In its secondary form, the APA syndrome has been linked to autoimmune disorders, particularly sys- temic lupus erythematosus, and malignancies. Sterile valvular vegetations form and embolize, clinically mimicking in many respects culture-negative IE. The mitral valve is most often affected, and valvular regurgitation is the predominant func- tional abnormality seen in APA syndrome with complicating valvular involvement. To complicate matters, the APA syn- drome may develop secondary to IE.239 Numerous other causes of noninfective vegetative endo- carditis can mimic IE. These can be categorized into 4 : neoplasia associated (atrial myxoma, marantic endocarditis, neoplastic disease, and carcinoid), autoimmune associated (rheumatic carditis, systemic lupus erythematosus, polyarteritis nodosa, and Beh et disease), postvalvular surgery (thrombus, stitch, or other postsurgery changes), and miscel- laneous (eosinophilic heart disease, ruptured mitral chordae, and myxomatous degeneration). Recommendations 1. An evaluation of epidemiological factors, history of prior infections including cardiovascular infections, exposure to antimicrobials, clinical course, sever- ity, and extracardiac sites of infection of the current infection should be performed in all culture-nega- tive endocarditis cases (Class I; Level of Evidence C). 2. Consultation with an infectious diseases specialist to define the most appropriate choice of therapy in patients with culture-negative endocarditis is rec- ommended (Class I; Level of Evidence C). 3. For patients with acute (days) clinical presentations of native valve infection, coverage for S aureus, -hemolytic streptococci, and aerobic Gram- negative bacilli is reasonable (Class IIa; Level of Evidence C). 4. For patients with a subacute (weeks) presenta- tion of NVE, coverage of S aureus, VGS, HACEK, and enterococci is reasonable (Class IIa; Level of Evidence C). 5. For patients with culture-negative PVE, cover- age for staphylococci, enterococci, and aerobic Gram-negative bacilli is reasonable if onset of symp- toms is within 1 year of prosthetic valve placement (Class IIa; Level of Evidence C). 6. If symptom onset is >1 year after valve placement, then IE is more likely to be caused by staphylococci, VGS, and enterococci, and antibiotic therapy for these potential pathogens is reasonable (Class IIa; Level of Evidence C). 7. If subsequent blood culture results or other labora- tory methodologies define a pathogen, then empiri- cal therapy should be revised to focused therapy that is recommended for the specific pathogen iden- tified (Class I; Level of Evidence C). Fungi Fungal IE is rare but can develop in a wide range of The well-recognized risk factors associated with fungal IE (eg, IDU and immunocompromised state) have become less prevalent compared with the presence of a car- diovascular device, including central venous catheters, perma- nent pacemakers and defibrillators, and prosthetic valves.240 246 Fungal IE has been recognized as a cause of early PVE, but a case series from a single medical center demonstrated that 43% of these cases had symptom onset >1 years after pros- thetic valve placement.242 In contrast to the expected older age predilection for the development of IE, patients with fungal IE have been younger, which was somewhat unanticipated, con- sidering the low prevalence of IDU among the cohort. Candida and Aspergillus species account for the large majority of fun- gal IE, and Candida-related IE is much more common than Blood cultures are ultimately positive in most cases caused by the former pathogen, whereas they are rarely positive in cases caused by the latter fungus. Thus, Aspergillus is a cause of culture-negative IE, and when this occurs, it is usually in a patient with a prosthetic cardiac A variety of other fungi, including endemic mycoses, can rarely cause IE and can involve both native and prosthetic valves. Noncardiac sites of metastatic infection often compli- cate fungal IE; this can include, for example, endophthalmitis in patients with candidal IE, which may require both systemic and intraocular antifungal therapy. Further guidelines are available from the Infectious Diseases Society of America for additional management aspects of several of the fungal patho- gens (http://www.idsociety.org/IDSA_Practice_Guidelines/). Despite aggressive combined medical and surgical inter- ventions and a younger cohort, mortality rates for fungal IE are unacceptably high. The survival rate for patients with mold-related IE is <20%. Historically, 2 treatment doctrines have prevailed in fungal IE despite the lack of prospective tri- als conducted to define the most appropriate therapy: Fungal IE is a stand-alone indication for surgical replacement of an infected valve; and amphotericin B, a fungicidal agent, is the initial drug of choice for fungal IE. Because of the alarming