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BAB I INTRODUCTION Infective endocarditis is a life-threatening disease. It is always fatal if untreated, and it continues to cause substantial morbidity and mortality despite modern antimicrobial and surgical treatments. Substantial morbidity and mortality results from this infection, (1) despite improvements in the outcome due to advances in antimicrobial therapy and an enhanced ability to diagnose and treat complications. Primary prevention is thus the most important. It was first suggested, at the beginning of the twentieth century, that oral bacteria are related to infective endocarditis. (2, 3) Since then, interest has grown in the relationship between tooth extraction and infective endocarditis, and bacteremia as a result of dental treatments has thus continued to be a subject of research interest. Antimicrobial chemotherapy is now widely advocated to protect at-risk patients, however, their frequent uses generates drug-resistant mutant bacteria, which has become a serious social problem. (4) This short review describes the current knowledge about the relationship between tooth extraction and infective endocarditis and the ongoing challenge to discover alternative candidate compounds for use as novel preventive drugs.

BAB II EXTRACTION

Tooth extraction also referres as Exodontia is the removal of a tooth from oral cavity by means of elevators and forceps who perform oral surgery. Conditions leading to the need for tooth extraction include badly decayed teeth, broken teeth, crowded teeth, inappropriate contact between teeth when the mouth is closed (malocclusion), and teeth that have become loose because of inflammation of the ligaments and bones that support the teeth. Compared with removal of an impacted tooth, tooth extraction appears to be a relatively simple technical procedure. However, both tooth extraction and removal of an impacted tooth must be performed in accordance with surgical principles that have evolved from both basic research and centuries of trial and error. Tooth extraction leaves a surgical wound, which has to heal. Accordingly, a basic understanding of wound healing is essential for performing this surgical procedure in the oral cavity. Like any other minor surgical procedure, tooth extraction requires careful medical evaluation of the patient. Patients with diabetes, hypertension, renal disease, thyroid disease, adrenal disease, or other organ disease must be treated and their disease controlled before tooth extraction. Because the oral cavity is full of microorganisms, any surgical procedure in this area may give rise to postoperative infection, especially in immunocompromised patients. And patients who have a predisposed risk for infective endocarditis, such as those with heart valve diseases, pacemaker implantation, the injection drug user must be treated (antibiotic prophylaxis) which can prevention bacteremia of infective endocarditis caused by tooth extraction or non-surgical dental prosedure.

Before, during, and after tooth extraction, pain management is an important issue. Medical, surgical, and legal considerations exist; for example, removing the wrong tooth is malpractice, as is breaking the jaw during extraction or causing paresthesia after extracting the mandibular third molar in close proximity to the inferior alveolar nerve without proper informed consent.

Indications Teeth are important for aesthetic purposes and for maintaining masticatory function. Accordingly, all efforts to avoid tooth extraction must be exhausted before the decision is made to proceed with removal of a tooth. Nevertheless, there are circumstances in which it is clear that a tooth must be extracted, such as the following:

A tooth that cannot be restored, because of severe caries A mobile tooth with severe periodontal disease, pulp necrosis, or periapical abscess, for which root canal treatment is required that the patient cannot afford (or for which endodontic treatment failed)

Overcrowding of teeth in the dental arch, resulting in orthodontic deformity.(5) Other conditions that may necessitate extraction include the following:

Malposed teeth causing soft tissue trauma to the cheek Cracked teeth from trauma Supernumerary teeth Teeth adjacent to a pathologic lesion that must be excised Planned radiation or intravenous (IV) bisphosphonate treatment, warranting prophylactic extraction

Teeth in the line of fracture

Aesthetic considerations (eg, teeth with endogenous staining)

Economic considerations (eg, teeth for which extensive restoration is required that the patient cannot afford.(6)

Contraindications There are few contraindications for tooth extraction, and most of those that do exist can be modified by additional medical consultation and treatment. Some contraindications can be so severe that extraction should not be performed until the severity of the medical condition has been resolved. Essentially, contraindications may be divided into local and systemic. Local contraindications are limited to the extraction sites. An example is an extraction site that was heavily exposed to radiation; if extraction is performed in the irradiated area, osteoradionecrosis results. Other local contraindication is proximity to a malignancy; extraction in the area of malignancy may increase the chances of dissemination of malignancy. Extraction may be contraindicated in an area of infection that has not been adequately treated (eg, an impacted third molar associated with pericoronitis that is not treated with an antibiotic). Extraction may also be contraindicated when it is adjacent to the site of jaw fracture, because the teeth may be required for stabilization of the fractured bone. If the patient has very limited mouth-opening ability, extracting a tooth may be extremely difficult because of limited access to local anesthesia.(7) A systemic contraindication systemic bisphosphonate therapy for malignancy. Extraction in patients receiving such therapy results in osteochemonecrosis, which is more severe than osteoradionecrosis and is more difficult to treat. Other systemic contraindications include

brittle uncontrolled diabetes, end-stage renal and liver disease, uncontrolled leukemia, lymphoma, hypertension, cardiac dysrhythmias, and cerebrovascular accidents. Pregnancy is a relative contraindication in the first or last trimester; extractions are deferred until after childbirth. Hemophiliac patients and those with severe platelet disorders or other bleeding diatheses should undergo extraction only after these coagulopathies have been corrected. Caution and extreme care are required before extraction in patients on long-term corticosteroids, immunosuppressants, or cancer chemotherapeutic agents.(8)

Preparation Before an extraction, the dentist will take the patient's medical history, nothing allergies and prescription medications. A dental history is also taken, with particular attention to previous extractions and reactions to anesthetics. The dentist may then prescribe antibiotics or recommend stopping certain medications prior to the extraction. The tooth is x-rayed to determine its full shape and position, especially if it is impacted. If the patient is going to have deep anesthesia, he or she should wear loose clothing with sleeves that are easily rolled up to allow for an intravenous line. The patient should not eat or drink anything for at least six hours before the procedure. Arrangements should be made for a friend or relative to drive the patient home after the surgery.

