Introduction
With significant changes to the epidemiology of infective endocarditis (IE) in recent years, it is important to highlight which pathogens are the major causes of this disease. In the United States, Staphylococcus aureus has overtaken Streptococcus species as the most common etiology for IE, contributing approximately 30% of all cases. This shift has resulted from a combination of increased use of prosthetic valves, cardiac devices such as pacemakers, and increased injection drug use [ ]. The trends among key gram-positive organisms are shown in Fig. 3.1 [ ]. Understanding the host–pathogen interaction at the heart of IE begins with the classification of pathogens and understanding of their origin, virulence factors, and antimicrobial resistance patterns.
Pathogens associated with native-valve endocarditis
Staphylococcus aureus
S. aureus is a ubiquitous gram-positive coccus with a classic “grape-like” cluster morphology on Gram stain. The name is derived from the Latin word aureus meaning golden after the yellow-gold appearance of the colonies on culture media. This organism grows aerobically but is also a facultative anaerobe. All staphylococci are catalase positive, which distinguishes them from streptococci. The coagulase test is used to differentiate S. aureus (coagulase positive) from most other clinically relevant staphylococci, collectively known as coagulase-negative staphylococcus (CoNS) [ ]. Staphylococci, including S. aureus , are common commensals of the skin and mucus membranes. Humans serve as the primary reservoir with approximately 30% of the population being colonized with S. aureus . The widespread prevalence coupled with several virulence factors make S. aureus the common cause of IE [ ]. These characteristics highlight why a blood culture positive for S. aureus is serious medical event. S. aureus , except in the rarest of rare circumstances, should never be considered a contaminant when recovered from the blood. S. aureus bacteremia should always prompt the clinician to consider the possibility of IE.
Virulence factors
S. aureus produces an extensive array of virulence factors (the most relevant of which are covered in this text). Functions range from growth and colonization promotion, host invasion, immune system evasion, and tissue destruction.
In a broad sense, nasal carriage represents a conglomerate of virulence factors. While nasal carriage has been shown to increase the risk of S. aureus infection, limited evidence has demonstrated that colonized individuals may present with less severe disease as compared to their noncolonized counterparts [ ]. Further evidence has suggested that this colonization produces an adaptive immunity which could account for the decreased severity [ ]. Once invasion has occurred, S. aureus has been found to live both extra- and intracellularly. In the extracellular environment, the organism is more susceptible to the immune system including opsonization through the complement cascade, leukocyte phagocytosis, and antibody binding. To counter these immune system processes, S. aureus can express multiple surface proteins including clumping factor A, protein A, and multiple compliment inhibitors [ , ].
S. aureus produces a multitude of virulence factors that contribute directly to the destruction of host cells and tissues. The best studied is the Panton–Valentine leucocidin (PVL) toxin. First described in 1932, the PVL toxin acts by forming a pore in the membrane of host defense cells, including leukocytes, which ultimately lead to cell death [ ]. This toxin is commonly associated with community-acquired methicillin-resistant S. aureus (MRSA) infections [ ].The role of this toxin in nasal colonization remains unclear; however, there has been a link to severe, necrotizing skin and soft tissue infections as well as pneumonia [ ].
Epidemiology
Local epidemiology is an important consideration given extensive geographic variation of resistance patterns. In the United States, for instance, MRSA rates have been historically higher in the south and northeast, with decreased resistance encountered in the western states [ ]. Europe has seen similar variability ranging from 0.5% MRSA in Iceland as compared to 44% in Greece during the same time frame (1999–2003) [ ]. Resistance rates are also known to vary within different populations within the same region: pediatrics versus adults, inpatient versus outpatient, units within the same hospital, injection drug users versus noninjection drug users, etc.
Methicillin-sensitive Staphylococcus aureus
Prior to the discovery and widespread utilization of penicillin for the treatment of S. aureus bacteremia, the mortality rates exceeded 80% [ ]. Following the introduction of penicillin, mortality rates fell precipitously; however, resistance followed shortly thereafter. First recognized in 1942 [ ], S. aureus produces a β-lactamase enzyme encoded by the blaZ gene which hydrolyzes the β-lactam ring permanently inactivating the compound [ ]. Penicillin, aminopenicillins (amoxicillin, ampicillin), and ureidopenicillins (piperacillin) are all effectively hydrolyzed by these extracellular β-lactamases.