mortality rate associated with fungal IE and the availability of newer antifungal drugs, in particular fungicidal drugs like the echinocandins, a re-evaluation of these principles seems in order. If done, however, this will probably be based on anec- dotal experience and expert opinion rather than on clinical trial data because of the rarity of the syndrome. Baddour et al Infective Endocarditis in Adults 1465 A 2-phase treatment of fungal IE has evolved. The initial or induction phase consists of control of infection. Treatment includes a combination of a parenteral antifungal agent, usu- ally an amphotericin B containing product, and valve sur- gery. Valve surgery should be done in most cases of fungal IE. Results of a meta-analysis that included 879 cases of Candida IE demonstrated a marked reduction in death (prevalence odds ratio, 0.56; 95% confidence interval, 0.16 1.99) among those who underwent adjunctive valve surgery.244 In addition, patients who were treated with combination therapy including amphotericin B and flucytosine had reduced mortality com- pared with those who received antifungal monotherapy. Antifungal therapy usually is given for >6 weeks. After completion of this initial therapy, long-term (lifelong) sup- pressive therapy with an oral azole is reasonable.243,244,246 Suppressive therapy has been used in 2 populations. First, because of the high relapse rate of fungal IE and the prolonged delay (years in some cases) in relapse, oral azoles have been administered after combined medical and surgical induction therapy. In a second population with fungal IE, lifelong oral antifungal suppressive therapy has been given to patients who respond clinically to induction medical therapy but are not deemed appropriate surgical candidates for valve replacement for attempted infection cure. Anecdotal case series243,245 indi- cate that IE has been successfully suppressed for months to years. A meta-analysis that included 64 reported patients with Candida IE who did not undergo valve surgery because they were deemed to be unacceptable surgical candidates supports the notion that fluconazole suppressive therapy is useful; 20 of 21 patients (95%) who were ultimately treated with long-term suppressive therapy survived during follow-up, which was 6 Recommendations 1. Valve surgery should be done in most cases of fungal IE (Class I; Level of Evidence B). 2. After completion of initial parenteral therapy, life- long suppressive therapy with an oral azole is rea- sonable (Class IIa; Level of Evidence B). Surgical Management There is a prevailing opinion that valve surgery is crucial for optimal therapy in selected patients with complicated IE.247 249 In a systematic review5 of 15 population-based IE investiga- tions from 7 countries, after adjustment for country, the pro- portion of IE cases undergoing valve surgery increased 7% between 1969 and 2000. In surveys involving population- and international multicenter cohorts,10,11 both NVE and PVE patients undergo valve surgery during the active phase of IE (during initial hospitalization before com- pletion of a full therapeutic course of antibiotics). Although valve replacement surgery has served as an important option in the management of individual IE cases, only 1 small, randomized trial17 has been performed to date to examine the role of valve surgery in the management of IE. In this trial, 76 patients with left-sided NVE, severe valve regur- gitation without heart failure, and vegetations >10 mm were assigned to early surgery within 48 hours or to conventional treatment. Although the authors17 report a reduction in the composite outcome of in-hospital deaths and embolic events with early surgery (3% versus 23%), the differences between the 2 groups were driven by a significant decrease in embolic events with early surgery. Thus, firm conclusions cannot be drawn from this trial on the effect of early surgery on mor- tality, given the small sample size of the study. In addition, patients in this trial were young and had limited comorbidity based on a EuroSCORE, a calculated risk of surgical mortality (http://www.euroscore.org), a low prevalence of S aureus IE, and lower mortality compared with most contemporary patient cohorts. Moreover, many patients had signs of embolization (a Class IIa indication for surgery) before randomization. Data from nonrandomized trials from a single-center experience250 and an international collaboration251 support the notion252 that early valve surgery may not be beneficial in all patients with native or PVE caused by S aureus. Over several decades, expert panels have relied on data from observational studies to make recommendations on the indications for early surgery. Despite the availability of new studies, the indications for surgery have not changed appre- ciably over time.18 Considering that observational studies are prone to bias