Technique For proper extraction of a tooth, the operator must elevate the gingival soft tissue attachment, luxate the tooth with small and large straight elevators, and adapt the forceps to the crown of the tooth. Luxation requires apical pressure, buccal force, lingual pressure, rotational

pressure, and tractional forces. The operator continues to luxate the tooth with the forceps in a buccolingual direction with slight rotation until the tooth is removed from the socket.(9) Tooth extraction can be difficult in older patients with dense supporting bone, dilacerated roots, and broken crowns with extensive caries. Special attention should be paid to adjacent teeth and vital structures (eg, the maxillary sinus, the inferior alveolar nerve, and the lingual and mental nerves). To minimize the risk of pushing the tooth into the maxillary sinus or fracturing the mandible, extensive force should be avoided.(10) The best and easiest way of managing tooth extraction complications is to prevent them. Tooth extraction often leads to root fracture. A small envelope flap can be reflected to expose fractured roots, and a small straight elevator can be used as a shoehorn to luxate broken roots. The buccal beak of the forceps can be used to grasp a portion of the bone at the same time it grasps the root. The extraction forceps is seated with strong apical pressure to expand the crestal bone around the root and allow root removal. A small root tip can be addressed by placing an endodontic file in the root canal and twisting it with a needle holder. The root can be removed with a No. 4 round bur in a dental handpiece or a small elevator, which displaces the root from its apex. Teeth that are liable to fracture during extraction are those with large carious lesions, those that have been treated by means of root canal procedures, and those surrounded by dense bone or with ankylosed and dilacerated roots. Although every effort should be made to remove fractured roots during extraction, there are some circumstances in which these roots are best left in place, as when the root is suspected to be on the verge of entering an anatomic space or when further instrumentation would cause

damage to a vital adjacent structure, would result in uncontrolled bleeding, or might necessitate an inordinate amount of bone excision. Extreme care is required in extracting maxillary teeth close to the maxillary sinus to avoid sinus exposure and subsequent oroantral fistula. Attention is also needed in extracting mandibular teeth close to the inferior alveolar canal and mental foramen to avoid paresthesia.

Prognosis Extraction usually corrects the underlying problem, and the wound heals completely in about 2 weeks. If multiple teeth are extracted, the healing time may be longer. A 3- to 6-month period may be required for bone and soft tissue to be completely healed and restructured, especially in more complex procedures. More than six teeth extracted in each arch is considered a more complex procedure with increased healing time. Most extractions result in complete healing without complications.

Complications of Procedure Potential complications of tooth extraction include bleeding and infection. Besides infection of the extraction site, infection of the membrane that lines the interior of the heart (endocarditis) is possible in individuals with heart murmurs or a history of rheumatic fever. These individuals may be given antibiotics before and after the procedure to minimize risk. Following an extraction, blood begins to nourish the tooth socket, and a clot forms. If a clot does not form, dry socket (alveolar osteitis) may result, in which the underlying bone is exposed to air and food, causing severe pain and prolonging healing time.

The most common intraoperative complications of tooth extraction are injuries to the soft tissue resulting from lack of attention to the delicate nature of the mucosa and the use of excessive and uncontrolled force during extraction; examples include lip abrasions or burns from a retractor or rotating handpiece. The next most common complications are injuries to osseous structures, such as fractures of the alveolar plate in the buccal cortex of maxillary canines, molars, and mandibular incisors. The maxillary tuberosity is often fractured during the extraction of a difficult molar (see the images below), especially a difficult maxillary third molar. (11) This complication can be prevented by performing a thorough clinical and radiographic examination and taking care not to apply an excessive amount of uncontrolled force. Fractured bone in the tuberosity can be carefully dissected from the tooth with a straight elevator; the bone and soft tissue can then be sutured in place and the extraction site closed primarily. Radiographically, the layers of the tooth are easily identifiable because they have different radiopacities. Enamel is the most mineralized of the calcified tissues of the body, and it is the most radiopaque of the 3 tooth layers. Dentin is less radiopaque than enamel and has a radiopacity similar to that of bone. The pulp tissue is not mineralized and appears radiolucent.
(12)

Extracting a maxillary molar tooth close to the maxillary sinus may result in oroantral communication, which in turn may lead to maxillary sinusitis and the formation of a chronic oroantral fistula. Intraoperatively, sinus communication can be detected by performing a nose-blowing test to check for passage of air or bubbling of blood in the extraction site. A small communication (< 2 mm) may close on its own with the formation of clot and, subsequently, granulation tissue. A moderate-sized communication (2-6 mm) necessitates the placement of a figure-eight suture to stabilize the blood clot. Postoperatively, the patient

should be instructed to avoid nose-blowing, violent sneezing, and sucking on straws. The patient should be placed on an antibiotic for 7 days, a nasal decongestant for 3 days, and an oral decongestant for 7 days. A larger communication (> 7 mm) necessitates a flap procedure to close the defect. Even with meticulous surgical technique, tooth extraction may result in injury to adjacent vital structures. Lingual nerve paresthesia may result after injection if the needle passes through the nerve, the distal incision is positioned too far lingually, or the nerve is cut during lingual bone removal.

Return to Work (Restrictions / Accommodations) After a surgical or forceps extraction, most individuals will require at least 1 day of rest following the procedure. For the first day or two after tooth extraction, aftercare may require frequent rinsing of the mouth or placement of an icepack to reduce swelling, requiring access to a restroom sink and a source of ice. If bone recontouring is performed for the placement of dentures, healing can be up to 1 week before the individual is comfortable and the dentures stable enough to return to work.

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BAB III INFECTIVE ENDOCARDITIS

Infective endocarditis (IE) is defined as an infection of the endocardial surface of the heart, which may include one or more heart valves, the mural endocardium, or a septal defect. Its intracardiac effects include severe valvular insufficiency, which may lead to intractable congestive heart failure and myocardial abscesses. IE also produces a wide variety of systemic signs and symptoms through several mechanisms, including both sterile and infected emboli and various immunological phenomena.(13, 14, 15) IE currently can be described as infective endocarditis in the era of intravascular devices, as infection of intravascular lines has been determined to be the primary risk factor for Staphylococcus aureus bloodstream infections (BSIs). S aureus has become the primary pathogen of endocarditis.(16) Moreover Viridans streptococcai account for 25% of case of endocarditis. These organism is normal human oral flora. IE generally occurs as a consequence of nonbacterial thrombotic endocarditis, which results from turbulence or trauma to the endothelial surface of the heart. A transient bacteremia then seeds the sterile platelet/fibrin thrombus, with IE as the end result. Pathologic effects due to infection can include local tissue destruction and embolic phenomena. In addition, secondary autoimmune effects, such as immune complex glomerulonephritis and vasculitis, can occur.

