a dilated, fluid-filled duodenum. Multiple splenic infarcts were identified, some of which were anechoic, consistent with the presence of fluid (see Figure 86-4). The spleen was enlarged, and a splenic venous thrombus was present. Echocardiography: The left ventricle and atrium were normal in size. There was laminar flow through the pulmonary artery and aorta. The right heart chambers were subjectively normal in size. There was no tricuspid regurgitation. There was a hyperechoic, oscillating vegetative lesion associated with the anterior mitral valve leaflet and possibly with the aortic valve. A small jet of mitral regurgitation was observed. No aortic insufficiency was observed. Microbiologic Testing: Aerobic urine culture (cystocentesis specimen): No growth. Aerobic and anaerobic blood culture (3 specimens): Large numbers of Staphylococcus aureus from the first 2 of 3 bottles. The isolate was susceptible to all antimicrobials tested. Treatment and Outcome: Before the results of diagnostic tests were available, treatment was initiated with shock doses of IV fluids (6 liters of lactated Ringer’s solution IV as a bolus over 1 hour). Ticarcillin-clavulanate (50 mg/ kg IV q6h), enrofloxacin (10 mg/kg IV q24h), famotidine (0.5 mg/kg IV q12h), prednisolone acetate ophthalmic

suspension (1 drop in each eye [OU] q6h), and atropine ophthalmic solution (1 drop OU q12h) were administered. Temperature, respiratory rate, and perfusion parameters were monitored by physical examination after each liter of fluid was administered. Systolic blood pressure was 180 mm Hg throughout the resuscitation period. Lactated Ringer’s solution with 30 mEq KCl/L and 2.5% dextrose was then continued at 4.7 mL/kg/hr, with monitoring of arterial blood pressure and urine output. Three units of fresh frozen plasma were administered because total plasma protein dropped to 4.2 g/dL, colloid osmotic pressure was 11.6 mm Hg, and further volume resuscitation was indicated. When severe hypoxemia in the face of maximal supplemental oxygen administration (PaO2/FiO2 ratio = 65) was identified on arterial blood gas analysis, the dog was anesthetized and mechanical ventilation commenced. Mean arterial pressure (measured via an arterial catheter) dropped to 45 mm Hg, so a dopamine constant rate infusion was administered to maintain arterial blood pressure >65 mm Hg; a diagnosis of septic shock was made. Subsequently, diagnoses of DIC, hypoglycemia, ARDS, and MODS became apparent. The dog developed melena, and hemorrhagic fluid with a PCV of 15% appeared in the endotracheal tube. Despite additional colloid support with fresh frozen plasma and hetastarch, colloid osmotic pressure remained low and pitting edema of the distal limbs developed. Creatinine increased to 2.6 mg/dL, albumin dropped to 1.4 mg/dL, globulin to 1.3 g/ dL, PCV to 22%, and liver enzyme activities increased (ALT 299 U/L, AST 408 U/L, ALP 617 U/L, total bilirubin 5.4 mg/ dL). Ultimately, the dog became oliguric (urine output 0.35 mL/kg/hr). Furosemide and mannitol constant rate infusions had no effect to increase urine output. Because of the poor prognosis, euthanasia was elected. Necropsy Findings: Gross necropsy findings included mucosal petechiations throughout the oral cavity, hemorrhagic nasal discharge, generalized icterus, subcutaneous edema, and 2 liters of cloudy, dark red fluid with floating fibrin strands within the abdomen. The spleen was enlarged and contained a large infarct (see Figure 864). A large infarct was also identified in one kidney, and there were multiple foci up to 5 mm in diameter throughout both kidneys. Multiple, slightly depressed, and nodular foci up to 1 cm in diameter were present on the surface of the liver and extended into the parenchyma. The mitral valve leaflets were thickened and rough, with thick fibrin clots adhering to their surfaces. Ecchymoses were present on the left ventricular wall. The lungs were diffusely wet, firm, and red and failed to collapse when the thorax was opened. They also contained multiple 2- to 4-mm tan foci. Histopathology revealed moderate chronic, active neutrophilic mitral valve endocarditis with a few grampositive intra­lesional cocci; acute multifocal neutrophilic and necro­tizing myocarditis; acute multifocal neutrophilic and necrotizing pneumonia with hemorrhage; acute diffuse alveolar septal necrosis with hemorrhage, fibrin, and hyaline membrane formation (ARDS); multifocal acute necrotizing and neutrophilic hepatitis, tubulointerstitial nephritis, and splenitis with thrombi and infarcts; hepatic congestion and bile stasis; and severe neutrophilic endophthalmitis with hypopyon. Enterococcus spp. and Continued

