https://doi.org/10.5812/pedinfect.41067

Periodontitis, Bacteremia and Infective Endocarditis: A Review Study

authors:

avatar Shree V. Dhotre 1 , avatar Milind S. Davane 2 , avatar Basavraj S. Nagoba 2 , *

Department of Microbiology, M.M. Patel Public Charitable Trust’s, Ashwini Medical College and Hospital, Kumbhari-413006, Solapur, M.S., India
Department of Microbiology, Maharashtra Institute of Medical Sciences and Research, Latur-413 531, M.S., India
Archives of Pediatric Infectious Diseases: Vol.5, issue 3; e41067
published online: January 16, 2017
article type: Review Article
received: July 26, 2016
revised: October 31, 2016
accepted: November 21, 2016

how to cite: Dhotre S V, Davane M S, Nagoba B S. Periodontitis, Bacteremia and Infective Endocarditis: A Review Study. Arch Pediatr Infect Dis. 2017;5(3):e41067. https://doi.org/10.5812/pedinfect.41067.

Abstract

Context:

Earlier evidences show that periodontitis with inflamed and ulcerated crevicular or pocket epithelium surrounding the teeth may be a portal of entry for bacteria into the bloodstream. A newly proposed causal model predicts that an early bacteremia may affect the endothelial surface of the heart over many years and promote valve thickening rendering the heart valve susceptible to vegetation by a later bacteremia that would culminate over a few weeks into fulminant infection.

Evidence Acquisition:

In this review, various published sources of information pertaining to periodontitis, bacteremia and infective endocarditis were reviewed. This review is focused on the role of the viridans group streptococci (VGS) in periodontitis, bacteremia and infective endocarditis.

Results:

The viridans group streptococci present in the oral cavity were the most important causes of bacteremia following dental procedures and infective endocarditis. In most of the studies, significantly higher rates of bacteremia occurring in patients with periodontitis than patients without periodontitis indicated that periodontitis opens up the route for oral streptococci to gain entry into the bloodstream. In addition, the significantly higher rates of isolation of the VGS from the patients of infective endocarditis with periodontitis showed that there was a positive association between periodontitis, infective endocarditis and the VGS.

Conclusions:

The literature survey presented in this review suggests that there is a definite relation between periodontitis, bacteremia and infective endocarditis and would provide valuable data for the future dentists as well as the physicians, because a large proportion of the world’s population lives a lifetime with periodontitis. Moreover, infective endocarditis still remains a cause of concern as this disease is a cause of considerable morbidity and mortality regardless of modern antimicrobial and surgical treatment.

1. Context

Periodontitis is a chronic inflammatory disease associated with destruction of connective tissue of gingiva, periodontal ligament and alveolar bone following untreated or improperly treated gingivitis (1). Bacterial biofilms (dental plaque) predominantly composed of the viridans group streptococci (VGS) are the primary etiological factors for the inflammatory process of gingiva leading to subsequent destruction of periodontal tissues (2). Loe et al. (1965) and Theilade et al. (1966) demonstrated that withdrawal of tooth brushing results in formation of plaque on the teeth and causes gingivitis in periodontally healthy individuals within 10 - 21 days (3, 4). Periodontitis is most commonly seen in adults and occasionally found in children.

Periodontitis induced inflammation may promote the oral VGS to gain access into the blood stream and eventually to the heart, resulting in the development of cardiovascular ailment such as infective endocarditis. There are several reports which have shown that the viridans streptococci are the most common cause of infective endocarditis (5, 6) and the viridans group streptococcal bacteremia is more frequently inducible in patients with severe periodontal disease (7, 8). However, there are no reports on the collective analysis of the oral VGS and its relation with infective endocarditis in cases of periodontitis.

In the light of the emerging scientific evidences, questioning the role of VGS as oral commensal. A better understanding of the distribution of viridans streptococci in the dental plaque and its role in oral induced bacteremia, periodontitis and infective endocarditis needs to be investigated.

A comprehensive analysis of the VGS and its relation to the oral inflammatory disease like periodontitis and systemic diseases like infective endocarditis would provide a clear understanding of the periodontitis-infective endocarditis relationship, which may assist health care providers in their efforts to detect both of the diseases earlier. Gingivitis and periodontitis are treatable and preventable conditions; therefore, their identification as risk factors for infective endocarditis would have a major impact on infective endocarditis prevention.

2. Pathogenesis

Periodontitis is initiated as a simple marginal gingivitis, which further progresses to ulceration of crevicular epithelium. It proliferates further and gradually involves deeper portions of the periodontium leading to the advance lesion of the periodontitis. Gingivitis induced by the VGS and other bacteria in dental plaque, leads to the gingival inflammation caused by organisms present at the gingival margin (9). In the early stages, the supragingival bacterial plaque contains primarily Gram-positive aerobic bacteria, predominantly the VGS. Subsequently this composition changes to a more anaerobic, Gram-negative flora, which increases in time (10). An inflammatory response to this microbial challenge is mounted by the host leading to increased flow of the gingival crevicular fluid. Associated clinical changes involve increased edema, reddening and an increased tendency to bleeding in response to mechanical probing. The development and progression of plaque-induced gingival inflammation can be influenced substantially by systemic factors, both inherited and related to the environment (11).

Periodontitis results from a chronic inflammatory response to the subgingival bacteria (12). The main causative factor is the formation of a microbial biofilm predominantly composed of VGS, at the gingivocrevical margin, which evokes an inflammatory response in the gingival tissue and progresses deeper into the periodontal tissue (13). Oral bacteria including the VGS, gather and coaggregate in colonies on the tooth surface, first supragingivally and thereafter subgingivally. With time, Gram-negative anaerobic microorganisms become more prevalent in the subgingival plaque, thereby enhancing its pathogenicity (14). The “red complex” that appears later in connection with the development of the biofilm consists of species of periodontal pathogens, such as, Porphyromonas gingivalis, Treponema denticola and Tannerella forsythensis, which occur more commonly in deeper tissue (10).

