Cardiovascular infections: bacterial endocarditis of oral origin. Pathogenesis and prophylaxis
Carl Erik Nord and Andero Heimdahl Departments of Microbiology and Oral Surgery, Huddinge University Hospital, Karolinska Institute and National Bacteriological Laboratory, Stockholm, Sweden
Nord CE and Heimdahl A: Cardiovascular infections: bacterial endocarditis of oral origin. Pathogenesis and prophylaxis. J Clin Periodontol1990; 17: 494496. Abstract. The diagnosis infective endocarditis describes infection of the endocardial surface of the heart and indicates the presence of micro-organisms in the lesion. In most cases, the heart valves are affected, but the disease can also occur on septa1 defects or on the mural endocardurn. The disease has been classified as acute or subacute based on the progression of the untreated disease. The acute form has a fulminant course with high fever and leukocytosis with death in less than 6 weeks. It is most often associated with infections caused by Staphylococcus aureus, Streptococcus pneumoniae or Streptococcus pyogenes. The subacute (death within 6 weeks to 3 months) and chronic (death more than 3 months) forms are mostly described together. These forms usually occur in patients with prior valvular disease and are characterized by a slow, indolent course with low-grade fever, night sweats, and weight loss. This form is usually caused by the viridansstreptococci. The above mentioned classification does not include the nonbacterial forms of endocarditis and enterococci often give rise to a disease intemediate between acute and subacute endocarditis. It is preferable to have a classification based on the micro-organism responsible since this classification has implications for the course followed and the appropriate antimicrobial agent to use. The clinical manifestations of the disease are so varied that they may be encountered in most medical subspecialities. SucCeSsful management is also dependent on the close cooperation of medical and dental disciplines.
In vitro results and experimental animal studies have shown that the development of infective endocarditis occurs in several phases. First the valve surface must be changed in order to produce a suitable site for bacterial attachment and colonization. Surface alterations can be caused by various local and systemic factors. These changes result in the deposition of platelets and fibrin and in the formation of nonbacterial thrombotic endocarditis (NBTE). Then the micro-organisms have to reach this site and adhere. Certain bacterial strains have the capacity to adhere to platelets and/or fibrin. After colonization, the surface is rapidly covered with fibrin and platelets and thereby an environment is
established suitable for bacterial multiplication and vegetation growth (Sande et al. 1984). Nonbacterlal thrombotic cndocardltlo
The initial colonization takes place on the endothelial surface of the valve. It is not possible to produce infective endocarditis in experimental animals with injections of bacteria unless the valvular surface is damaged. When a polyethylene catheter is placed along the aortic valve of a rabbit, endocarditis can easily be induced with intravenously injected micro-organisms. Microscopic examination demonstrates micro-organisms adhering to the fibrin-platelet deposits. Alteration of the valve surface is a prerequisite for bacterial colonization both in animals and humans. Nonbacterial
Key words: bacterial endocarditis; oral origin; pathogenesis: prophylaxis.
thrombotic endocarditis has been found in patients with malignancies, rheumatic or congenital heart diseases and connective tissue diseases (Sande et al. 1984). Dynamlc factors
When endocarditis is associated with valvular insufficiency, the lesion is found on the atrial surface of the mitral valve and the ventricular surface of the aortic valve. This localization is associated with the decrease in lateral pressure immediately downstream from the regurgitant flow. Lesions with high turbulence create conditions that lead to bacterial colonization, whereas defects with large surface area, or low flow, are seldom implicated in endocarditis.
Cardiovascular infections Bacbremia
Transient bacteremia may lead to colonization of preexistent NBTE and to the development of infective endocarditis. Bacteremia is always observed when a mucosal surface heavily colonized with bacteria is traumatized, such as in dental extractions and other oral surgical procedures. The degree of bacteremia is related to the trauma induced by the surgical procedure and to the number of micro-organisms inhabiting the surface. The isolated micro-organisms reflect the resident microflora. The transient bacteremia is in most cases of low grade, and the blood stream is in most patients sterile within 20 min (Sande et al. 1984).