and confounding, researchers have used regres- sion analysis and calculated propensity scores to adjust for prognostically important baseline differences between surgi- cal and medical patients.14,253 examin- ing the association between valve surgery and outcome in left-sided IE using propensity score analysis, however, have demonstrated conflicting results, likely because of the use of different analytical approaches. Until 2007, none of the published studies adjusted for sur- vivor bias, which occurs because patients who live longer are more likely to undergo surgery than those who die early.A cor- relation between longer survival and surgery may be wrongly interpreted as evidence that surgical treatment improves sur- have documented the effect of survivor bias on the association between surgery and mortality in IE patients. When adjusted for survivor bias, analyses have shown either a statistical loss of benefit of early surgery or findings indicating that the surgical intervention may actually result in harm. Between 2007 and 2013, at least 6 observational stud- that adjusted for selection bias, confounding, and survivor bias were conducted. Three studies that included 2 cohorts of patients with NVE and PVE and 1 cohort with NVE showed an association between early surgery and lower mortality in IE patients in general or in specific subgroups of patients such as those with heart failure or paravalvular com- plications. Only 1 study examined the role of valve surgery After adjustment for differences in clinical char- acteristics and survival bias, early valve replacement was not associated with lower mortality compared with medical therapy in the overall cohort. Subgroup analysis indicated a lower in-hospital and 1-year mortality with early surgery only in the group of patients with the highest surgical propensity. Table 17 summarizes the characteristics of rigorously con- ducted observational studies that support the role of surgery in IE management. Indications for Surgery Decisions on surgical intervention are complex and depend on many clinical and prognostic factors257 262 that vary among patients, including infecting organism, vegetation size, presence of perivalvular infection, presence of embolism or heart failure, age, noncardiac comorbidities, and available surgical expertise. There is a paucity of evidence available to define the optimal timing of valve surgery. Decisions on the indication and timing of surgical intervention should be determined by a multispecialty team with expertise in cardiology, imaging, cardiothoracic sur- gery, and infectious diseases.261 Recommendations for early sur- gery in patients with recurrent emboli and persistent vegetations have generally been enacted after clinical events. Whether recur- rent, asymptomatic emboli detected on advanced imaging stud- ies should influence decision making should be considered on an individual basis. Risk stratification models such as the Society of Thoracic Surgeons Endocarditis Score are available to predict morbidity and mortality risks in IE patients after valve surgery and to assist in decision making and patient counseling.260 Early Valve Surgery in Left-Sided NVE: Recommendations 1. Early surgery (during initial hospitalization and before completion of a full course of antibiotics) is indicated in patients with IE who present with valve dysfunction resulting in symptoms or signs of heart failure (Class I; Level of Evidence B). 2. Early surgery should be considered particularly in patients with IE caused by fungi or highly resistant organisms (eg, vancomycin-resistant Enterococcus, multidrug-resistant Gram-negative bacilli) (Class I; Level of Evidence B). 3. Early surgery is indicated in patients with IE com- plicated by heart block, annular or aortic abscess, or destructive penetrating lesions (Class I; Level of Evidence B). 4. Early surgery is indicated for evidence of persistent infection (manifested by persistent bacteremia or fever lasting >5 7 days and provided that other sites of infection and fever have been excluded) after the start of appropriate antimicrobial therapy (Class I; Level of Evidence B). 5. Early surgery is reasonable in patients who present with recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy (Class IIa; Level of Evidence B). 6. Early surgery is reasonable in patients with severe valve regurgitation and mobile vegetations >10 mm (Class IIa, Level of Evidence B). 7. Early surgery may be considered in patients with mobile vegetations >10 mm, particularly when involving the anterior leaflet of the mitral valve and associated with other relative indications for sur- gery (Class IIb; Level of Evidence C). Early Valve Surgery in PVE: Recommendations 1. Early surgery is indicated in patients with symp- toms or signs of heart failure resulting from valve dehiscence, intracardiac fistula, or severe prosthetic valve dysfunction (Class I; Level of Evidence B). 