The mechanisms underlying the progression of gingivitis into periodontitis have not yet been established. Possibly, the bacteria themselves and/or their products (e.g., lipopolysaccharides- bacterial endotoxin) acquire the ability to penetrate deeper into the connective tissue, and/or perturbation of the host defenses allows deeper penetration (15).

The ecological plaque theory proposes that the increasing quantity of plaque provides an appropriate environment for colonization by and growth of more pathogenic bacteria (16). In this manner, the inflammatory response results in subgingival environmental changes and alters the balance of the resident microflora, which changes the gingivally healthy situation to gingivitis. Bacteria then move further through the junctional epithelium and into underlying tissues, thereby predisposing to periodontitis (17).

3. Periodontitis and Bacteremia

Periodontal infections are inflammatory diseases. These are caused by a bacterial biofilm (dental plaque) that affects the tissues surrounding the teeth. In gingivitis, the infection is generally limited to the gingiva and the condition is reversible by taking due care of oral hygiene. However, in periodontitis, the inflammation extends deeper into the tissues affecting the attachment apparatus of the tooth. The occurrence of gingivitis and moderate periodontitis is very common and their prevalence increases with age (9).

Inflammation of periodontal tissue leads to deepening of the gingival crevice and formation of periodontal pockets, acting as a reservoir for a large number of microorganisms. Periodontal infections affect the oral tissues, in addition bacteria may get entry into the bloodstream via ulcerated inflamed crevice and pocket epithelium, and the adjacent gingival microcirculation. Invasive dental procedures and normal daily activities, such as chewing and tooth brushing are the important predisposing factors for entry of microbes into bloodstream (7, 18-22). Bacteremia and low-grade inflammation because of periodontal infections may carry a risk for systemic conditions. It has been observed that periodontitis is one of the causes or consequences of developing atherosclerosis. Microorganisms or their products present in circulation may promote pathogenesis and enhance local inflammatory changes in vessel walls and thereby may promote process of clotting and clot formation (23). The periodontal disease has also been reported to be an important risk factor for nonhemorrhagic stroke (24). Several other studies have also found that there is the oral-systemic link in various conditions like infective endocarditis and cardiovascular diseases, premature low birth weight deliveries, and diabetes mellitus (25-27).

Studies have shown that smoking increases the frequency and severity of periodontal disease (26). Smoking is associated with poor oral hygiene and hence, smokers have increased accumulations of plaque, calculus and increase the susceptibility of the host to bacterial growth (26, 27). Smoking also influences the periodontal disease through a variety of systemic effects such as decreased chemotaxis and phagocytosis by both oral and peripheral neutrophils, and reduced antibody production, which enhances the breakdown of periodontal tissues in smokers. As a result, smokers with chronic periodontitis have more attachment and bone loss, more furcation involvement and deeper pockets, consequently smoking may enhance periodontitis induced bacteremia (28-32).

Most of the earlier studies show that inflamed and ulcerated crevicular or pocket epithelium around the teeth in patients with periodontitis may act as a portal of entry for bacteria into the bloodstream. In a study by Lockhart et al. (18), it has been observed that gingival bleeding after tooth brushing is associated with an almost eightfold increase in risk of bacteremia. The incidence and the magnitude of bacteremia that occurs following chewing, tooth brushing, and invasive dental procedures are associated with gingival inflammation rather than with pocket depths (19). Bacteremia originating from the oral cavity is caused by a wide variety of microorganisms, including Gram-negative anaerobes and the VGS (17).

In many earlier studies, It has been found that the incidence and magnitude of bacteremia in patients with the periodontal disease are higher than those with a healthy periodontium (8, 19, 33). It has been reported that among patients with chronic periodontitis, the magnitude of bacteremia was directly associated with the level of gingival inflammation. However, there was no relationship found between probing depth and the magnitude of bacteremia, indicating that active inflammation was more important than periodontal attachment loss (19).

4. Bacteremia and Viridans Group Streptococci

It is a well-known fact that the oral cavity is the most likely origin of bacteremia due to the presence of the VGS in the oral cavity. Streptococcus mitis and Streptococcus oralis are the most common VGS found in the oral cavity, particularly in the setting of ulcerative oral mucositis (34, 35).

In 1978, studies in the United States produced the first report of the viridans streptococcal bacteremia. Hoecker et al. (1978) described six children in whom S. salivarius bacteremia was diagnosed. Their ages ranged from 6 - 14 years. The most common routes of entry were the mouth, pharynx or respiratory tract. Three patients, who were profoundly neutropenic, died in spite of antibiotic treatment with intravenous penicillin. The “penicillin G was found to be the antibiotic of choice in treating infections due to S. salivarius” and found that “these organisms were sensitive to the majority of antibiotics except aminoglycosides and tetracycline occasionally” (27).

In the 1980s, reports from other centers followed. In the U. K., Cohen et al. (1983) (35) evoked considerable interest and prompted groups elsewhere in Europe as well as in North America, to describe their recent clinical experience of the viridans streptococcal sepsis (28, 36). Substantial morbidity and mortality associated with a severe form of the viridans streptococcal bacteremia became documented with complications such as septic shock and an acute respiratory distress syndrome (35, 36). In certain cases, in spite of the use of appropriate antibiotics, high mortality rates were associated with the severe form of the viridans streptococcal sepsis (35). During the 1980s, several studies described the viridans streptococcal bacteremia and a predominance of Gram-positive organisms in bacteremia patients, with the main organisms responsible, being coagulase-negative staphylococci, Staphylococcus aureus, and viridans streptococci (36). Identification schemes used in these studies suggested that S. mitis and S. sanguis were the most common species of the viridans streptococci causing bacteremia (35, 36).