Types of infective endocarditis Endocarditis has evolved into several variations, keeping it near the top of the list of diseases that must not be misdiagnosed or overlooked. Endocarditis can be broken down into the following categories:

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Native valve endocarditis (NVE), acute and subacute Prosthetic valve endocarditis (PVE),(17) early and late Intravenous drug abuse (IVDA) endocarditis

Other terms commonly used to classify types of IE include pacemaker IE and nosocomial IE (NIE). The classic clinical presentation and clinical course of IE has been characterized as either acute or subacute. Indiscriminate antibiotic usage and an increase in immunosuppressed patients have blurred the distinction between these 2 major types; however, the classification still has clinical merit.(18) Acute NVE frequently involves normal valves and usually has an aggressive course. It is a rapidly progressive illness in persons who are healthy or debilitated. Virulent organisms, such as S aureus and group B streptococci, are typically the causative agents of this type of endocarditis. Underlying structural valve disease may not be present. Subacute NVE typically affects only abnormal valves. Its course, even in untreated patients, is usually more indolent than that of the acute form and may extend over many months. Alpha-hemolytic streptococci or enterococci, usually in the setting of underlying structural valve disease, typically are the causative agents of this type of endocarditis. PVE accounts for 10-20% of cases of IE. Eventually, 5% of mechanical and bioprosthetic valves become infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and, after 1 year, bioprosthetic valves are more likely to be infected. The valves in the mitral valve position are more susceptible than those in the aortic areas.(17) Early PVE occurs within 60 days of valve implantation. Traditionally, coagulase-negative staphylococci, gram-negative bacilli, and Candida species have been the common infecting

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organisms. Late PVE occurs 60 days or more after valve implantation. Staphylococci, alphahemolytic streptococci, and enterococci are the common causative organisms. Recent data suggest that S aureus may now be the most common infecting organism in both early and late PVE.(19) In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of these infections involve the tricuspid valve.(20) S aureus is the most common causative organism. Analogous to PVE are infections of implantable pacemakers and cardioverter-defibrillators. Usually, these devices are infected within a few months of implantation. Infection of pacemakers includes that of the generator pocket (the most common), infection of the proximal leads, and infection of the portions of the leads in direct contact with the endocardium. This last category represents true pacemaker IE, is the least common infectious complication of pacemakers (0.5% of implanted pacemakers), and is the most challenging to treat. Of pacemaker infections, 75% are produced by staphylococci, both coagulase-negative and coagulase-positive. NIE is defined as an infection that manifests 48 hours after the patient is hospitalized or that is associated with a hospital, based on a procedure performed within 4 weeks of clinical disease onset. The term healthcare-associated infective endocarditis (HCIE) is preferable to NIE, since it is inclusive of all sites that deliver patient care, such as hemodialysis centers. The term NIE should be applied to cases of IE acquired in the hospital. An appropriate alternative term would be iatrogenic IE.

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Two types of NIE have been described. The right-sided variety affects a valve that has been injured by placement of an intravascular line (eg, Swan-Ganz catheter). Subsequently, the valve is infected by a nosocomial bacteremia. The second type develops in a previously damaged valve and is more likely to occur on the left side.S aureus has been the predominant pathogen of NIE/HCIE since the recent prevalence of intravascular devices. Enterococci are second most commonly isolated pathogens. These usually arise from a genitourinary source.

Etiology The different types of IE have varying causes and involve different pathogens. Native valve endocarditis The following are the main underlying causes of NVE:

Rheumatic valvular disease (30% of NVE) - Primarily involves the mitral valve followed by the aortic valve

Congenital heart disease (15% of NVE) - Underlying etiologies include a patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot, or any native or surgical high-flow lesion.

Mitral valve prolapse with an associated murmur (20% of NVE) Degenerative heart disease - Including calcific aortic stenosis due to a bicuspid valve, Marfan syndrome, or syphilitic disease

Approximately 70% of infections in NVE are caused by Streptococcus species, including S viridans, Streptococcus bovis, and enterococci. Staphylococcusspecies cause 25% of cases and generally demonstrate a more aggressive acute course (see the images below).

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Prostethic valve endocarditis Early PVE, which presents shortly after surgery, has a different bacteriology and prognosis than late PVE, which presents in a subacute fashion similar to NVE. Infection associated with aortic valve prostheses is particularly associated with local abscess and fistula formation, and valvular dehiscence. This may lead to shock, heart failure, heart block, shunting of blood to the right atrium, pericardial tamponade, and peripheral emboli to the central nervous system and elsewhere. Early PVE may be caused by a variety of pathogens, including S aureus and S epidermidis. These nosocomially acquired organisms are often methicillin-resistant (eg, MRSA).[14] Late disease is most commonly caused by streptococci. Overall, CoNS are the most frequent cause of PVE (30%). S aureus causes 17% of early PVE and 12% of late PVE. Corynebacterium,nonenterococcal streptococci, fungi (eg, C the albicans, HACEK Candida (ie, Haemophilus stellatoidea, aphrophilus,

Aspergillus species), Legionella, and

Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) organisms cause the remaining cases. IVDA infective endocarditis Diagnosis of endocarditis in IV drug users can be difficult and requires a high index of suspicion. Two thirds of patients have no previous history of heart disease or murmur on admission. A murmur may be absent in those with tricuspid disease, owing to the relatively small pressure gradient across this valve. Pulmonary manifestations may be prominent in patients with tricuspid infection: one third have pleuritic chest pain, and three quarters demonstrate chest radiographic abnormalities.

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S aureus is the most common (< 50% of cases) etiologic organism in patients with IVDA IE. MRSA accounts for an increasing portion of S aureus infections and has been associated with previous hospitalizations, long-term addiction, and nonprescribed antibiotic use. Groups A, C, and G streptococci and enterococci are also recovered from patients with IVDA IE. Currently, gram-negative organisms are involved infrequently. P aeruginosa and the HACEK family are the most common examples. Nosocomial/healthcare-associated infective andocarditis Endocarditis may be associated with new therapeutic modalities involving intravascular devices such as central or peripheral intravenous catheters, rhythm control devices such as pacemakers and defibrillators, hemodialysis shunts and catheters, and chemotherapeutic and hyperalimentation lines.(21) These patients tend to have significant comorbidities, more advanced age, and predominant infection with S aureus. The mortality rate is high in this group. The organisms that cause NIE/HCIE obviously are related to the type of underlying bacteremia. The gram-positive cocci (ie, S aureus, CoNS, enterococci, nonenterococcal streptococci) are the most common pathogens. Fungal endocarditis Fungal endocarditis is found in intravenous drug users and intensive care unit patients who receive broad-spectrum antibiotics. Blood cultures are often negative, and diagnosis frequently is made after microscopic examination of large emboli.