2. Early surgery should be done in patients who have persistent bacteremia despite appropriate antibi- otic therapy for 5 to 7 days in whom other sites of infection have been excluded (Class I; Level of Evidence B). 3. Early surgery is indicated when IE is compli- cated by heart block, annular or aortic abscess, or destructive penetrating lesions (Class I; Level of Evidence B). 4. Early surgery is indicated in patients with PVE caused by fungi or highly resistant organisms (Class I; Level of Evidence B). 5. Early surgery is reasonable for patients with PVE who have recurrent emboli despite appropriate anti- biotic treatment (Class IIa; Level of Evidence B). 6. Early surgery is reasonable for patients with relaps- ing PVE (Class IIa; Level of Evidence C). 7. Early surgery may be considered in patients with mobile vegetations >10 mm (Class IIb; Level of Evidence C). Valve Surgery in Patients With Right-Sided IE Although outcomes are better for patients with right-sided IE compared with patients with left-sided infection, surgi- cal intervention is occasionally considered in the former group. Because many of the patients with right-sided IE develop infection as a result of IDU (see the Right-Sided IE in IDUs section), the general approach is to treat these patients Table 17. Direct Evidence Supporting an Association Between Valve Surgery and Lower Mortality From Observational Studies: Level of Evidence B Study Mortality IE Group PE vs SA Lalani et al10 In-hospital mortality NVE PE Bannay et al15 5-y mortality NVE+PVE PE Kiefer et al11 In-hospital and 1-y mortality CHF (NVE+PVE) PE Lalani et al10 In-hospital mortality Paravalvular complications (NVE) SA Bannay et al15 5-y mortality Intracardiac abscess (NVE+PVE) SA Lalani et al10 In-hospital mortality Systemic embolization (NVE) SA Bannay et al15 5-y mortality Systemic embolization (NVE+PVE) SA Lalani et al10 In-hospital mortality S aureus (NVE) SA Bannay et al15 5-y mortality CHF (NVE+PVE) SA Lalani et al259 In-hospital and 1-y mortality PVE with the highest propensity to undergo surgery SA CHF indicates congestive heart failure; NVE, native valve infective endocarditis; PE, primary end point; PVE, prosthetic valve infective endocarditis; and SA, subgroup analysis. All studies have adjusted for selection and survivor bias and confounding. Valve surgery was performed during the active phase of the disease (during initial hospitalization before completion of a full therapeutic course of antibiotics). Baddour et al Infective Endocarditis in Adults 1467 medically and to avoid placement of valve prostheses because of the subsequent risk of device infection with continued IDU. Surgical intervention is reasonable for patients with the fol- lowing complications: right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy, sustained infection caused by difficult-to-treat organisms (ie, fungi, multidrug resistant bacteria) or lack of response to appropriate antimicrobial therapy, and tricuspid valve vegeta- tions that are 20 mm in diameter and recurrent pulmonary embolism despite antimicrobial therapy. Valve repair rather than replacement should be performed when feasible. If valve replacement is performed, then an individualized choice of prosthesis by the surgeon is reasonable.263,264 Recommendations 1. Surgical intervention is reasonable for patients with certain complications (Class IIa; Level of Evidence C). 2. Valve repair rather than replacement should be per- formed when feasible (Class I; Level of Evidence C). 3. If valve replacement is performed, then an individu- alized choice of prosthesis by the surgeon is reason- able (Class IIa; Level of Evidence C). 4. It is reasonable to avoid surgery when possible in patients who are IDUs (Class IIa; Level of Evidence C). Valve Surgery in Patients With Prior Emboli/ Hemorrhage/Stroke The timing of valve surgery in IE patients with stroke remains controversial. Stroke is an independent risk factor for post- operative mortality in IE patients. After stroke, neurological deterioration can occur as a result of hemorrhagic transforma- tion with anticoagulation during cardiopulmonary bypass or exacerbation of cerebral ischemia attributable to hypotension during cardiac surgery. The risk of intracranial hemorrhage is dependent on several factors, including extent and size of infarction, whether it is ischemic or hemorrhagic, and the exact timing of surgery. One clinical quandary is whether early valve surgery can be safely performed within 7 days after a stroke or if it is better to postpone surgery for at least 1 week. No randomized trials have addressed this conundrum. The high rates of postoperative mor- bidity and mortality seen in earlier studies265 267 have resulted in a reluctance to refer patients with IE and acute stroke for imme- diate valve surgery. However, these initial