In an effort to combat the development penicillin resistance, methicillin was introduced in 1961 [ ]. Methicillin belongs to a subclass of penicillins, known as anti-staphylococcal penicillins, which are immune to blaZ -encoded β-lactamase hydrolyzation. Methicillin has fallen out of favor due to toxicity concerns, specifically the development of interstitial nephritis. However, oxacillin and nafcillin (also anti-staphylococcal penicillins) remain in widespread use.
Established literature further supports that patients treated with β-lactams experience improved outcomes as compared to vancomycin as definitive therapy for MSSA bacteremia and endocarditis [ ]. However, not all β-lactams are created equal. First-generation cephalosporins, such as cefazolin, have been found to be non-inferior to anti-staphylococcal penicillins. However, some evidence suggests that cefazolin has improved tolerability compared to nafcillin [ ]. Still, the choice of β-lactam agent for MSSA is a continued debate in the infectious disease community. Of noted importance, retrospective evidence suggests that β-lactam/β-lactamase inhibitor combinations (ampicillin/sulbactam and piperacillin/tazobactam) may have higher mortality rates when compared to oxacillin, nafcillin, and cefazolin [ ].
Methicillin-resistant Staphylococcus aureus
Methicillin resistance was first reported in Britain in 1961, shortly after the introduction of anti-staphylococcal penicillins [ ]. As discussed, S. aureus becomes resistant to penicillin due to the production of a β-lactamase whereas it becomes resistant to anti-staphylococcal penicillins and cephalosporins via an altered binding site on the target penicillin-binding proteins (PBPs). PBPs are essential enzymes required for bacterial cell wall synthesis and specifically function during the cross-linking stage of cell wall synthesis. S. aureus produces four PBPs, PBP1-4. The mecA gene encodes for an altered PBP2 named PBP2a. This altered protein has a decreased binding affinity for most β-lactams which results in high-level resistance [ ]. Vancomycin remains a mainstay in the treatment of severe MRSA infections, but given its nephrotoxicity and dosing challenges, there has been a push to discover and utilize newer, safer alternatives.
Vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus
Resistance finds a way. Vancomycin has been a mainstay in the treatment armamentarium against MRSA since the 1950s. Vancomycin-resistant S. aureus was first encountered in the United States in 2002. However, it remains quite rare with less than 20 cases reported [ ]. Resistance is conferred by the vanA operon acquired from enterococcal plasmids during distinct conjugation events. Vancomycin binds to the D-Ala-D-Ala peptidoglycan precursors which ultimately interfere with cell wall synthesis. vanA alters the cell wall synthesis by encoding for D-Ala-D-Lac which is not susceptible to vancomycin binding and thus confers resistance [ ].
A more frequently encountered isolate than VRSA is vancomycin-intermediate S. aureus (VISA). These organisms experience reduced susceptibility to vancomycin without full resistance. This phenotype is often preceded by a mixed population of vancomycin-susceptible and vancomycin-intermediate isolates termed heterozygous VISA (hVISA) [ ].The mechanisms behind the development of VISA and the transition to hVISA are outside the scope of this text and remain an area of investigation. The important takeaway is that populations of hVISA exposed to prolonged glycopeptides (vancomycin) are associated with the progression to VISA [ ]. Thus, when hVISA is suspected, alternative therapies such as daptomycin, ceftaroline, or linezolid are often employed.
Alpha-hemolytic streptococci
Alpha-hemolytic streptococci possess the same universal characteristics of all streptococci: facultatively anaerobic, gram-positive cocci in pairs or chains that do not produce catalase or coagulase [ ]. Alpha-hemolysis refers to the green discoloration noted when the organism is plated on blood agar due to erythrocyte destruction.
The viridans group streptococci encompass several species of alpha- and nonhemolytic streptococci that commonly colonize the oropharynx and upper respiratory tract. “Viridans” is derived from the Latin word for “green,” referring to alpha-hemolysis. Taxonomy of this group includes subspecies such as mitis , sanguinis , mutans , and salivarius , among many others [ ]. Laboratory molecular diagnostics have drastically altered the identification of individual streptococcal subspecies, though conventional techniques remain in clinical use at various institutions (lack of bile solubility and resistance to optochin are distinguishing characteristics of viridans group streptococci). They are suspected to comprise roughly 20% of native IE cases [ ], though epidemiologic estimates of disease burden vary globally. Virulence factors include production of extracellular dextran [ ] that enables adherence to cardiac valves as well as varying degrees of penicillin resistance compared to nondextran-producing streptococci, though clinical onset of IE is typically subacute.