a virulence factor in the pathogenesis of endocarditis. The role of dextran in the adherence of viridansstreptococci to NBTE has also been investigated using artificial platelet-fibrin matrix. The amount of dextran produced correlated with adherence and was increased by adding sucrose to the medium and was decreased by the addition of dextranase. The ability of these organisms to produce endocarditis in vivo in the rabbit model was also correlated to the production of dextran (Finch et al. 1987). Colonization
The importance of adherence factors in the development of endocarditis has also been investigated by preincubation of organisms with antimicrobial agents. Micro-organisms Many antimicrobial agents, after incuThe ability of micro-organisms to ad- bation at subinhibitory concentrations, here to NBTE is an important step in decrease adhesion of streptococcal spethe development of endocarditis. Micro- cies to platelet-fibrin matrix and damorganisms frequently associated with aged canine valves. Experimental studendocarditis (viridans streptococci, en- ies in animals have confirmed this in terococci, Staphylococcus aureus, vitro observation since preincubation of Staphylococcus epidermidis, Pseudo- the micro-organism in subinhibitory monas aeruginosa) adhered better to antimicrobial concentrations prevents normal canine aortic leaflets than mic- the development of endocarditis in vivo. ro-organisms (Escherichiacoli, Klebsiel- This observationhas a relevance to antila pneumoniae) uncommon in endocar- microbial prophylaxis of endocarditis. ditis. S. aureus and viridansstreptococci Subinhibitory concentrations of penicilalso produce endocarditis more easily lin can release streptococcal lipoteichoic than E. coli in the experimental rabbit acid with decreased adhesion to NBTE model ofendocarditis (Finch et al. 1987). and thereby reduced ability to cause enActinobacillus actinomycetemcomit- docarditis. The role of the platelets in the pathom,a pathogen in periodontal diseases, has only recently been identified as a genesis of endocarditis has also been causative micro-organism in infective investigated. Endocarditis-producing endocarditis. There are now more than streptococcal strains aggregate platelets 60 reported cases of endocarditis caused more than other strains less frequently by this micro-organism (Grace et al. inducing endocarditis. Platelet-bacterial aggregates are recovered in blood from 1988). The adherence of oral streptococci to patients with bacteremia. The signifiNBTE depends on the production of an cance of bacterial-platelet aggregates in extracellular polysaccharide, dextran. the formation of the vegetation or in The ability to adhere to surfaces is im- the removal of micro-organisms from portant in the pathogenesis of endocar- the blood is still not known. When the colonization of the valve ditis. In a study where 317 cases of streptococcal endocarditis were ana- has started and a critical mass of adherlyzed, the most common isolates were S. ent bacteria has been produced, the vegsanguis (16.4%) and S . mutans (14.2%). etation increases by more deposition of When a ratio endocarditis to nonendo- platelet-fibrin and the proliferation of carditis bacteremia was calculated, the bacteria continues. The bacteria are relative disposition for a certain organ- found beneath the vegetation surface ism to cause endocarditis could be cal- and the infiltration by phagocytes is culated. The ratios were from 14.2:l for minimal. These vegetations produce an S. mutans to 1:32 for S. pyogenes. Only environment of decreased host resistthe first 4 micro-organisms, S. mutans, ance with bacterial growth in colony S. bovis. S. mitior and S. sanguis, pro- counts of 109-10'0 bacteria/g tissue. The duced extracellular dextran. Dextran role of granulocytes is unknown (Sande production is therefore considered to be et al. 1984).
Infective endocarditis gives rise to humoral and cellular immune responses such as hypergammaglobulinemia, splenomegaly, and the presence of macrophages in the peripheral blood. Studies in animals have demonstrated a protective role for circulating antibodies. Rabbits pre-immunized with heat-killed streptococci plus Freund's adjuvant had a significantly higher ID, than nonimmunized rabbits. Intravascular agglutination of bacteria can reduce the endocarditis by decreasing the number of circulating micro-organisms. Rheumatoid factor is observed in 50% of patients with infective endocarditis of more than 6 weeks' duration. Rheumatoid factor may play a role in endocarditis by blocking opsonic activity, stimulating phagocytosis, and accelerating microvascular damage. Infective endocarditis is associated with an intravascular antigenic challenge and consequently the development of several classes of circulating antibodies is observed. Opsonic (IgG), agglutinating (IgG, IgM), and complement-fixing (IgG, IgM) antibodies, cryoglobulins (IgG, IgM, IgA, C3, fibrinogen), and macroglobulins have beed'observed in endocarditis. Circulating immune complexes are found in an increased frequency with long illness, extravalvular manifestations, and rightsided endocarditis. With successful therapy, the levels of immune complexes decrease significantly. Quantitative determinations of serum immune complex concentrations are useful in following the response to treatment. Effective treatment leads to a decrease in circulating immune complexes. Treatment failures or relapses are characterized by rising titers or a reappearance of circulating immune complexes (Sande et al. 1984). Prophylaxis
Infective endocarditis is a life-threatening disease. The causative micro-organism can in most cases be eradicated by antimicrobial treatment, but permanent valvular damage is often observed. A few patients die during the active phase of infection but many patients suffer later morbidity. Prophylaxis of infective endocarditis has therefore been accepted by most clinicians. It is important to stress that only a minor proportion of all cases of endocarditis can
Nord & Heirndahl
Table I. Scandinavian Society for Antimicrobial Chemotherapy:Recommendations for antimicrobial prophylaxis of infective endocarditis for dental procedures
Not allergic to penicillin amoxycillin, single 3 g oral dose 1 h before