In a study by Tomas et al. (2007), the prevalence of bacteremia following dental extractions was 96.2% at 30 seconds, 64.2% at 15 minutes and 20% at 1 hour after completing the surgical procedure. The bacteria most frequently identified in the positive blood cultures were viridans streptococci (63.8%) (32). During the early 1990s, studies on risk factors for viridans streptococcal and some case control studies were carried out (37, 38). Several studies associated the prophylactic use of certain antimicrobial agents, with the development of viridans streptococcal bacteremia (37, 39).

The majority of studies published at the beginning of the 1990s suggested that S. mitis and S. sanguis were the predominant species causing the viridans streptococcal bacteremia (39, 40). However, two groups of investigators found a different pattern. McWhinney et al. identified 47 sequential blood culture isolates of viridans streptococci from febrile patients (41) according to the scheme described by Beighton et al. (42) and also using the commercial system, API 20 Strep (bioMerieux). The former system, which accommodated the recent taxonomic changes of that time, identified 39 isolates of S. oralis, five of S. mitis and one of S. parasanguis. Two isolates could not be identified to the species level. One year later, the report by Beighton et al. using the same two identification schemes, also demonstrated that the more modern and comprehensive system identified S. oralis as the predominant strain (43).

Vergis et al. (2001) reported a decrease in bacteremia after dental extraction in 60% cases, who received prophylactic amoxycillin and in 89% cases who received no prophylaxis (P = 0.30), but their results were not statistically significant (44). Rajasuo et al. (2004) found that the detectable bacteremia at 10, 15, and 30 minutes were 44%, 25%, and 13%, respectively. Most prevalent aerobes were VGS and the Streptococcus milleri group (45). The world literature on the incidence of bacteremia after dental extraction shows that the incidence of bacteremia varies from 13% to 96% and the incidence of bacteremia appears to be influenced positively by the presence of gingivitis, periodontitis, and other odontogenic infections (46).

5. Infective Endocarditis

Infective endocarditis (IE) is a severe disease that may affect one or more of the aortic, mitral, tricuspid valves but seldom the pulmonary valve. Preexisting valve diseases such as mitral valve prolapse (47), rheumatic fever, mitral stenosis, aortic stenosis (48) and aortic regurgitation, bicuspid aortic valve (45), coarctation of the aorta, previous endocarditis, prosthetic heart valves, and intravenous drug use are predisposing factors (49-53).

The viridans group streptococci have earlier been reported as the most frequent agents in IE. Kanafani et al. (2002) reported positive blood cultures in 77.5% of IE cases. Streptococcus spp. (51%; of which 57% were viridans streptococci) and Staphylococcus spp. (36%; of which 72% were S. aureus and 28% were coagulase-negative staphylococci) were the most commonly isolated organisms (54). In a study by Barrau et al. (2004), Streptococcus spp. were found to be associated with native valves, coagulase-negative staphylococci and Coxiella burnetii were associated with intracardiac prosthetic devices, and S. bovis and S. aureus were the predominant species associated with presumably healthy valves, whereas oral streptococci caused IE exclusively in patients with previous valve damage (55). Tariq et al. (2004) found VGS in 35% cases and staphylococci in 24% cases (56). Garg et al. (2005) reported streptococci in 23.2% cases, staphylococci in 19.7%, Gram-negative bacilli in 13.6%, enterococci in 8.1% and polymicrobial and fungal infections in 1.5% of IE cases (57). Nakatani et al. (2013) found that decayed teeth and periodontitis were the leading predisposing factors and VGS were isolated in 52% cases whereas, staphylococci were isolated from 32% cases (58).

In all, VGS are now the most frequent etiological agents in IE (54-61). Moreover, in nonintravenous users, where aortic or mitral IE dominates, VGS are the major etiological agents (25, 62). However, few studies have reported staphylococci to be the predominant isolates in IE cases (63, 64). These variations in frequency of isolation could be explained by differences in geographical regions as well as differences in patient populations. These reports show that rapid identification of the etiological agent is vital for successful management of the patient. Van Scoy demonstrated that patients who became afebrile in the first week of antibiotic therapy survived longer than those who remained febrile after the first week (61). Staphylococcus aureus is the most frequent etiological agent in IE among intravenous drug users, where the tricuspid valve is usually affected, even if recent data have shown that the aortic or the mitral valve can be coinfected (65).

Dental scaling and extraction lead to bacteremia in 70% - 100% (66) and tooth brushing leads to bacteremia in 40% of the children, where VGS were found in 50% of the cases (67, 68). Why VGS bacteremia in some cases leads to endocarditis depends on different factors. Old nonbacterial vegetation may be a predisposing factor in the valvular heart disease, a locus minoris (69, 70). Bacteria may infect the nonbacterial vegetations, which with adhesins attach to the endothelium of the damaged site on the valvular wall. Blood production of monocyte cytokines and other factors are parts of the pathogenesis (71). Bacterial components as dextran, fibronectin-binding protein and the teichoic acid have been described as important factors in adhesion to the platelet-fibrin matrix on the valvular wall contributing to the pathogenesis of IE (72). It is known that 60% of the Streptococcus sanguinis strains can cause platelet aggregation (73, 74), which is mediated by platelet aggregation-associated proteins (PAAP) (75). Activated platelets release dense and alpha granules, which in combination with thromboxane production play a role in the later aggregation response. Alpha granules include platelet microbicidal proteins (PMP) that kill bacteria; they also induce production of fibrinogen and clotting factors V and VII. The later activates thrombin, which initiates the polymerization of fibrinogen to fibrin (76). In earlier reports, dextran production by Streptococcus sanguinis has been reported to play a role in the pathogenesis of IE (73, 76); however, in another study it has been found that only 60% of the Streptococcus sanguinis strains produce dextran (77). Studies have showed that Streptococcus gordonii can attach fibronectin, which is adsorbed to collagen (78). The viridans group streptococci have glucosyltransferase (GTF), an enzyme using sucrose for synthesizing extracellular polysaccharide (79). The glucosyltransferase from VGS has been suggested as a factor forming biofilm on the surfaces of the teeth (80).