The Streptococcus anginosus group consists of three subspecies: anginosus , constellatus , and intermedius [ ]. They represent commensal flora of the oropharyngeal and gastrointestinal microbiome and can be differentiated from other Lancefield group streptococci by the relatively small size of colony formation on routine agar media. S. anginosus only comprises up to 5% of native IE cases though it tends to predispose to pyogenic abscess formation [ ]. Virulence factors include enhanced fibronectin binding, platelet aggregation, and thrombin-like activity via hydrolytic enzyme production [ ]. S. anginosus is typically penicillin sensitive, though decreased penicillin susceptibility and penicillin resistance have previously been described in the literature.
Streptococcus pneumoniae is the major cause of bacterial pneumonia, otitis media, sinusitis, and meningitis, though it is also an uncommon cause of endovascular infections such as IE [ ]. Nasopharyngeal colonization rates peak during the second and third year of life, then decline to approximately 10% of adults. Invasive pneumococcal disease tends to disproportionately affect adults >65 years of age, those with underlying organ dysfunction (heart, lung, kidney, liver, and spleen) and those with various immunodeficiencies (e.g., complement deficiency, antibody defects, neutropenia, etc.). S. pneumoniae can be identified microbiologically by alpha-hemolysis, susceptibility to optochin, as well as solubility in bile salts. Virulence factors include a polysaccharide capsule that enables the ability to resist opsonization, phagocytosis, and intracellular killing [ ]. The vast majority of clinical disease is caused by 23 serotypes targeted by the pneumococcal polysaccharide vaccine (PPSV-23) [ ]. Comprehensive vaccination efforts of the pediatric population with PCV-7 and PCV-13 have also contributed to declining incidence rates of invasive pneumococcal disease in adults. Reduced penicillin susceptibility and penicillin resistance is increasingly common for S. pneumoniae , though beta-lactams remain standard of care antimicrobial treatment.
Enterococcus species
Enterococcus were previously classified as group D streptococci, though have since been codified independently. The most common pathogenic subspecies are Enterococcus faecalis and Enterococcus faecium , which normally constitute the gastrointestinal, hepatobiliary, and genitourinary flora and comprise 10% of native-valve IE cases. Of these, E. faecalis is by far the more common cause of IE. They produce smooth, gray colonies that are either alpha- or nonhemolytic and are capable of growing in media containing 6.5% NaCl and at temperatures between 10 and 45°C [ ]. Virulence factors include production of aggregation substance proteins that facilitate enterococcal adherence to cardiac vegetations in animal models [ ] as well as extracellular surface proteins that are involved in biofilm formation [ ]. Antimicrobial treatment is complicated due to relatively high MICs for penicillins and cephalosporins compared to other streptococci due to the diminished affinity of enterococcal cell wall PBPs as well as emerging vancomycin-resistant enterococci (primarily E. faecium ) due to a mutation in vanA and vanB (most commonly), which replaces the D-Ala-D-Ala terminus of cell wall peptidoglycan with D-Ala-D-Lac, thereby preventing vancomycin from inhibiting cell wall cross-linking. Treatment often consists of two active agents, classically ampicillin combined with an aminoglycoside, though use of ampicillin combined with ceftriaxone has become more common in recent years.
Nutritionally variant streptococci
First isolated in 1961 from patients with endocarditis, nutritionally variant streptococci (NVS) were felt to be subspecies of S. mitis because of their characteristics [ ]. Over time, based on 16S ribosomal RNA sequence analysis, they were reclassified into two genera with four species that cause human infection: Abiotrophia defectiva , Granulicatella adiacens , Granulicatella elegans , and Granulicatella para-adiacens [ ]. They are part of the normal human flora of the upper respiratory and gastrointestinal tracts. All NVS species are fastidious, and require pyridoxal or l -cysteine for growth in subculture media. They can look pleomorphic with variable Gram-staining, and produce small colonies that are either nonhemolytic or alpha-hemolytic on blood agar [ ].