Allergic to penicillin clindamycin, single 600 mg oral dose 1 h
procedure; children: 50 mg/kg body weight as a single dose
children: 15 mg/kg body weight as a single
be attributed to bacteremia caused by previous dental treatment (Finch et al. 1987). Determination of risk for endocardltis
To estimate when antimicrobial prophylaxis should be inserted, the relative risk of developing infective endocarditis after various medical and surgical procedures has to be determined. There are many reports in the literature on the incidence of bacteremia following different manipulations. The incidence of bacteremia varies largely between various investigators and therefore every new study published should be carefully evaluated with regard to certain bacterial species, especially viridansstreptococci entering the blood stream. Many hundreds of cases of infective endocarditis related to prior dental procedures have been published. In many of these cases, the onset of endocarditis symptoms appeared after the dental procedures which makes a relationship most likely. The risk of developing infective endocarditis due to dental treatment should be low, since transient bacteremia occurs in all patients after oral surgery and the incidence of endocarditis is rare. The estimated risk for acquiring infective endocarditis without antimicrobial prophylaxis varies between different authors from 1 in 533 patients to 1 in 115,200 patients or zero. The risk of developing infective endocarditis related to the patient’s underlying cardial condition must also be taken into account. Certain conditions strongly predispose to endocarditis such as prosthetic valves, arteriovenous fistulas, patent ductus arteriosus, Fallot’s tetralogy, ventricular septal defect, coarctation of the aorta, aortic valve disease, mitral stenosis, Marfan’s syndrome, intra-atrial alimentation catheters and previous infective endocarditis. Patients at intermediate risk of acquiring endocarditis are those with mitral valve prolapse, tricuspid valve disease, pulmonary valve disease and asymmetric septal hypertrophy. Patients with arteriosclerotic plaques, coronary artery disease, atrial septal defects, cardiac pacemakers
before procedure; dose
and surgical corrected lesions without prosthetic implants are considered to be at a low or negligible risk (Finch et al. 1987). General aspects on antimlcroblal prophylaxis of Infective endocarditis
Most authorities agree that it is important to give antimicrobial prophylaxis to cover certain procedures associated with bacteremia in patients with suspected or known heart lesions. Viridansstreptococci are still the most frequent cause of infective endocarditis of oral origin and therefore protection against these bacteria is recommended during dental procedures. As mentioned above, there are still many uncertainties concerning the value of antimicrobial prophylaxis in the prevention of endocarditis. About 25% of the patients developing infective endocarditis have a history of dental treatment which may indicate that only a small group of patients can be protected by antimicrobial prophylaxis. The maintenance of good oral health is also important to reduce spontaneous bacteremia and thereby lower the incidence of streptococcal endocarditis. Oral surgical procedures such as tooth extraction and gingivectomy are the most frequent dental treatments implicated in the development of endocarditis but also other procedures causing bleedings in the oral cavity may need antimicrobial prophylaxis. It is not possible to start multicentre clinical trials to determine the efficacy of different antimicrobial prophylaxis regimens, since at least 6000 patients with valvular heart disease have to be included in such a trial to reach statistical significance. There are also ethical objections against this type of trial. The recommendations for antimicrobial prophylaxis of infective endocarditis for dental procedures are therefore based on indirect data from in-vitro results, experimental animal model and bacteremia studies. It is also important to obtain maximum compliance from patients, physicians and dentists with simple recommendations, since most patients are treated outside the hospitals (Finch et al. 1987).
Scandinavian Society for Antimicrobial Chemotherapy: Recommendationsfor antimicrobial prophylaxis of infective endocardltis for dental procedures
At the Annual Meeting of the Scandinavian Society for Antimicrobial Chernotherapy, October 1987, new recommendations for antimicrobial prophylaxis of infective endocarditis for dental procedures were presented by a working group in the Society (Cars et al. 1988). The recommendations are shown in Table 1. The group recommended a single oral 3 g dose of amoxycillin for adults 1 h before the dental procedure. For patients allergic to penicillin or receiving penicillin treatment, clindamycin given as an oral 600 mg dose 1 h before the procedure is recommended. Patients who have localized juvenile periodontitis, and others with A . actinornycetemcomirans infections, should be managed differently if they are at risk of developing infective endocarditis. These patients have 2 types of bacteria that are capable of causing endocarditis: viridansstreptococci that are sensitive to penicillin and Gram-negative bacteria that are usually resistant to penicillin. In these cases, it is recommended that patients first be given tetracycline for several weeks to suppress the A . actinornyceterncomitans. This is then followed by the general prophylactic regimen of amoxycillin, starting 1 h before the dental procedure. References
Cars, O., Nord, C. E. & Nordbring, F. (1988) Antibiotic prophylaxis of endocarditis. Swedish Medical Journal 85, 1046-1047.
Finch, R., Shanson, D. C. & Littler, W. A. (1987) Infective endocarditis. Journal of Antimicrobial Chemotherapy 20, Suppl. A, 1-192.
Grace, C. J., Levitz, R. E., Katz-Pollak, H. & Brettman, L. R. (1988) Actinohacillusactinomycetemcomitans prosthetic valve endocarditis. Reviews of Infectious Diseases 10, 922-929. Sande, M. A., Kaye, D. & Root, K.K. (1984) Endocarditis. Churchill Livingstone, New York.
Carl Erik Nord Department of Microbiology Huddinge University Hospital Karolinska Institute 5-14186 Huddinge Sweden