studies included a limited number of patients, and risk adjustments were not per- formed. The largest early series of operated patients with cere- bral complications included 181 patients.267 Hospital mortality rates as a function of the interval between evidence of cerebral infarction to cardiac surgery were 66.3% when surgery was per- formed within 24 hours of stroke and gradually decreased every week to 7.0% with surgery >4 weeks after stroke. Investigations have suggested better outcomes for IE patients with ischemic stroke who undergo early cardiac sur- Ruttmann et al270 analyzed 65 patients who under- went cardiac surgery after cardioembolic (embolic) stroke (median time, 4 days; range, 0 38 days). Surgery in this time frame was not associated with worse patient outcomes. Fifty of the 61 patients (81.9%) with CT-verified preopera- tive stroke survived cardiac surgery. Latency between the neurological event and cardiac surgery was not a significant factor with respect to the perioperative neurological compli- cation rate or the postoperative neurological recovery rate. Full neurological recovery was achieved in 70% of 50 stroke patients. Other studies6 8 suggest that the risk of neurologi- cal deterioration during cardiac surgery after a stroke is lower than previously assumed, particularly in patients with silent cerebrovascular emboli. The first study to evaluate the timing of surgery after stroke in IE that included a risk adjustment for differences in patient characteristics comprised 198 patients.273 Fifty-eight patients who underwent surgery within 1 week of stroke were compared with 140 patients who underwent surgery 8 days after stroke. Hospital mortality was numerically but not significantly higher in the early surgery group (22.4% versus 12%). After adjustment for other risk factors such as age, paravalvular abscess, and heart failure, the risk of hos- pital mortality remained nonsignificantly higher in the early surgery group (odds ratio, 2.308; 95% confidence interval, 0.942 5.652). Differences in 1-year mortality were less pro- nounced, with an adjusted hazard ratio of 1.138 (95% con- fidence interval, 0.802 1.650). In-hospital mortality in the early surgery group was comparable to that of the medically treated patients. After hemorrhagic stroke, the risk of exacerbation by sur- gery is prohibitively high in the first month but can extend beyond 1 month in some patients, possibly because of the presence of undetected mycotic aneurysms (MAs). In a mul- ticenter study of patients with hemorrhagic stroke, mortality was higher when surgery was performed within 4 weeks of the hemorrhagic event compared with later surgery (75% versus These data support the following recommendations: Valve surgery may be performed in IE patients with stroke or sub- clinical cerebral emboli without delay if intracranial hemor- rhage has been excluded by imaging studies and neurological damage is not severe (ie, coma). In patients with major isch- emic stroke or intracranial hemorrhage, it is reasonable to delay valve surgery for at least 4 weeks. Recommendations 1. Valve surgery may be considered in IE patients with stroke or subclinical cerebral emboli and residual vegetation without delay if intracranial hemorrhage has been excluded by imaging studies and neurolog- ical damage is not severe (ie, coma) (Class IIb; Level of Evidence B). 2. In patients with major ischemic stroke or intra- cranial hemorrhage, it is reasonable to delay valve surgery for at least 4 weeks (Class IIa; Level of Evidence B). Risk of Embolization Systemic embolization occurs in 22% to 50% of cases of Rates can be higher if noninvasive imaging, including MRI and CT scanning, is routinely done to detect asymptomatic (silent) emboli. Emboli often involve major arterial beds, including the brain, lungs, coronary arteries, spleen, bowel, and extremities. Up to 65% of embolic events involve the CNS, and >90% of CNS emboli lodge in the distri- bution of the middle cerebral artery.277 The highest incidence of embolic complications is seen with mitral valve IE (and more with anterior rather than posterior mitral leaflet involve- ment) and with IE caused by S aureus, Candida, and HACEK organisms. Emboli can occur before diagnosis, during therapy, or after therapy is completed, although most emboli occur within the first 2 to 4 weeks of antimicrobial therapy.58,278 Of note, 2 inde- pendent studies have confirmed that the rate of embolic events decreases dramatically during and after the first 2 to 3 weeks of successful antibiotic therapy. In a study from 1991, the embolic rate dropped from 13 to <1.2 embolic events per 1000 patient-days during that time.58 Vilacosta et al278 confirmed the reduced frequency of embolization after 2 weeks of therapy. Moreover, the latter study reemphasized the increased risk of embolization with increasing vegetation size during