CHAPTER 86  Infections of the Cardiovascular System

Acinetobacter spp. were cultured in enrichment broth from the heart valve. Diagnosis: Staphylococcus aureus IE with septic shock. Comments: This dog had mitral valve IE and widespread thromboembolic complications as a result of over­ whelming S. aureus infection. Notably, a heart murmur was absent; echocardiography was performed when infarction was recognized on abdominal sonography. MODS with septic shock was present based on the diagnosis of sepsis (endocarditis with positive blood cultures and 4 of 4 SIRS criteria met) and dysfunction of the coagulation, hepatic,

SUGGESTED READINGS Greiner M, Wolf G, Hartmann K. A retrospective study of the clinical presentation of 140 dogs and 39 cats with bacteraemia. J Small Anim Pract. 2008;49:378-383. Lewis DH, Chan DL, Pinheiro D, et al. The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells. J Vet Intern Med. 2012;234:457-482. Sykes JE, Kittleson MD, Chomel BB, et al. Clinicopathologic findings and outcome in dogs with infective endocarditis: 71 cases (19922005). J Am Vet Med Assoc. 2006;228:1735-1747. Sykes JE, Kittleson MD, Pesavento PA, et al. Evaluation of the relationship between causative organisms and clinical characteristics of infective endocarditis in dogs: 71 cases (1992-2005). J Am Vet Med Assoc. 2006;228:1723-1734.

REFERENCES 1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864-874. 2. Greiner M, Wolf G, Hartmann K. A retrospective study of the clinical presentation of 140 dogs and 39 cats with bacteraemia. J Small Anim Pract. 2008;49:378-383. 3. Dow SW, Curtis CR, Jones RL, et  al. Bacterial culture of blood from critically ill dogs and cats: 100 cases (1985-1987). J Am Vet Med Assoc. 1989;195:113-117. 3a. Lewis DH, Chan DL, Pinheiro D, et al. The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells. J Vet Intern Med. 2012;234:457-482. 4. Schumann RR. Old and new findings on lipopolysaccharide-­ binding protein: a soluble pattern-recognition molecule. Biochem Soc Trans. 2011;39:989-993. 5. Brady CA, Otto CM, Van Winkle TJ, et al. Severe sepsis in cats: 29 cases (1986-1998). J Am Vet Med Assoc. 2000;217:531-535. 6. Lombard CW, Buergelt CD. Vegetative bacterial endocarditis in dogs; echocardiographic diagnosis and clinical signs. J Small Anim Pract. 1983;24:325-339. 7. MacDonald KA, Chomel BB, Kittleson MD, et  al. A prospective study of canine infective endocarditis in northern California (19992001): emergence of Bartonella as a prevalent etiologic agent. J Vet Intern Med. 2004;18:56-64. 8. Sykes JE, Kittleson MD, Chomel BB, et al. Clinicopathologic findings and outcome in dogs with infective endocarditis: 71 cases (1992-2005). J Am Vet Med Assoc. 2006;228:1735-1747. 9. Taboada J, Palmer GH. Renal failure associated with bacterial endocarditis in the dog. J Am Anim Hosp Assoc. 1989;25:243-251.

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cardiovascular, and pulmonary systems. Aggressive treatment with broad-spectrum antimicrobial drugs, fluids, colloids, pressors, and mechanical ventilation was not successful despite the in  vitro susceptibility of the S. aureus isolated. The significance of the Enterococcus spp. and Acinetobacter spp. isolated from the valve at necropsy is unclear; they may have represented contaminants or may have been present as part of a polymicrobial infection. The source of bacteremia and endocarditis was not apparent. The blood culture results became available the day the dog was euthanized.