5.1. Viridans Streptococci and infective endocarditis

The threat posed by viridans streptococci is a consequence of their physical exodus from the oropharynx and skill in adapting to a new microenvironment. It is evident from various earlier studies that the oral cavity can act as the origin for the dissemination of bacteria to the heart; lungs and the peripheral blood capillary system, and this dissemination occurs in less than one minute after an oral procedure (81). The oral cavity has several barriers such as the surface epithelium, defensins, electrical barrier, antibody-forming cells, and the reticuloendothelial system (RES) to prevent bacterial penetration from dental plaque into the tissue (82). Those organisms involved in transient bacteremia are usually eliminated by the RES within minutes and are generally asymptomatic to the host (81, 83).

A newly proposed causal model predicts that an early bacteremia may target the endothelial surface of the heart over many years and promote valve thickening thereby rendering the valve susceptible to adherence and colonization by a later bacteremia that would culminate over a few weeks into fulminant infection (6).

There are three steps critical for infection of the sterile vegetation leading up to IE pathology, these include bacterial adherence, platelet activation and fibrin overlaying. Microbial adhesion can be mediated by a variety of surface components and receptors, which act as virulence factors for the colonization of the endothelium. Adherence rates upon damaged aortic valve leaflets were measured from several species and it was found that Enterococcus spp. and viridans streptococci showed the highest rates of adherence than Escherichia coli (84). The ubiquitous presence of fibronectin on damaged tissue enables a surface binding protein, Fim A, to aid in colonization. Eighty percent of IE streptococci express this binding protein on the cell surface to reduce, ostensibly to coat the surface with the host protein and minimize a host immune response (85). Additionally, the streptococcal cell wall component, lipoteichoic acid (LTA), has been implicated as a fibronectin receptor (86).

More than 60% of S. sanguinis strains activate human platelets in vitro; this mechanism was elucidated by Herzberg et al. for this particular VGS member (76). The bacterial cell is thought to come into close proximity of the platelet via interaction between a cell surface adhesin (SsaB) and an unidentified ligand of the platelet. Platelet aggregation is stimulated by the action of the bacterial PAAP binding to the platelet α2β1 integrin. An epitope on PAAP mimics the integrin’s physiological ligands, collagen and von Willebrand factor, thus activates the platelet. The effect is morphological changes, surface expression of receptors for stimulators, followed by degranulation, results in release of clotting factors and fibrinogen. The resulting fibrin-platelet network increases in mass as cells colonize and expand layer upon layer of vegetation (87).

The newly colonized vegetation represents a unique biofilm environment that is surrounded by antimicrobial dangers. Planktonic cells, resulting from transient bacteremia or released from friable pieces of vegetation, will generally succumb to immune surveillance. The situation inside the fibrin barrier is quite different. Those organisms that can resist antimicrobial defence mechanisms multiply rapidly in the vegetation, soon reaching high numbers and then entering a stationary growth phase. As the vegetation enlarges, the colonies are gradually buried below the accumulating layers and large numbers of cells (109 to 1015 per gram of tissue) are the consequence of the unimpeded thrombus growth (88). A phenomenon of sessile VGS biofilm communities is their ability to withstand host immune responses in regard to leukocyte access and impeded diffusion of materials compounded with slowed growth of the cells. The vegetation provides the bacteria with a “protected or privileged site” in which polymorphonuclear leukocytes penetrate poorly and are unable to check colony growth. Polymeric substances are known to retard the diffusion of antibiotics (89).

6. Conclusions

The results of the various earlier studies indicate that periodontitis is associated with increased incidence of bacteremia. In most of the studies, significantly higher rates of bacteremia were observed in patients with periodontitis than patients without periodontitis, indicating that periodontitis opens up the route for oral VGS to gain entry into bloodstream through the highly inflamed gingiva. Moreover, the higher rates of isolation of VGS from the patients of infective endocarditis with periodontitis support a positive association between periodontitis and infective endocarditis.

A clear understanding of this relationship between VGS, periodontitis associated bacteremia and infective endocarditis may help health-care providers in their efforts to detect both of the diseases earlier. Gingivitis and periodontitis are treatable and preventable conditions; therefore, their identification as risk factors for infective endocarditis would have a major impact on infective endocarditis prevention and assists in maintaining the optimal health of patients. However, large interventional studies can be performed to establish a causal relationship between periodontitis and infective endocarditis.

References

  • 1.

    Hugoson A, Norderyd O, Slotte C, Thorstensson H. Distribution of periodontal disease in a Swedish adult population 1973, 1983 and 1993. J Clin Periodontol. 1998;25(7):542-8. [PubMed ID: 9696253].

  • 2.

    Haffajee AD, Socransky SS. Microbial etiological agents of destructive periodontal diseases. Periodontol 2000. 1994;5:78-111. [PubMed ID: 9673164].

  • 3.

    Loe H, Theilade E, Jensen SB. Experimental Gingivitis in Man. J Periodontol. 1965;36:177-87. [PubMed ID: 14296927]. https://doi.org/10.1902/jop.1965.36.3.177.