NVS account for a small percentage of IE cases, and tend to cause indolent infections usually in the setting of underlying valvular disease. Besides difficulty with isolation and identification, in vitro antimicrobial susceptibility testing of NVS is challenging for most routine clinical laboratories to perform. All NVS isolates are susceptible to vancomycin without high-level resistance to aminoglycosides, but have highly variable susceptibility to penicillin, cephalosporins, clindamycin, and daptomycin, based on multiple in vitro studies [ ]. Another large study of 599 clinical isolates of NVS from all over the United States showed uniform susceptibility to vancomycin, >90% susceptibility to levofloxacin, with significant species and geographic differences in penicillin and ceftriaxone susceptibility; A. defectiva was least susceptible to penicillin [ ]. In vitro and experimental animal models have shown synergy between penicillin or vancomycin and aminoglycosides.
IE due to NVS tends to have greater morbidity and mortality compared to that due to other streptococci. One study comparing cases of IE due to NVS versus other streptococci showed 14% versus 5% mortality, 33% versus 11% embolization events, and 33% versus 18% rates of heart failure [ ]. Another study of 33 cases noted surgery was required in 50% of cases, with overall two-thirds of cases surviving at 10 years [ ]. Relapses can be seen even in cases with strains that are susceptible to penicillin. Thus species-level identification can help in treatment choices when susceptibility testing cannot be done and combination therapy is favored for 4–6 weeks.
Streptococcus gallolyticus
These gram-positive cocci usually express the Lancefield group D antigen, are an important cause of IE, and are noteworthy due to the strong association between bacteremia or IE caused by them and the presence of colonic malignancy or disease in adults [ ]. There is also an association between hepatic disease and bacteremia, with impaired function of the reticuloendothelial system postulated to lower bacterial clearance from the portal or systemic circulation [ ]. Formerly called the Streptococcus bovis group, they have been reclassified recently, which has been a source of confusion for clinicians due to the missed significance of their isolation in cultures given the new species names. S. bovis biotype I (the most common one to cause IE and bacteremia) is now designated S. gallolyticus ssp. gallolyticus ; the S. bovis biotype II/1 is S. infantarius ssp. coli while biotype II/2 is S. gallolyticus ssp. pasteurianus [ ]. Colonies are usually small, are nonhemolytic on blood agar, and grow in 40% bile and hydrolyze esculin [ , ]. Differentiation between the species can be challenging and most laboratories use automated systems, gene sequencing, or other methods for subspecies identification.
Symptoms of IE are often subacute and can be nonspecific with fever, night sweats, anorexia, and weight loss. Vegetation size can be large, often >10 mm compared to IE caused by other streptococcal and non-streptococcal pathogens (50% vs. 20% vs. 34%) [ ]. Presence of bacteremia should prompt echocardiography and colonoscopy in all cases, especially if due to S. gallolyticus ssp. gallolyticus , and an assessment of liver function. Penicillins, ceftriaxone, carbapenems, vancomycin, daptomycin, and linezolid work reliably [ , ]. The AHA recommends use of either a β-lactam (penicillin G or ceftriaxone) or vancomycin alone, or in combination with an aminoglycoside, for 2–6 weeks, depending on the penicillin MIC of the isolate and whether native- or prosthetic-valve IE is being treated [ ].
Listeria monocytogenes
Listeria are facultatively anaerobic, short, nonbranching, gram-positive rods that have characteristic tumbling motility on light microscopy [ ]. Only L. monocytogenes causes human infection, often in relation to sporadic foodborne exposure, and affects neonates, the elderly, the pregnant patient, and those with defective cell-mediated immunity [ ]. While it causes a gastrointestinal illness often and shows tropism for the central nervous system, frequently causing meningoencephalitis and brain abscess, it can cause bacteremia without a clear focus, and rarely IE, affecting both native and prosthetic valves [ ]. A review of 68 cases published in the literature found that treatment with penicillin or ampicillin alone or in combination with gentamicin was successful in most cases, with vancomycin plus gentamicin a reasonable alternative; surgery is not always indicated [ ].