10. Peddle GD, Drobatz KJ, Harvey CE, et  al. Association of periodontal disease, oral procedures, and other clinical findings with bacterial endocarditis in dogs. J Am Vet Med Assoc. 2009;234: 100-107. 11. Sykes JE, Kittleson MD, Pesavento PA, et al. Evaluation of the relationship between causative organisms and clinical characteristics of infective endocarditis in dogs: 71 cases (1992-2005). J Am Vet Med Assoc. 2006;228:1723-1734. 12. Calvert CA. Valvular bacterial endocarditis in the dog. J Am Vet Med Assoc. 1982;180:1080-1084. 13. Sisson D, Thomas WP. Endocarditis of the aortic valve in the dog. J Am Vet Med Assoc. 1984;184:570-577. 14. Que YA, Haefliger JA, Piroth L, et  al. Fibrinogen and fibronectin binding cooperate for valve infection and invasion in Staphylococcus aureus experimental endocarditis. J Exp Med. 2005;201:1627-1635. 15. Piroth L, Que YA, Widmer E, et al. The fibrinogen- and fibronectinbinding domains of Staphylococcus aureus fibronectin-binding protein A synergistically promote endothelial invasion and experimental endocarditis. Infect Immun. 2008;76:3824-3831. 16. Declue AE, Sharp CR, Harmon M. Plasma inflammatory mediator concentrations at ICU admission in dogs with naturally developing sepsis. J Vet Intern Med. 2012;26:624-630. 17. Osterbur K, Whitehead Z, Sharp CR, et al. Plasma nitrate/nitrite concentrations in dogs with naturally developing sepsis and noninfectious forms of the systemic inflammatory response syndrome. Vet Rec. 2011;169:554. 18. DeClue AE, Osterbur K, Bigio A, et al. Evaluation of serum NTpCNP as a diagnostic and prognostic biomarker for sepsis in dogs. J Vet Intern Med. 2011;25:453-459. 19. Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2012;67:269-289. 20. Meurs KM, Heaney AM, Atkins CE, et  al. Comparison of polymerase chain reaction with bacterial 16S primers to blood culture to identify bacteremia in dogs with suspected bacterial endocarditis. J Vet Intern Med. 2011;25:959-962. 21. Wiinberg B, Jensen AL, Johansson PI, et al. Thromboelastographic evaluation of hemostatic function in dogs with disseminated intravascular coagulation. J Vet Intern Med. 2008;22:357-365. 22. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheterrelated infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49:1-45. 23. Davenport AC, Mascarelli PE, Maggi RG, et al. Phylogenetic diversity of bacteria isolated from sick dogs using the BAPGM enrichment culture platform [Abstract]. J Vet Intern Med. 2012;26: 786-787.

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SECTION 5  Infections of Selected Organ Systems

24. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377. 25. Reinhart K, Perner A, Sprung CL, et  al. Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med. 2012;38:368-383. 26. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125-139. 27. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303:739-746. 28. Annane D, Bellissant E, Bollaert PE, et  al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301:2362-2375. 29. Moran JL, Graham PL, Rockliff S, et al. Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective. Crit Care. 2010;14:R134. 30. Burkitt JM, Haskins SC, Nelson RW, et al. Relative adrenal insufficiency in dogs with sepsis. J Vet Intern Med. 2007;21:226-231. 31. Peyton JL, Burkitt JM. Critical illness-related corticosteroid insufficiency in a dog with septic shock. J Vet Emerg Crit Care. 2009;19:262-268. 32. Xigris [drotrecogin alfa (activated)]: Market Withdrawal—­ Failure to Show Survival Benefit. 2011. http://www.fda.gov/Safety/ MedWatch/SafetyInformation/SafetyAlertsforHumanMedical Products/ucm277143.htm, Last accessed January 23, 2013. 33. Turgeon AF, Hutton B, Fergusson DA, et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med. 2007;146:193-203.

34. Kreymann KG, de Heer G, Nierhaus A, et  al. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med. 2007;35(12):2677-2685. 35. Kumar A, Roberts D, Wood KE, et  al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589-1596. 36. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J. 2009;30:2369-2413. 37. Kenney EM, Rozanski EA, Rush JE, et  al. Association between outcome and organ system dysfunction in dogs with sepsis: 114 cases (2003-2007). J Am Vet Med Assoc. 2010;236:83-87. 38. Chretin JD, Rassnick KM, Shaw NA, et  al. Prophylactic trimethoprim-sulfadiazine during chemotherapy in dogs with lymphoma and osteosarcoma: a double-blind, placebo-controlled study. J Vet Intern Med. 2007;21:141-148. 39. Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med. 2005;353:988-998.