  • 4.

    Theilade E, Wright WH, Jensen SB, Loe H. Experimental gingivitis in man. II. A longitudinal clinical and bacteriological investigation. J Periodontal Res. 1966;1:1-13. [PubMed ID: 4224181].

  • 5.

    Douglas CW, Heath J, Hampton KK, Preston FE. Identity of viridans streptococci isolated from cases of infective endocarditis. J Med Microbiol. 1993;39(3):179-82. [PubMed ID: 8366515]. https://doi.org/10.1099/00222615-39-3-179.

  • 6.

    Drangsholt MT. A new causal model of dental diseases associated with endocarditis. Ann Periodontol. 1998;3(1):184-96. [PubMed ID: 9722702]. https://doi.org/10.1902/annals.1998.3.1.184.

  • 7.

    Silver JG, Martin AW, McBride BC. Experimental transient bacteraemias in human subjects with varying degrees of plaque accumulation and gingival inflammation. J Clin Periodontol. 1977;4(2):92-9. [PubMed ID: 325021].

  • 8.

    Daly CG, Mitchell DH, Highfield JE, Grossberg DE, Stewart D. Bacteremia due to periodontal probing: a clinical and microbiological investigation. J Periodontol. 2001;72(2):210-4. [PubMed ID: 11288795]. https://doi.org/10.1902/jop.2001.72.2.210.

  • 9.

    Albandar JM, Kingman A. Gingival recession, gingival bleeding, and dental calculus in adults 30 years of age and older in the United States, 1988-1994. J Periodontol. 1999;70(1):30-43. [PubMed ID: 10052768]. https://doi.org/10.1902/jop.1999.70.1.30.

  • 10.

    Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontol 2000. 2005;38:135-87. [PubMed ID: 15853940]. https://doi.org/10.1111/j.1600-0757.2005.00107.x.

  • 11.

    Mariotti A. Dental plaque-induced gingival diseases. Ann Periodontol. 1999;4(1):7-19. [PubMed ID: 10863371]. https://doi.org/10.1902/annals.1999.4.1.7.

  • 12.

    Page RC. The pathobiology of periodontal diseases may affect systemic diseases: inversion of a paradigm. Ann Periodontol. 1998;3(1):108-20. [PubMed ID: 9722695]. https://doi.org/10.1902/annals.1998.3.1.108.

  • 13.

    Axelsson P, Albandar JM, Rams TE. Prevention and control of periodontal diseases in developing and industrialized nations. Periodontol 2000. 2002;29:235-46. [PubMed ID: 12102711].

  • 14.

    Ximenez-Fyvie LA, Haffajee AD, Socransky SS. Comparison of the microbiota of supra- and subgingival plaque in health and periodontitis. J Clin Periodontol. 2000;27(9):648-57. [PubMed ID: 10983598].

  • 15.

    Graves DT, Cochran D. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J Periodontol. 2003;74(3):391-401. [PubMed ID: 12710761]. https://doi.org/10.1902/jop.2003.74.3.391.

  • 16.

    Marsh PD. Microbial ecology of dental plaque and its significance in health and disease. Adv Dent Res. 1994;8(2):263-71. [PubMed ID: 7865085].

  • 17.

    Raber-Durlacher JE, Laheij AM, Epstein JB, Epstein M, Geerligs GM, Wolffe GN, et al. Periodontal status and bacteremia with oral viridans streptococci and coagulase negative staphylococci in allogeneic hematopoietic stem cell transplantation recipients: a prospective observational study. Support Care Cancer. 2013;21(6):1621-7. [PubMed ID: 23288398]. https://doi.org/10.1007/s00520-012-1706-2.

  • 18.

    Lockhart PB, Brennan MT, Thornhill M, Michalowicz BS, Noll J, Bahrani-Mougeot FK, et al. Poor oral hygiene as a risk factor for infective endocarditis-related bacteremia. J Am Dent Assoc. 2009;140(10):1238-44. [PubMed ID: 19797553].

  • 19.

    Forner L, Larsen T, Kilian M, Holmstrup P. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J Clin Periodontol. 2006;33(6):401-7. [PubMed ID: 16677328]. https://doi.org/10.1111/j.1600-051X.2006.00924.x.

  • 20.

    Lockhart PB, Brennan MT, Sasser HC, Fox PC, Paster BJ, Bahrani-Mougeot FK. Bacteremia associated with toothbrushing and dental extraction. Circulation. 2008;117(24):3118-25. [PubMed ID: 18541739]. https://doi.org/10.1161/CIRCULATIONAHA.107.758524.

  • 21.

    Kinane DF, Riggio MP, Walker KF, MacKenzie D, Shearer B. Bacteraemia following periodontal procedures. J Clin Periodontol. 2005;32(7):708-13. [PubMed ID: 15966875]. https://doi.org/10.1111/j.1600-051X.2005.00741.x.

  • 22.

    Lucas VS, Gafan G, Dewhurst S, Roberts GJ. Prevalence, intensity and nature of bacteraemia after toothbrushing. J Dent. 2008;36(7):481-7. [PubMed ID: 18448227]. https://doi.org/10.1016/j.jdent.2008.03.005.

  • 23.

    Bartova J, Sommerova P, Lyuya-Mi Y, Mysak J, Prochazkova J, Duskova J, et al. Periodontitis as a risk factor of atherosclerosis. J Immunol Res. 2014;2014:636893. [PubMed ID: 24741613]. https://doi.org/10.1155/2014/636893.

  • 24.

    Gorelick PB. Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review. Stroke. 2002;33(3):862-75. [PubMed ID: 11872916].

  • 25.