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Epidemiology In the United States, the incidence of IE is approximately 2-4 cases per 100,000 persons per year. This rate has not changed in the past 50 years.(22) The incidence of IE in other countries is similar to that in the United States. Although endocarditis can occur in a person of any age, the mean age of patients has gradually risen over the past 50 years. Currently, more than 50% of patients are older than 50 years. Mendiratta et al, in their retrospective study of hospital discharges from 1993-2003 of patients aged 65 years and older with a primary or secondary diagnosis of IE, found that hospitalizations for IE increased 26%, from 3.19 per 10,000 elderly patients in 1993 to 3.95 per 10,000 in 2003.(23) IE is 3 times as common in males as in females. It has no racial predilection.

Pathophysiology IE develops most commonly on the mitral valve, closely followed in descending order of frequency by the aortic valve, the combined mitral and aortic valve, the tricuspid valve, and, rarely, the pulmonic valve. Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection. All cases of IE develop from a commonly shared process, as follows: 1. Bacteremia (nosocomial or spontaneous) that delivers the organisms to the surface of the valve 2. Adherence of the organisms 3. Eventual invasion of the valvular leaflets

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The common denominator for adherence and invasion is nonbacterial thrombotic endocarditis, a sterile fibrin-platelet vegetation. The development of subacute IE depends on a bacterial inoculum sufficient to allow invasion of the preexistent thrombus. This critical mass is the result of bacterial clumping produced by agglutinating antibodies. In acute IE, the thrombus may be produced by the invading organism (ie, S aureus) or by valvular trauma from intravenous catheters or pacing wires (ie, NIE/HCIE). S aureus can invade the endothelial cells (endotheliosis) and increase the expression of adhesion molecules and of procoagulant activity on the cellular surface. Nonbacterial thrombotic endocarditis may result from stress, renal failure, malnutrition, systemic lupus erythematosus, or neoplasia. The Venturi effect also contributes to the development and location of nonbacterial thrombotic endocarditis. This principle explains why bacteria and the fibrin-platelet thrombus are deposited on the sides of the low-pressure sink that lies just beyond a narrowing or stenosis. In patients with mitral insufficiency, bacteria and the fibrin-platelet thrombus are located on the atrial surface of the valve. In patients with aortic insufficiency, they are located on the ventricular side. In these examples, the atria and ventricles are the low-pressure sinks. In the case of a ventricular septal defect, the low-pressure sink is the right ventricle and the thrombus is found on the right side of the defect. Nonbacterial thrombotic endocarditis may also form on the endocardium of the right ventricle, opposite the orifice that has been damaged by the jet of blood flowing through the defect (ie, the MacCallum patch).

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The microorganisms that most commonly produce endocarditis (ie, S aureus; Streptococcus viridans; group A, C, and G streptococci; enterococci) resist the bactericidal action of complement and possess fibronectin receptors for the surface of the fibrin-platelet thrombus. Among the many other characteristics of IE-producing bacteria demonstrated in vitro and in vivo, some features include the following:

Increased adherence to aortic valve leaflet disks by enterococci, S viridans,and S aureus Mucoid-producing strains of S aureus Dextran-producing strains of S viridans S viridans and enterococci that possess FimA surface adhesin Platelet aggregation by S aureus and S viridans and resistance of S aureusto platelet microbicidal proteins

The pathogenesis of pacemaker IE is similar. Shortly after implantation, the development of a fibrin-platelet thrombus (similar to the nonbacterial thrombotic endocarditis described above) involves the generator box and conducting leads. After 1 week, the connective tissue proliferates, partially embedding the leads in the wall of the vein and endocardium. This layer may offer partial protection against infection during a bacteremia. Bacteremia (either spontaneous or due to an invasive procedure) infects the sterile fibrinplatelet vegetation described above. BSIs develop from various extracardiac types of infection, such as pneumonias or pyelonephritis, but most commonly from gingival disease. Of those with high-grade gingivitis, 10% have recurrent transient bacteremias (usually streptococcal species). Most cases of subacute disease are secondary to the bacteremias that develop from the activities of daily living (eg, brushing teeth, bowel movements). The skin is quite resistant to S aureus infection due in great part to its production of antimicrobial peptides. Soong et al discovered that, in vitro, the secretion of alpha toxin by S

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aureus allows the organism to successfully penetrate the keratinocyte layer. This could explain the presence of staphylococcal bacteremia in the absence of any gross damage to the epithelial layer. Bacteremia can result from various invasive procedures, ranging from oral surgery to sclerotherapy of esophageal varices to genitourinary surgeries to various abdominal operations. The potential for invasive procedures to produce a bacteremia varies greatly. Procedures, rates, and organisms are as follows:

Endoscopy - Rate of 0-20%; coagulase-negative staphylococci (CoNS), streptococci, diphtheroids

Colonoscopy - Rate of 0-20%; Escherichia coli, Bacteroides species Barium enema - Rate of 0-20%; enterococci, aerobic and anaerobic gram-negative rods Dental extractions - Rate of 40-100%; S viridans Transurethral resection of the prostate - Rate of 20-40%; coliforms, enterococci, S aureus Transesophageal echocardiography - Rate of 0-20%; S viridans, anaerobic organisms, streptococci

The incidence of nosocomial bacteremias, mostly associated with intravascular lines, has more than doubled in the last few years. Up to 90% of BSIs caused by these devices are secondary to the placement of various types of central venous catheters. Hickman and Broviac catheters are associated with the lowest rates, presumably because of their Dacron cuffs. Peripherally placed central venous catheters are associated with similar rates. Intravascular catheters are infected from 1 of the following 4 sources:

Infection of the insertion site Infection of the catheter Bacteremia arising from another site

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Contamination of the infused solution