Beta-hemolytic streptococci
Streptococci are gram-positive cocci bacteria that are catalase negative and appear in pairs or chains on Gram stain. They are facultatively anaerobic and can colonize the human skin, oropharynx and gastrointestinal/genitourinary tracts. Beta-hemolytic streptococci demonstrate complete hemolysis when plated on blood agar, differentiating them from alpha-hemolytic streptococci. The specific cell wall carbohydrate antigens of these streptococci determine their Lancefield grouping. Of these Group A ( Streptococcus pyogenes ) and Group B ( Streptococcus agalactiae ) cause IE, but only do so rarely (~1%–2% of all IE cases). Resistance to penicillin has only rarely been observed for S. pyogenes or S. agalactiae ; treatment of beta-hemolytic streptococci IE classically consists of penicillin with an aminoglycoside frequently used in combination [ , ].
S. pyogenes is a major cause of human disease but is an uncommon cause of IE. It can more commonly cause pharyngitis and skin infections (erysipelas) along with necrotizing infections. An important virulence factor is the M-protein which is a fibrillar protein on the cell wall that prevents phagocytosis and can contribute to cell adhesion while preventing complement fixation [ ]. A hyaluronic acid capsule is another key virulence factor that prevents phagocytosis. Secreted streptolysin O is toxic to erythrocytes and to neutrophils via pore formation in cell membranes. In addition, this decreases phagocytosis [ ].
S. agalactiae is known to cause neonatal sepsis, urinary tract infections, and skin infections. Risk factors for S. agalactiae IE include HIV infection, diabetes mellitus, malignancy, and cirrhosis. Approximately one-third of the population is colonized in the GI tract and perineum. Similar to S. pyogenes , S. agalactiae has a polysaccharide capsule that helps prevent phagocytosis. In addition, it secretes a beta-hemolysin/cytolysin that damages host cells via pore formation. It also produces a C5a peptidase which interferes with complement fixation [ ].
HACEK group
The HACEK group is comprised of gram-negative bacteria from five genera that are responsible for <1% of IE in the United States [ ]. They are associated mostly with native left-sided valvular disease in patients with either underlying heart disease, poor dentition, or both. IE due to HACEK classically presents with a subacute course including weeks of symptoms. In previous decades these organisms were often considered agents of “culture-negative” endocarditis requiring prolonged incubation for identification, but more recent blood culture techniques include increased yield of culture during routine incubation [ ]. Patients with HACEK IE are of a younger median age than non-HACEK and have a lower overall mortality [ ].
Haemophilus parainfluenzae remains the most common etiology of HACEK IE. It is a pleomorphic nonmotile gram-negative bacillus that is part of the normal respiratory flora and can cause both upper and lower respiratory infections. A classic infection linked to H. parainfluenzae is an acute exacerbation of chronic obstructive pulmonary disease. Given its ability to cause non-IE infections, presence of H. parainfluenzae in the blood has only a 55% positive predictive value of IE [ ]. While resistance to penicillin is present in one-third of isolates, aminopenicillins, ceftriaxone, levofloxacin, tetracycline, and carbapenems have reliable (95%–100%) activity in vitro [ , ].
Aggregatibacter species were formerly classified either as Actinobacillus or Haemophilus species and are the second most common cause of HACEK IE. These organisms ( Aggregatibacter actinomycetemcomitans, Aggregatibacter aphrophilus , and Aggregatibacter segnis ) are human flora from the oral cavity and are associated with periodontitis and dental plaque [ ]. These are nonmotile and facultatively anaerobic bacteria; A. actinomycetemcomitans (the most common) is often found in mixed infection with Actinomyces species in invasive infections. Bacteremia with these organisms is highly predictive of endocarditis [ ]. Penicillin resistance has been reported in one-fifth of isolates [ ].
The Cardiobacterium species, Cardiobacterium hominis and Cardiobacterium valvarum , are pleomorphic, nonmotile, and facultatively anaerobic. While they represent normal oral flora they are also respiratory flora and can colonize the female genital tract [ ]. As non-IE infections with Cardiobacterium spp. are rare, bacteremia has a >90% positive predictive value for endocarditis [ ]. Penicillin may be inactivated by beta-lactamases in some isolates [ ].
More classically associated with infected human bites, IE from Eikenella corrodens is the least common of the HACEK genera. These facultatively anaerobic bacteria are human oral flora and associated with dental infections, and also can be transmitted to wound via licking or biting leading to skin infections. Bacteremia is not a strong predictor of IE as other infections are more common [ ]. Penicillin resistance has been reported, but prevalence is low [ ].