    Bouvet A. [Invasive infections by Streptococcus viridans (oral streptococci) excluding pneumococci]. Presse Med. 1997;26(37):1768-73. [PubMed ID: 9569897].

  • 26.

    Coulter WA, Coffey A, Saunders ID, Emmerson AM. Bacteremia in children following dental extraction. J Dent Res. 1990;69(10):1691-5. [PubMed ID: 2212215].

  • 27.

    Hoecker JL, Pickering LK, Groschel D, Kohl S. Streptococcus salivarius sepsis in children with malignancies. J Pediatr. 1978;92(2):337-8. [PubMed ID: 621618].

  • 28.

    Mascret B, Maraninchi D, Gastaut JA, Novakovitch G, Sebahoun G, Meyer G, et al. Risk factors for streptococcal septicaemia after marrow transplantation. Lancet. 1984;1(8387):1185-6. [PubMed ID: 6144912].

  • 29.

    Lockhart PB, Bolger AF, Papapanou PN, Osinbowale O, Trevisan M, Levison ME, et al. Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation. 2012;125(20):2520-44. [PubMed ID: 22514251]. https://doi.org/10.1161/CIR.0b013e31825719f3.

  • 30.

    Li X, Kolltveit KM, Tronstad L, Olsen I. Systemic diseases caused by oral infection. Clin Microbiol Rev. 2000;13(4):547-58. [PubMed ID: 11023956].

  • 31.

    Sreedevi M, Ramesh A, Dwarakanath C. Periodontal status in smokers and nonsmokers: a clinical, microbiological, and histopathological study. Int J Dent. 2012;2012:571590. [PubMed ID: 22505904]. https://doi.org/10.1155/2012/571590.

  • 32.

    Tomas I, Alvarez M, Limeres J, Potel C, Medina J, Diz P. Prevalence, duration and aetiology of bacteraemia following dental extractions. Oral Dis. 2007;13(1):56-62. [PubMed ID: 17241431]. https://doi.org/10.1111/j.1601-0825.2006.01247.x.

  • 33.

    Takai S, Kuriyama T, Yanagisawa M, Nakagawa K, Karasawa T. Incidence and bacteriology of bacteremia associated with various oral and maxillofacial surgical procedures. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99(3):292-8. [PubMed ID: 15716834]. https://doi.org/10.1016/j.tripleo.2004.10.022.

  • 34.

    Brennan MT, Kent ML, Fox PC, Norton HJ, Lockhart PB. The impact of oral disease and nonsurgical treatment on bacteremia in children. J Am Dent Assoc. 2007;138(1):80-5. [PubMed ID: 17197406].

  • 35.

    Cohen J, Donnelly JP, Worsley AM, Catovsky D, Goldman JM, Galton DA. Septicaemia caused by viridans streptococci in neutropenic patients with leukaemia. Lancet. 1983;2(8365-66):1452-4. [PubMed ID: 6140545].

  • 36.

    Henslee J, Bostrom B, Weisdorf D, Ramsay N, McGlave P, Kersey J. Streptococcal sepsis in bone marrow transplant patients. Lancet. 1984;1(8373):393. [PubMed ID: 6141448].

  • 37.

    Kern W, Kurrle E, Schmeiser T. Streptococcal bacteremia in adult patients with leukemia undergoing aggressive chemotherapy. A review of 55 cases. Infection. 1990;18(3):138-45. [PubMed ID: 2365465].

  • 38.

    Richard P, Amador Del Valle G, Moreau P, Milpied N, Felice MP, Daeschler T, et al. Viridans streptococcal bacteraemia in patients with neutropenia. Lancet. 1995;345(8965):1607-9. [PubMed ID: 7783538].

  • 39.

    Classen DC, Burke JP, Ford CD, Evershed S, Aloia MR, Wilfahrt JK, et al. Streptococcus mitis sepsis in bone marrow transplant patients receiving oral antimicrobial prophylaxis. Am J Med. 1990;89(4):441-6. [PubMed ID: 2171333].

  • 40.

    McWhinney PH, Gillespie SH, Kibbler CC, Hoffbrand AV, Prentice HG. Streptococcus mitis and ARDS in neutropenic patients. Lancet. 1991;337(8738):429. [PubMed ID: 1671448].

  • 41.

    McWhinney PH, Patel S, Whiley RA, Hardie JM, Gillespie SH, Kibbler CC. Activities of potential therapeutic and prophylactic antibiotics against blood culture isolates of viridans group streptococci from neutropenic patients receiving ciprofloxacin. Antimicrob Agents Chemother. 1993;37(11):2493-5. [PubMed ID: 8285642].

  • 42.

    Beighton D, Hardie JM, Whiley RA. A scheme for the identification of viridans streptococci. J Med Microbiol. 1991;35(6):367-72. [PubMed ID: 1753394]. https://doi.org/10.1099/00222615-35-6-367.

  • 43.

    Beighton D, Carr AD, Oppenheim BA. Identification of viridans streptococci associated with bacteraemia in neutropenic cancer patients. J Med Microbiol. 1994;40(3):202-4. [PubMed ID: 8114071]. https://doi.org/10.1099/00222615-40-3-202.

  • 44.

    Vergis EN, Demas PN, Vaccarello SJ, Yu VL. Topical antibiotic prophylaxis for bacteremia after dental extractions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91(2):162-5. [PubMed ID: 11174592].

  • 45.

    Rajasuo A, Perkki K, Nyfors S, Jousimies-Somer H, Meurman JH. Bacteremia following surgical dental extraction with an emphasis on anaerobic strains. J Dent Res. 2004;83(2):170-4. [PubMed ID: 14742658].

  • 46.