Bacterial adherence to intravascular catheters depends on the response of the host to the presence of this foreign body, the properties of the organism itself, and the position of the catheter. Within a few days of insertion, a sleeve of fibrin and fibronectin is deposited on the catheter. S aureus adheres to the fibrin component. S aureus also produces an infection of the endothelial cells (endotheliosis), which is important in producing the continuous bacteremia of S aureus BSIs. Endotheliosis may explain many cases of persistent methicillin-susceptible S aureus (MSSA) and methicillinresistant S aureus (MRSA) catheter-related BSIs without an identifiable cause. S aureus catheter-related BSIs occur even after an infected catheter is removed, apparently attributable to specific virulence factors of certain strains of S aureusthat invade the adjacent endothelial cells. At some point, the staphylococci re-enter the bloodstream, resulting in bacteremia. Four days after placement, the risk of infection markedly increases. Lines positioned in the internal jugular are more prone to infection than those placed in the subclavian vein. Colonization of the intracutaneous tract is the most likely source of short-term catheterrelated BSIs. Among lines in place for more than 2 weeks, infection of the hub is the major source of bacteremia. In some cases, the infusion itself may be a reservoir of infection. Colonization of heart valves by microorganisms is a complex process. Most transient bacteremias are short-lived, are without consequence, and are often not preventable. Bacteria rarely adhere to an endocardial nidus before the microorganisms are removed from the circulation by various host defenses.

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Once microorganisms do establish themselves on the surface of the vegetation, the process of platelet aggregation and fibrin deposition accelerate at the site. As the bacteria multiply, they are covered by ever-thickening layers of platelets and thrombin, which protect them from neutrophils and other host defenses. Organisms deep in the vegetation hibernate because of the paucity of available nutrients and are therefore less susceptible to bactericidal antimicrobials that interfere with bacterial cell wall synthesis. Complications of subacute endocarditis result from embolization, slowly progressive valvular destruction, and various immunological mechanisms. The pathological picture of subacute IE is marked by valvular vegetations in which bacteria colonies are present both on and below the surface. The cellular reaction in SBE is primarily that of mononuclear cells and lymphocytes, with few polymorphonuclear cells. The surface of the valve beneath the vegetation shows few organisms. Proliferation of capillaries and fibroblasts is marked. Areas of healing are scattered among areas of destruction. Over time, the healing process falls behind, and valvular insufficiency develops secondary to perforation of the cusps and damage to the chordae tendineae. Compared with acute disease, little extension of the infectious process occurs beyond the valvular leaflets. levels of agglutinating and complement-fixing bactericidal antibodies and cryoglobulins are markedly increased in patients with subacute endocarditis. Many of the extracardiac manifestations of this form of the disease are due to circulating immune complexes. Among these include glomerulonephritis, peripheral manifestations (eg, Osler nodes, Roth spots, subungual hemorrhages), and, possibly, various musculoskeletal abnormalities. Janeway lesions usually arise from infected microemboli.

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The microscopic appearance of acute bacterial endocarditis differs markedly from that of subacute disease. Vegetations that contain no fibroblasts develop rapidly, with no evidence of repair. Large amounts of both polymorphonuclear leukocytes and organisms are present in an ever-expanding area of necrosis. This process rapidly produces spontaneous rupture of the leaflets, of the papillary muscles, and of the chordae tendineae. The complications of acute bacterial endocarditis result from intracardiac disease and metastatic infection produced by suppurative emboli. Because of their shortened course, immunological phenomena are not a part of acute IE.

History and clinical In patients with infective endocarditis (IE), the present illness history is highly variable. Symptoms commonly are vague, emphasizing constitutional complaints, or complaints may focus on primary cardiac effects or secondary embolic phenomena. Fever and chills are the most common symptoms; anorexia, weight loss, malaise, headache, myalgias, night sweats, shortness of breath, cough, or joint pains are common complaints as well. Primary cardiac disease may present with signs of congestive heart failure due to valvular insufficiency. Secondary phenomena could include focal neurologic complaints due to an embolic stroke or back pain associated with vertebral osteomyelitis. As many as 20% of cases present with focal neurologic complaints and stroke syndromes. Subacute native valve endocardtis The symptoms of early subacute native valve endocarditis (NVE) are usually subtle and nonspecific. They include low-grade fever (absent in 3-15% of patients), anorexia, weight loss, influenzalike syndromes, polymyalgia-like syndromes, pleuritic pain, syndromes similar

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to rheumatic fever (eg, fever, dulled sensorium as in typhoid, headaches), and abdominal symptoms (eg, right upper quadrant pain, vomiting, postprandial distress, appendicitis-like symptoms). When appropriate therapy is delayed for weeks or months, additional clinical features, embolic or immunological in origin, develop. Signs and symptoms secondary to emboli include acute meningitis with sterile spinal fluid, hemiplegia in the distribution of the middle cerebral artery, regional infarcts that cause painless hematuria, infarction of the kidney or spleen, unilateral blindness caused by occlusion of a retinal artery, and myocardial infarction arising from embolization of a coronary artery. Bacteria-free infective endocarditis Rarely observed today, the bacteria-free state of IE is one in which patients have multiple negative blood culture results in the presence of severe congestive heart failure, renal failure, multiple sterile emboli, massive splenomegaly, severe anemia, brown facial pigmentation, bilateral thigh pain, and massive leg edema. These patients are usually afebrile. This process appears to indicate prolonged and unchecked stimulation of the immune system. Acute infective endocarditis The clinical symptoms of acute IE result from either embolic or intracardiac suppurative complications. The onset of illness is abrupt, with rapidly progressive destruction of the infected valve (see the images below). The valvular leaflets are quickly destroyed by bacteria that multiply rapidly within the ever-growing friable vegetations. Complications develop within a week. These include the dyspnea and fatigue of severe congestive heart failure and a wide spectrum of neuropsychiatric complications resulting from CNS involvement.