Kingella kingae and Kingella denitrificans are normal flora of the human oropharyngeal and genitourinary tract that are facultatively anaerobic and nonmotile. While it is uncommon among the HACEK for causing endocarditis, K. kingae has been associated with septic arthritis in young children and has been associated with meningitis in this population as well [ ]. Bacteremia has less than a 50% positive predictive value of endocarditis [ ]. Approximately one-fourth of isolates have been found to have resistance to penicillin and aminopenicillins, while susceptibility to cephalosporins was found to be 100% [ ].
Pathogens associated with injection drug use
Epidemiology
The distribution of pathogens in patients who inject drugs (PWIDs) who develop IE has changed over time. Prior to the 1980s, S. aureus represented a plurality of cases (40%) with Pseudomonas aeruginosa and Candida spp. making up 15%, respectively [ ]. More recent studies indicate that S. aureus now accounts for the majority of IE cases in PWID (nearly 60%) [ , ]. However, most cases of Pseudomonas IE are related to injection drug use. Serratia marcescens and Candida IE also remain closely associated with injection drug use [ ]. While S. marcescens is within the Enterobacteriaceae family, it is a rarely part of endogenous flora and is considered more of an environmental pathogen with outbreaks being associated with water [ ]. Endocarditis due to P. aeruginosa or S. marcescens can result from mixing drugs with unboiled tap or toilet water prior to injecting [ ]. Common practices including licking needles, crushing drugs in mouth, using saliva exposed to oropharyngeal microbiota including viridians streptococci and oral gram-negative bacteria. Other practices such as skin popping, wiping the injection site with saliva increases the risk of infections, bacteremia, and IE with skin flora. PWIDs have higher rates of skin colonization with staph compared to those who do not inject [ ]. Rarely PWIDs will present with IE due to unusual bacteria, including Corynebacterium spp. , Fusobacterium spp. , Clostridium spp., and Neisseria spp. Polymicrobial IE is seen among PWID with as many as eight different pathogens have been recovered from blood cultures of an individual patient [ , ]. Presentation of symptoms of IE in PWIDs differs due to the increased rate of right-sided IE in this population. As such, lower rates of murmur, systemic embolization, and vascular and immunologic phenomena are observed.
Pseudomonas aeruginosa
The opportunistic pathogen P. aeruginosa is an obligate aerobic gram-negative bacillus. It is an environmental organism that can be found in the soil and in water. The colonies often have a green or blue-green pigment due to production of pyocyanin and pyoverdine. This organism is not considered to be part of the healthy human microbiome, but can colonize cells in the respiratory tract, urinary tract, and skin (e.g., burns) and can use multiple virulence factors to cause infections at those sites and other sites [ ].
Key virulence factors in P. aeruginosa include a polar flagellum and multiple pili. The flagellum helps to orient the bacillus and provides motility which may be required for acute infection. The pili allow adherence to cells and facilitate bacterial aggregation on surfaces. Aggregation allows P. aeruginosa to utilize another key virulence factor: biofilm. Biofilm is an extracellular polysaccharide matrix which also includes proteins and lipids. The biofilm can function as a shield, protecting the bacteria from immune cells and antimicrobials, and an anchor, preventing displacement. Within biofilm, P. aeruginosa can persist in low growth that can lead to decreased antimicrobial activity. In addition, pyocyanin increases oxidative stress in host phagocytes, decreasing their effectiveness [ ].
Antimicrobial resistance is a hallmark of P. aeruginosa infections, and mechanisms of resistance are diverse. Both efflux pumps and decreased outer membrane permeability are intrinsic mechanisms that produce drug resistance to multiple classes of antimicrobials. Multiple chromosomal β-lactamase including AmpC and OXA-50 hydrolyze β-lactam antimicrobials as well. Acquired mechanisms of resistance include DNA gyrase mutations, production of aminoglycoside-modifying enzymes, and hyperproduction or modification of β-lactamases [ , ].
Pseudomonal IE is usually treated with combination medical therapy, classically an anti-pseudomonal β-lactam along with an aminoglycoside for 6 weeks of therapy, though fluoroquinolone therapy may also be used as the second agent. Left-sided IE has a very high mortality rate without valve replacement so surgical consultation is indicated [ , ].