    Parahitiyawa NB, Jin LJ, Leung WK, Yam WC, Samaranayake LP. Microbiology of odontogenic bacteremia: beyond endocarditis. Clin Microbiol Rev. 2009;22(1):46-64. Table of Contents. [PubMed ID: 19136433]. https://doi.org/10.1128/CMR.00028-08.

  • 47.

    MacMahon SW, Roberts JK, Kramer-Fox R, Zucker DM, Roberts RB, Devereux RB. Mitral valve prolapse and infective endocarditis. Am Heart J. 1987;113(5):1291-8. [PubMed ID: 3578027].

  • 48.

    Gershon AS, de Azavedo JC, McGeer A, Ostrowska KI, Church D, Hoban DJ, et al. Activities of new fluoroquinolones, ketolides, and other antimicrobials against blood culture isolates of viridans group streptococci from across Canada, 2000. Antimicrob Agents Chemother. 2002;46(5):1553-6. [PubMed ID: 11959597].

  • 49.

    Li W, Somerville J. Infective endocarditis in the grown-up congenital heart (GUCH) population. Eur Heart J. 1998;19(1):166-73. [PubMed ID: 9503191].

  • 50.

    van der Meer JT, Thompson J, Valkenburg HA, Michel MF. Epidemiology of bacterial endocarditis in The Netherlands. I. Patient characteristics. Arch Intern Med. 1992;152(9):1863-8. [PubMed ID: 1520052].

  • 51.

    Strom BL, Abrutyn E, Berlin JA, Kinman JL, Feldman RS, Stolley PD, et al. Dental and cardiac risk factors for infective endocarditis. A population-based, case-control study. Ann Intern Med. 1998;129(10):761-9. [PubMed ID: 9841581].

  • 52.

    Lepeschkin E. On the relation between the site of valvular involvement in endocarditis and the blood pressure resting on the valve. Am J Med Sci. 1952;224(3):318-9. [PubMed ID: 14952510].

  • 53.

    Sande MA, Kartalija M, Anderson J. Infective Endocarditis. In: Fuster V, Alexander RW, O'Rourke RA, editors. The Heart. New York: McGraw-Hill; 2001. p. 2087-125.

  • 54.

    Kanafani ZA, Mahfouz TH, Kanj SS. Infective endocarditis at a tertiary care centre in Lebanon: predominance of streptococcal infection. J Infect. 2002;45(3):152-9. [PubMed ID: 12387770].

  • 55.

    Barrau K, Boulamery A, Imbert G, Casalta JP, Habib G, Messana T, et al. Causative organisms of infective endocarditis according to host status. Clin Microbiol Infect. 2004;10(4):302-8. [PubMed ID: 15059118]. https://doi.org/10.1111/j.1198-743X.2004.00776.x.

  • 56.

    Tariq M, Alam M, Munir G, Khan MA, Smego RA Jr. Infective endocarditis: a five-year experience at a tertiary care hospital in Pakistan. Int J Infect Dis. 2004;8(3):163-70. [PubMed ID: 15109591]. https://doi.org/10.1016/j.ijid.2004.02.001.

  • 57.

    Garg N, Kandpal B, Garg N, Tewari S, Kapoor A, Goel P, et al. Characteristics of infective endocarditis in a developing country-clinical profile and outcome in 192 Indian patients, 1992-2001. Int J Cardiol. 2005;98(2):253-60. [PubMed ID: 15686775]. https://doi.org/10.1016/j.ijcard.2003.10.043.

  • 58.

    Nakatani S, Mitsutake K, Ohara T, Kokubo Y, Yamamoto H, Hanai S, et al. Recent picture of infective endocarditis in Japan--lessons from Cardiac Disease Registration (CADRE-IE). Circ J. 2013;77(6):1558-64. [PubMed ID: 23524445].

  • 59.

    Loupa C, Mavroidi N, Boutsikakis I, Paniara O, Deligarou O, Manoli H, et al. Infective endocarditis in Greece: a changing profile. Epidemiological, microbiological and therapeutic data. Clin Microbiol Infect. 2004;10(6):556-61. [PubMed ID: 15191385]. https://doi.org/10.1111/j.1469-0691.2004.00884.x.

  • 60.

    Tariq M, Siddiqui BK, Jadoon A, Alam M, Khan SA, Atiq M, et al. Clinical profile and outcome of infective endocarditis at the Aga Khan University Hospital. Int J Collaborat Res Intern Med Public Health. 2009;1:84-99.

  • 61.

    Van Scoy RE. Culture-negative endocarditis. Mayo Clin Proc. 1982;57(3):149-54. [PubMed ID: 7038318].

  • 62.

    Wilson WR, Karchmer AW, Dajani AS, Taubert KA, Bayer A, Kaye D, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. American Heart Association. JAMA. 1995;274(21):1706-13. [PubMed ID: 7474277].

  • 63.

    Bayliss R, Clarke C, Oakley CM, Somerville W, Whitfield AG, Young SE. The microbiology and pathogenesis of infective endocarditis. Br Heart J. 1983;50(6):513-9. [PubMed ID: 6651993].

  • 64.

    Roberts RB, Krieger AG, Schiller NL, Gross KC. Viridans streptococcal endocarditis: the role of various species, including pyridoxal-dependent streptococci. Rev Infect Dis. 1979;1(6):955-66. [PubMed ID: 551516].

  • 65.

    Piper C, Hetzer R, Korfer R, Bergemann R, Horstkotte D. The importance of secondary mitral valve involvement in primary aortic valve endocarditis; the mitral kissing vegetation. Eur Heart J. 2002;23(1):79-86. [PubMed ID: 11741365]. https://doi.org/10.1053/euhj.2001.2689.

  • 66.