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Intravenous-drug-abuse infective endocarditis Patients with right-sided intravenous drug abuse (IVDA) IE (53% of cases) frequently present with pleuropulmonary (pneumonia and/or empyema) manifestations. Symptoms due to metastatic infection develop early in a disease course caused by S aureus. Right-sided disease is associated with a low rate of congestive heart failure and valvular perforation. Infection with P aeruginosa has a high rate of neurological involvement, with 2 distinctive features: (1) mycotic aneurysms with a higher-than-average rate of rupture and (2) panophthalmitis (10% of patients). The course of infection with P aeruginosa is much slower than that of S aureus. The course of left-sided IVDA IE is similar to that of non-IVDA disease. Approximately 5-8% of febrile individuals who abuse intravenous drugs have underlying IE. Many users of illicit drugs may lose their fever within a few hours of hospitalization. This phenomenon, termed cotton wool fever, is probably caused by the presence of adulterants contained within the injected drugs. Prosthetic valve endocarditis The clinical presentation in a person with a pacemaker infection and pacemaker IE depends on several factors, including the site of infection (eg, generator pocket vs intravascular leads or epicardial leads), the type of organism, and the origin of the infection (eg, pocket erosion, localized infection of the generator pocket, bacteremia from a remote site). Early infections, within a few months of implantation, manifest as acute or subacute infections of the pulse-generator pocket. Bacteremia may be present even in the absence of clinical signs and symptoms. Fever is the most common finding and may be the only finding in approximately 33% of patients.

25

Late infections of the pocket may be due to erosion of the overlying skin without systemic involvement. Such erosions always indicate infection of the underlying device. The most significant late infections involve the transvenous or epicardial leads. With epicardial infection, signs and symptoms of pericarditis or mediastinitis may be present along with bacteremia. Infection of the transvenous electrode produces signs and symptoms of right-sided endocarditis. Those that occur early after implantation (33% of cases) show prominent systemic signs of infection, often with obvious localization to the pacemaker pocket. Late infections have much more subtle manifestations. They may occur up to several years after implantation or reimplantation. Fever is almost universal in persons with pacemaker IE. Signs of right-sided endocarditis (ie, pneumonia, septic emboli) are observed in up to 50% of patients. Pacemaker infective endocarditis NIE commonly manifests with elements of a sepsis syndrome (ie, hypotension, metabolic acidosis fever, leukocytosis, and multiple organ failure). The source of bacteremia may develop from an infection in another organ (eg, pneumonia, pyelonephritis) or from a central venous catheter. Most often, these patients are in the intensive care unit. Approximately 45% of cases of NIE/HCIE occur in patients with prosthetic valves.

Physical Examination General findings Fever, possibly low-grade and intermittent, is present in 90% of patients.

26

The AHA (endorsed by the Infectious Diseases Society of America [IDSA]) 2010 guideline update on cardiovascular implantable electronic device (CIED) infections and their management recommends that patients with CIED who develop unexplained fever or bloodstream infection should seek evaluation for CIED infection by cardiologists or infectious disease specialists.(24) Heart murmurs are heard in approximately 85% of patients. Change in the characteristics of a previously noted murmur occurs in 10% of these patients and increases the likelihood of secondary congestive heart failure. One or more classic signs of IE are found in as many as 50% of patients. They include the following:

Petechiae - Common but nonspecific finding (see the image below) Subungual (splinter) hemorrhages - Dark red linear lesions in the nailbeds Osler nodes - Tender subcutaneous nodules usually found on the distal pads of the digits Janeway lesions - Nontender maculae on the palms and soles Roth spots - Retinal hemorrhages with small, clear centers; rare and observed in only 5% of patients.

Signs of neurologic disease occur in as many as 40% of patients. Embolic stroke with focal neurologic deficits is the most common etiology. Other etiologies include intracerebral hemorrhage and multiple microabscesses. Signs of systemic septic emboli are due to left heart disease and are more commonly associated with mitral valve vegetations. Multiple embolic pulmonary infections or infarctions are due to right heart disease.

27

Signs of congestive heart failure, such as distended neck veins, frequently are due to acute left-sided valvular insufficiency. Splenomegaly may be present. Other signs include the following:

Stiff neck Delirium Paralysis, hemiparesis, aphasia Conjunctival hemorrhage Pallor Gallops Rales Cardiac arrhythmia Pericardial rub Pleural friction rub

Workup Blood and urine studies Send baseline studies, such as complete blood count (CBC), electrolytes, creatinine, blood urea nitrogen (BUN), glucose, and coagulation panel, to the laboratory for testing. Anemia is common in subacute endocarditis. Leukocytosis is observed in acute endocarditis. Erythrocyte sedimentation rate (ESR), while not specific, is elevated in more than 90% of cases. Decreased C3, C4, and CH50 are evident in subacute endocarditis.

28

Rheumatoid factor (ie, poor mans circulating immune complex) becomes positive in 50% of patients with subacute disease. It becomes negative after successful treatment. Proteinuria and microscopic hematuria are present in approximately 50% of cases. Blood culture The criterion standard test for diagnosing IE is the documentation of a continuous bacteremia (>30 min in duration) based on blood culture results. Exceptions are observed in patients with prosthetic valve endocarditis (PVE) and right-sided IE. About 5-10% of patients with IE have false-negative blood culture results. Prior use of antibiotics is the most common cause of false-negative blood culture results. Other causes include fastidious organisms and inadequate blood volume; a blood-to-broth ratio of 1:10 is needed. Currently, with modern automated blood culture systems, fastidious organisms such as nutritionally variant streptococci and members of the HACEK group rarely cause culturenegative IE. As many as 50% of positive blood culture results have been estimated to be falsely positive. This rate has probably decreased, but false-positive blood culture results remain a major diagnostic challenge. One such result can lead to 4 days of unnecessary patient hospitalization. The significance of positive blood culture results correlates with the following:

The type of organism The clinical setting (coagulase-negative staphylococci [CoNS] are significant in patients with prosthetic valves but not in those with native valves)

Multiple blood cultures positive for the same organism Shorter incubation time for recovery

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The degree of severity of clinical illness

Echocardiography Echocardiography has become the indirect diagnostic method of choice, especially in patients who present with a clinical picture of IE but who have nondiagnostic blood culture results (eg, some patients with fungal endocarditis). The diagnosis of IE can never be excluded based on negative echocardiogram findings, either from TTE or from TEE. Echocardiography has become the indirect diagnostic method of choice, especially in patients who present with a clinical picture of IE but who have nondiagnostic blood culture results (eg, some patients with fungal endocarditis). The diagnosis of IE can never be excluded based on negative echocardiogram findings, either from TTE or from TEE. Echocardiographic predictors of systemic embolization in patients with IE are the following:

Large valvular vegetations (>10 mm in diameter) Multiple vegetations Mobile but pedunculated vegetations Noncalcified vegetations Vegetations that are increasing in size Prolapsing vegetations

Echocardiography is also highly useful for detecting abscesses. As with valvular lesions, the transesophageal technique is generally more sensitive. In summary, the indications for performing echocardiography with Doppler in patients with IE are to provide a baseline in proven or highly suggestive cases of IE and to provide a means of documenting complications during therapy.