Candida species
Candida species are budding yeasts that range in size from 1 to 8 μm. Pathogenic Candida spp. can also be part of normal human flora, predominantly on mucosa, skin, and gastrointestinal tracts. They are the most common cause of fungal endocarditis [ ]. Candida endocarditis was first reported in 1940 caused by Candida parapsilosis in a PWID [ ]. Increased injection drug use in the United States has been associated with candidemia in the last decade [ ]. Other risk factors for Candida IE include health contact such as central venous catheters, prosthetic valves, implantable cardiac devices, immunosuppression, antibiotics, and hemodialysis [ ].
The most common fungal species reported in IE is Candida albicans (44%) followed by C. parapsilosis (27%), Candida tropicalis (10%), and Candida glabrata (6%) [ ]. Some risk factors for IE vary due to differences between species: C. parapsilosis can be associated with venous catheters and parenteral nutrition, whereas C. tropicalis has been linked with malignancy and chemotherapy. Of note, C. glabrata is haploid and has a higher rate of fluconazole resistance than C. albicans. [ ].
Candida IE has a higher mortality rate than bacterial IE and requires aggressive workup and treatment. Candida endophthalmitis complicates candidemia at a higher rate than endocarditis so ophthalmological evaluation is indicated in suspected Candida IE [ , , ]. Given the high mortality risk, surgical evaluation is indicated and treatment with a lipid formulation amphotericin B or high-dose echinocandin is recommended for initial treatment [ , ].
Zoonotic pathogens associated with endocarditis
Brucella species
Brucella is a small, nonmotile gram-negative coccobacilli that can cause human infection from zoonotic spread from contact of infected animal tissue, inhalation of infected aerosolized particles, or consumption of infected animal products such as meat or dairy. There are three species that more commonly cause zoonotic infection: Brucella melitensis, Brucella abortus , and Brucella suis [ ]. Cardiovascular complications are the leading cause of death in all cases of brucellosis [ ]. While this disease can be found more worldwide in general populations, it is associated with occupational hazards such as meat packing, dairy farming, cattle ranching, veterinary medicine, or microbiology lab technicians in the Western countries. Clinically, acute infection can present with systemic symptoms such as fevers, chills, night sweats, weight loss, and arthralgias for days or weeks. Cardiovascular infections are categorized as chronic infections and usually present with end organ damage consistent with endocarditis for which workup of conventional causes is negative [ ].
Diagnosis of Brucella endocarditis by the gold standard of culture is difficult since this organism is very fastidious to grow especially in chronic infections. The microbiology lab should be notified that there is concern of Brucella on differential diagnosis so appropriate precautions can be made. Cultures should be held for 6 weeks to improve yield. Serologies can be used for diagnosis in the appropriate clinical setting. A fourfold increase in serum agglutination test (SAT) titers staggered 2 weeks apart is definitive for infection [ ]. A presumptive diagnosis can be made when SAT titer is greater than 1:160, though it should be noted that areas where Brucella spp. is endemic may have a higher baseline SAT titer (1:160) compared to nonendemic areas (1:80) [ ]. Molecular PCR can aide in diagnosis though this is limited by availability and lack of standardization among PCR assays.
While there are no formal treatment guidelines, it usually consists of triple therapy with doxycycline, rifampin for at least 12 weeks, and an aminoglycoside for the first 4 weeks. Valve replacement surgery has also been shown to decrease overall mortality when paired with antimicrobial therapy compared to medical therapy alone, though there remain no formal indications for surgical intervention [ ].
Bartonella species
One of the most common causes of culture-negative endocarditis stems from Bartonella spp., a fastidious gram negative, with the bulk of cases originating from Bartonella henselae and Bartonella quintana [ ]. Cases involving B. quintana are usually associated with unsanitary environmental conditions where lice, the primary vector, are abundant. B. henselae infections result from exposure to cats that are bacteremic with this pathogen from either flea bites or bodily fluid exposure from other cats. Prior to valvular disease and prosthetic-valve replacement are human risk factors that can lead to IE [ ]. There is an increased incidence of immune-complex-mediated glomerulonephritis with many of these cases presenting as necrotizing ANCA-positive glomerulonephritis [ ].