    Heimdahl A, Hall G, Hedberg M, Sandberg H, Soder PO, Tuner K, et al. Detection and quantitation by lysis-filtration of bacteremia after different oral surgical procedures. J Clin Microbiol. 1990;28(10):2205-9. [PubMed ID: 2229342].

  • 67.

    Roberts GJ, Holzel HS, Sury MR, Simmons NA, Gardner P, Longhurst P. Dental bacteremia in children. Pediatr Cardiol. 1997;18(1):24-7. [PubMed ID: 8960488]. https://doi.org/10.1007/s002469900103.

  • 68.

    Kennedy HF, Morrison D, Tomlinson D, Gibson BE, Bagg J, Gemmell CG. Gingivitis and toothbrushes: potential roles in viridans streptococcal bacteraemia. J Infect. 2003;46(1):67-70. [PubMed ID: 12504614].

  • 69.

    Baddour LM, Christensen GD, Lowrance JH, Simpson WA. Pathogenesis of experimental endocarditis. Rev Infect Dis. 1989;11(3):452-63. [PubMed ID: 2665003].

  • 70.

    Freedman LR. The pathogenesis of infective endocarditis. J Antimicrob Chemother. 1987;20 Suppl A:1-6. [PubMed ID: 3316154].

  • 71.

    Moreillon P, Que YA, Bayer AS. Pathogenesis of streptococcal and staphylococcal endocarditis. Infect Dis Clin North Am. 2002;16(2):297-318. [PubMed ID: 12092474].

  • 72.

    Brown M, Griffin GE. Immune responses in endocarditis. Heart. 1998;79(1):1-2. [PubMed ID: 9505905].

  • 73.

    Ford I, Douglas CW, Preston FE, Lawless A, Hampton KK. Mechanisms of platelet aggregation by Streptococcus sanguis, a causative organism in infective endocarditis. Br J Haematol. 1993;84(1):95-100. [PubMed ID: 8338784].

  • 74.

    Herzberg MC, Gong K, MacFarlane GD, Erickson PR, Soberay AH, Krebsbach PH, et al. Phenotypic characterization of Streptococcus sanguis virulence factors associated with bacterial endocarditis. Infect Immun. 1990;58(2):515-22. [PubMed ID: 2137112].

  • 75.

    Herzberg MC, Brintzenhofe KL, Clawson CC. Aggregation of human platelets and adhesion of Streptococcus sanguis. Infect Immun. 1983;39(3):1457-69. [PubMed ID: 6188697].

  • 76.

    Herzberg MC. Platelet-streptococcal interactions in endocarditis. Crit Rev Oral Biol Med. 1996;7(3):222-36. [PubMed ID: 8909879].

  • 77.

    Larsen T, Fiehn NE, Gutschik E, Bangsborg JM. Current status of taxonomic groups of oral streptococci in endocarditis. Can virulence factors discriminate between endocarditis and non-endocarditis strains? Clin Microbiol Infect. 1999;5(2):73-7. [PubMed ID: 11856221].

  • 78.

    Lowrance JH, Hasty DL, Simpson WA. Adherence of Streptococcus sanguis to conformationally specific determinants in fibronectin. Infect Immun. 1988;56(9):2279-85. [PubMed ID: 2970435].

  • 79.

    Monchois V, Lakey JH, Russell RR. Secondary structure of Streptococcus downei GTF-1 glucansucrase. FEMS Microbiol Lett. 1999;177(2):243-8. [PubMed ID: 10474191].

  • 80.

    Coykendall AL. Classification and identification of the viridans streptococci. Clin Microbiol Rev. 1989;2(3):315-28. [PubMed ID: 2670193].

  • 81.

    Kilian M. Systemic Disease: Manifestations of Oral Bacteria. In: McGhee JR, editor. Dental Microbiology. Philadelphia: Harpers and Row; 1982. p. 832-8.

  • 82.

    Loesche WJ. Ecology of the Oral Flora. In: Nisengard RJ, editor. Oral Microbiology and Immunology. Philadelphia: Saunders; 1994. p. 307-19.

  • 83.

    Van Dyke TE, Bartholomew E, Genco RJ, Slots J, Levine MJ. Inhibition of neutrophil chemotaxis by soluble bacterial products. J Periodontol. 1982;53(8):502-8. [PubMed ID: 6956714]. https://doi.org/10.1902/jop.1982.53.8.502.

  • 84.

    Gould K, Ramirez-Ronda CH, Holmes RK, Sanford JP. Adherence of bacteria to heart valves in vitro. J Clin Invest. 1975;56(6):1364-70. [PubMed ID: 811687]. https://doi.org/10.1172/JCI108216.

  • 85.

    Kuusela P, Vartio T, Vuento M, Myhre EB. Attachment of staphylococci and streptococci on fibronectin, fibronectin fragments, and fibrinogen bound to a solid phase. Infect Immun. 1985;50(1):77-81. [PubMed ID: 3899940].

  • 86.

    Nealon TJ, Beachey EH, Courtney HS, Simpson WA. Release of fibronectin-lipoteichoic acid complexes from group A streptococci with penicillin. Infect Immun. 1986;51(2):529-35. [PubMed ID: 3510980].

  • 87.

    Mandell GL, Korzeniowski OM. Cardiovascular infections. Philadelphia: Current Medicine; 1998.

  • 88.

    Durack DT, Beeson PB. Experimental bacterial endocarditis. I. Colonization of a sterile vegetation. Br J Exp Pathol. 1972;53(1):44-9. [PubMed ID: 5014243].

  • 89.

    Ishida H, Ishida Y, Kurosaka Y, Otani T, Sato K, Kobayashi H. In vitro and in vivo activities of levofloxacin against biofilm-producing Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1998;42(7):1641-5. [PubMed ID: 9660997].