30

In most cases, TTE is sufficient. TEE is indicated when mechanical prosthetic valves are present; to detect right-sided lesions; and to visualize myocardial abscesses. Because of the endoscopic portion of the test, TEE carries the risk factor of inducing bacteremias. Approximately 15% of cases of IE do not demonstrate any detectable vegetations at the time of the echocardiographic study. Radiography
Pulmonary embolic phenomena on radiographs strongly suggest tricuspid disease.
A young adult with a history of intravenous drug use, endocarditis involving the tricuspid valve with Staphylococcus aureus, and multiple septic pulmonary emboli. Pulmonary lesions on chest radiograph are most prominent in the right upper lobe with both solid and cavitary appearance.

Multiple embolic pyogenic abscesses may be visualized (see the image below).
A young adult with a history of intravenous drug use diagnosed with rightsided staphylococcal endocarditis and multiple embolic pyogenic abscesses on chest radiograph.

Treatment The major goals of therapy for infective endocarditis (IE) are to eradicate the infectious agent from the thrombus and to address the complications of valvular infection. The latter includes both the intracardiac and extracardiac consequences of IE. Some of the effects of IE require surgical intervention. Emergent care should focus on making the correct diagnosis and stabilizing the patient with acute disease and cardiovascular instability. General measures include the following:

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Treatment of congestive heart failure Oxygen Hemodialysis (may be required in patients with renal failure)

In most cases, the etiologic microbial agent is not known while the patient is in the ED. Three sets of blood cultures should be drawn over a few hours, and then empiric antibiotic therapy tailored to the patients history and circumstances may be administered . Mild congestive heart failure resulting from valvular insufficiency or myocarditis may be managed with standard medical therapy. Often, this is progressive, and despite achieving a microbiological cure, it requires valvular surgery.

Medication Antibiotics remain the mainstay of treatment for IE. In the setting of acute IE, institute antibiotic therapy as soon as possible to minimize valvular damage. Three to 5 sets of blood cultures are obtained within 60-90 minutes, followed by the infusion of the appropriate antibiotic regimen. By necessity, the initial antibiotic choice is empiric in nature, determined by clinical history and physical examination findings. Empiric antibiotic therapy is chosen based on the most likely infecting organisms. Native valve endocarditis (NVE) has often been treated with penicillin G and gentamicin for synergistic coverage of streptococci. Patients with a history of intravenous (IV) drug use have been treated with nafcillin and gentamicin to cover for methicillin-sensitive staphylococci. The emergence of methicillin-resistant S aureus (MRSA) and penicillin-resistant streptococci has led to a change in empiric treatment with liberal substitution of vancomycin in lieu of a penicillin antibiotic.

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Prosthetic valve endocarditis (PVE) may be caused by MRSA or coagulase-negative staphylococci (CoNS); thus, vancomycin and gentamicin may be used for treatment, despite the risk of renal insufficiency. Rifampin is necessary in treating individuals with infection of prosthetic valves or other foreign bodies because it can penetrate the biofilm of most of the pathogens that infect these devices. However, it should be administered with vancomycin or gentamicin. These latter 2 agents serve to prevent the development of resistance to the rifampin. Substitution of linezolid for vancomycin should be considered in patients with unstable renal function because of the difficulty of achieving therapeutic trough levels in this situation. Linezolid or daptomycin are options for patients with intolerance to vancomycin or resistant organisms.(25) Organisms with a minimum inhibitory concentration (MIC) to vancomycin of equal to or greater than 2 mcg/mL should be treated with alternative agents. Appropriate regimens should be devised in consultation with a specialist in infectious disease. In the case of subacute IE, treatment may be safely delayed until culture and sensitivity results are available. Waiting does not increase the risk of complications in this form of the disease. Eradicating bacteria from the fibrin-platelet thrombus is extremely difficult because (1) the high concentration of organisms present within the vegetation (ie, 10-100 billion bacteria per gram of tissue), (2) their position deep within the thrombus, (3) their location in both a reduced metabolic and reproductive state, and (4) the interference of fibrin and white cells with antibiotic action. For all of these reasons, bactericidal antibiotics are considered necessary for cure of valvular infection.

33

IV administration is preferred because more reliable therapeutic levels are achieved with this route. Orally administered antibiotics have been used as suppressive therapy for incurable valvular infections (ie, inoperable PVE). Treat all patients in a hospital or skilled nursing facility to allow adequate monitoring of the development of complications and the response to antibiotic therapy. Diet No special diets are recommended for patients with endocarditis; however, if the patient has congestive heart failure, administer a sodium-restricted diet. Activity limitations are determined by the severity of the illness, complications (eg, stroke), and the presence of significant congestive heart failure. Indication Surgery Approximately 15-25% of patients with IE eventually require surgery. Indications for surgical intervention in patients with NVE are as follows:

Congestive heart failure refractory to standard medical therapy Fungal IE (except that caused by Histoplasma capsulatum) Persistent sepsis after 72 hours of appropriate antibiotic treatment Recurrent septic emboli, especially after 2 weeks of antibiotic treatment Rupture of an aneurysm of the sinus of Valsalva Conduction disturbances caused by a septal abscess Kissing infection of the anterior mitral leaflet in patients with IE of the aortic valve

Consultations In general, both a cardiologist and an infectious diseases specialist should be involved in the care of patients with IE. Consulting a cardiothoracic surgeon may be necessary. Personnel in

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the clinical microbiology laboratory must have the skill to isolate the organism, properly identify it, and perform susceptibility testing appropriate for the growth characteristics and requirements of the organism (with determination of the MIC of clinically relevant antimicrobial agents). To obtain the best possible information, the attending physician should work closely with the microbiology laboratory personnel. Complications The following are potential complications of IE:

Myocardial infarction, pericarditis, cardiac arrhythmia Cardiac valvular insufficiency Congestive heart failure Sinus of Valsalva aneurysm Aortic root or myocardial abscesses Arterial emboli, infarcts, mycotic aneurysms Arthritis, myositis Glomerulonephritis, acute renal failure Stroke syndromes Mesenteric or splenic abscess or infarct

Congestive heart failure due to aortic valve insufficiency is the most common intracardiac complication of subacute endocarditis. It develops after months of untreated disease but may occur a full year following microbiological cure. The complication of arterial embolization is second in frequency to congestive heart failure for both subacute and acute IE. The frequency of this complication has decreased, from 80% in the preantibiotic era to 15-35% today. The emboli are usually sterile because of the minimally invasive nature of the causative organisms (eg, S viridans).