Diagnosis is challenging given the fastidious growth of Bartonella spp. in culture. This diagnosis is frequently made by serology via enzyme-linked immunosorbent assay and indirect fluorescence antibody testing, which can be limited by cross-reactivity with Chlamydia spp. and Coxiella burnetii [ ]. In addition, IgM may be low in acute infection leading to a false negative [ ]. Histopathology of the valve using Warthin–Starry staining can also aide in diagnosis. Molecular diagnostics, specifically DNA amplification and 16s rRNA sequencing, have helped improve sensitivity and specificity of testing even with prior antibiotic therapy, though these techniques are not widely available [ ]. While there are no specific guidelines for therapy, expert opinion typically suggests 2 weeks of initial aminoglycoside therapy with 6 weeks of concurrent doxycycline therapy [ ].
Q fever
In cases of chronic Q fever secondary to C. burnetii, a small, obligate intracellular gram-negative rod, the most common presentation is subacute endocarditis which typically can occur within 12 months of initial infection [ ]. Q fever endocarditis is the second most common cause of culture-negative endocarditis only behind Bartonella spp. The inoculation with this bacterium occurs from inhalation of aerosolized infected animal bodily fluids such as birth products, urine, feces, or ingestion of contaminated unpasteurized dairy products. This bacterium is found mostly around the world. The primary risk factor for developing endocarditis is preexisting valvular disease. Other risk factors include pregnancy and immunocompromised status [ ].
Diagnosis is difficult since both TTE and TEE rarely visualize vegetative lesions. When lesions are noted, typically on the aortic and mitral valves, they are often small [ ]. Because of this, diagnosis is confirmed when a patient meets Duke’s Criteria and has serological findings consistent with chronic infection such as Phase I IgG titers > 1:800. Serological data can be supportive, though not confirmatory, when Phase I IgG titers range between 1:128–1:800 [ ]. Otherwise, diagnosis can also be supported by positive culture, 16s rRNA PCR, or immunohistochemistry of the cardiac valve. Further supportive evidence can be made by positive 16s rRNA PCR of the blood [ ].
Treatment of Q fever endocarditis consists of doxycycline 100 mg po bid and hydroxychloroquine 200 mg po TID. Duration of treatment is a minimum of 18 months or until phase I IgG is < 1:200 [ ]. Surgical consult for valve replacement should also be considered since many of these patients have issues with hemodynamic flow [ ].
Pathogens associated with prosthetic-valve endocarditis
Prosthetic-valve endocarditis (PVE) classically has two phases: early and late. This is defined by a time of 1 year from valve replacement. In early PVE S. aureus predominates, with CoNS as the second most common; CoNS are a very rare cause of native-valve IE [ ]. In late PVE, the microbiology mirrors more closely native-valve IE with streptococci and enterococci more common, but the risk of CoNS persists in this period. The risk of Candida IE is increased in PVE, along with other bacteria including Corynebacterium spp. [ , ].
Coagulase-negative staphylococci
All CoNS are gram-positive cocci that test catalase positive. The Staphylococcus epidermidis group, which includes S. epidermidis, Staphylococcus hominis, Staphylococcus haemolyticus , and Staphylococcus capitus along with a few other species, has similar microbiological and clinical characteristics. They are distinguished from Staphylococcus lugdunensis by three key features: S. lugdunensis uniquely can produce clumping factor which can cause a false-positive catalase test, S . epidermidis group nearly always causes PVE, S. lugdunensis causes native-valve IE 80% of the time, and S . epidermidis is resistant to beta-lactam antimicrobials in the majority of cases, while S. lugdunensis often remains susceptible to oxacillin. Clinically S. lugdunensis in a blood culture should be treated similarly to S. aureus [ ].
The S . epidermidis group is skin flora that are distributed throughout the surface of the body, with some variations in species from site to site. Their main virulence factors involve adherence to foreign body surfaces and production of biofilm. They have limited ability to invade d e novo , but can adhere first to the endovascular catheters, cardiac devices, or prosthetic joints. They then adhere to some extracellular proteins such as fibrinogen and collagen. The production of biofilm protects the bacteria from both the host immune system and antimicrobial agents [ ].
S . epidermidis group frequently harbors genes that allow for the expression of PBP2a, which confers beta-lactam resistance. These proteins are encoded by mecA gene in most cases [ ]. As such, treatment of systemic S . epidermidis group infections usually involves vancomycin therapy, though combination therapy is indicated for PVE with Staphylococcus spp. [ ].
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