35

The persons most at risk are younger (20-40 y), have mitral or aortic valve (native or prosthetic) involvement, and are infected with certain organisms such B

asCandida or Aspergillus species, S

aureus,

Haemophilus

parainfluenzae, group

streptococci, and nutritionally variant streptococci. The prevalence of embolization appears to be the same for both types of disease. The most common areas of deposition include the coronary arteries, kidneys, brain, and spleen. Infarction at the site of embolization is common; abscess formation is not. Cerebral emboli occur in 33% of patients. The middle cerebral artery is involved most often. Other neurological embolic damage includes cranial nerve palsies, cerebritis, and mycotic aneurysms caused by weakening of the vessel walls and produced by embolization to the vasa vasorum. Mycotic aneurysms may occur in the abdominal aorta and the splenic, coronary, and pulmonary arteries. In acute IE, the frequency of aneurysms and other suppurative intracardiac complications is high. In addition to valvular insufficiency, other intracardiac complications of acute IE include (1) aortocardiac and other fistulas, (2) aneurysms of the sinus of Valsalva, (3) intraventricular abscesses, (4) ring abscesses, (5) myocardial abscesses, (6) mycotic aneurysms, (7) septic coronary arterial emboli, and (8) pericarditis. In patients with acute disease, especially disease caused by S aureus infection,emboli almost inevitably lead to abscesses in the areas where they are deposited. Multiple abscesses can occur in almost every organ, including the kidneys, heart, and brain. Mycotic aneurysms may occur in almost any artery. Paradoxically, they are less common in patients with acute IE.

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Prognosis Prognosis largely depends on whether or not complications develop. If left untreated, IE is generally fatal. Early detection and appropriate treatment of this uncommon disease can be lifesaving. Cure rates for appropriately managed (including both medical and surgical therapies) NVE are as follows:

For S viridans and S bovis infection, the rate is 98%. For enterococci and S aureus infection in individuals who abuse intravenous drugs, the rate is 90%.

For community-acquired S aureus infection in individuals who do not abuse intravenous drugs, the rate is 60-70%.

For infection with aerobic gram-negative organisms, the rate is 40-60%. For infection with fungal organisms, the rate is lower than 50%.

For PVE, the cure rates are as follows:

Rates are 10-15% lower for each of the above categories, for both early and late PVE. Surgery is required far more frequently. Approximately 60% of early CoNS PVE cases and 70% of late CoNS PVE cases are curable.

Anecdotal reports describe the resolution of right-sided valvular infection caused by S. aureus infection in individuals who abuse intravenous drugs after just a few days of oral antibiotics. The role of valvular surgery in reducing mortality among patients with IE has been unclear. Challenges to resolving this question include the necessity of performing multicentered studies with an apparent difficulty of ensuring that the patients' preoperative assessments and

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surgical approaches are comparable. The largest study to date indicates that in cases of IE complicated by heart failure, valvular surgery reduces the 1-year mortality rate. Mortality rates in NVE range from 16-27%. Mortality rates in patients with PVE are higher. More than 50% of these infections occur within 2 months after surgery. The fatality rate of pacemaker IE ranges up to 34%. Increased mortality rates are associated with increased age, infection involving the aortic valve, development of congestive heart failure, central nervous system (CNS) complications, and underlying disease such as diabetes mellitus. Catastrophic neurological events of all types due to IE are highly predictive of morbidity and mortality. Mortality rates also vary with the infecting organism. Acute endocarditis due to S aureus is associated with a high mortality rate (30-40%), except when it is associated with IV drug use. Endocarditis due to streptococci has a mortality rate of approximately 10%.

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BAB IV CORRELATION BETWEEN EXTRACTION AND INFECTIVE ENDOCARDITIS

The problem of whether patients with extractions especially periodontal diseases are at higher risk from infective endocarditis than people who have healthy gingivae has not yet been fully addressed. However, several reports indicate that bacteremia is more frequently inducible in patients with severer periodontal diseases than those who have healthier periodontal tissue after extraction. Gum inflammation loosens the gingival epithelial tissues and it often becomes ulcerative at the inner part of periodontal pockets. It can thus provide oral bacteria the route for getting into the host circulation. Furthermore, some periodontopathic bacteria such as A. Actinomycetemcomitans and P. gingivalis have the capacity to invade the host epithelial and connective tissues, and these characteristics are considered to be involved in the enlargement of inflammatory lesions. Periodontopathic bacteria which seem to be less important etiologic agents of infective endocarditis may play important roles in the induction of this disease by causing gum inflammation and opening a route toward the blood circulation for endocardiopathic viridans streptococci. Indirect evidence for relationship between extraction and infective endocarditis . And then direct evidence for the relationship between the prevalence of periodontal disease and the incidence of infective endocarditis remains to be investigated. Cohort studies are expected to provide better evidence to elucidate this relationship.

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BAB V CONCLUSION

Common extraction, even non-surgical dental procedures, often cause bacteremia that can result in infective endocarditis in people who have a predisposing risk for this disease, such as valvular heart diseases including prosthetic valves, congenital heart diseases, cardiomyopathy, coronary artery disease, pacemaker implantation, etc. The infection is established when all 3 conditions simultaneously occur, i.e., a predisposing impairment in the heart, the introduction of bacteremia and the virulence of the introduced bacteria. Common dental procedures often cause bacteremia and periodontally diseased patients may even suffer from bacteremia after extraction. Antibiotics have to be used adequately in order to prevent such infections during dental procedures, however, theirfrequent use can also generate drug-resistant mutant bacteria. The development of novel drugs to be used as an alternative to the current antibiotics is therefore highly desired.

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