therapy, mitral valve involvement, and staphylococcal pathogenesis. In a survey that included the International Collaboration on Endocarditis cohort, Dickerman and colleagues280 focused on the incidence of stroke in a multicenter IE population and demonstrated that acute stroke rates fell significantly after initiation of antibiotic therapy regardless of valve involved or pathogen identified. Moreover, only 3.1% of the cohort suf- fered stroke after the first week of antimicrobial therapy; this finding has led to the opinion that stroke prevention as a sole indication for valve surgery after 1 week of appropriate antibi- otic therapy is not warranted. Prediction of individual patient risk for embolization is extremely difficult. Many studies have attempted to use echocardiography to identify a high-risk subset of IE patients who might benefit from early surgery to avoid embolization. Several studies with TTE have demonstrated a trend toward higher embolic rates with left-sided vegetations >1 cm in De Castro and colleagues276 compared TTE with multiplane TEE and found that neither technique was help- ful in defining embolic risk in patients with vegetations. In a based on TEE, mitral vegetations >1 cm in diameter were associated with the greatest frequency of embolism. The association was strengthened when the analysis was limited to those patients who had not yet experienced a clinical embolic event. Another prospective TEE study, however, found no clear correlation of vegetation size with embolization.59 Nevertheless, the same investigators later reported the results of a new prospective study of 118 patients who underwent TEE and found that, on multivariable analysis, risk factors associated with embolic risk included vegetation size >10 mm and mitral valve involvement.56 Overall, these data are com- patible with previous observations that indicate that, in gen- eral, mitral vegetations of any size are associated with a higher risk of embolization (25%) than aortic vegetations (10%). As noted above, the highest embolic risk (37%) has been seen in the subset of patients with mitral vegetations attached to the anterior rather than the posterior mitral leaflet.59,63 This sug- gests that the mechanical effects of broad and abrupt leaflet excursion, occurring twice per heartbeat, may contribute to the propensity of a vegetation in this location to fragment and embolize. In another study, the effect of vegetation size on embolic potential was dependent on the infecting organism, with large vegetations independently predicting embolic events only in the setting of streptococcal IE.60 In contrast, as confirmed above byVilacosta et al,278 staphylococcal or fungal IE appears to carry a high incidence rate of embolization independently of vegetation size. Prognosis based on echocardiographic findings was exam- ined in a large, multicenter, prospective investigation. On the basis of TEE findings in 384 consecutive adult patients with definite IE, vegetation length >15 mm was a predictor of 1-year mortality (adjusted relative risk, 1.8; 95% confidence The role of echocardiography in predicting embolic events has been controversial. In 1 survey282 that included 4 echocar- diographers who were blinded to clinical data, interobserver agreement was mixed on the characterization of vegetations. Agreement was high for the presence of vegetation (98%) and involved site (97%); interobserver agreement was consider- ably less for vegetation size (73%), mobility (57%), shape (37%), and attachment (40%). However, all of the series that included >100 patients who underwent TEE showed a positive relationship between embolic events and vegetation size. Moreover, the study with the largest number of patients (n=176) that assessed the value of TEE and included silent embolism detected by CT scanning demonstrated that the risk of embolic events was highly related to vegetation size and mobility but not to other known risk factors associated with embolism in IE.283 The conflicting results on the relationship between echocardiography and embolic risk can be explained at least partially by the poor standardization of diagnostic cri- teria for IE in older series, inclusion or not of silent embolism, inclusion or not of previous embolism, echocardiographic method used, lack of focus on future embolic events after TEE, and sample size. An increase in vegetation size over 4 to 8 weeks of therapy as documented by TEE appears to predict embolic events.282 In addition, a second, albeit infrequent, peak of late embolic events has been observed to occur 15 to 30 weeks after the diagnosis of IE and has been associated with nonhealing veg- etations (failure of a vegetation to stabilize or diminish in size) as defined by echocardiography.63 The traditional indication for valvular surgery for IE to avoid embolization has been 2 major embolic events.284 This criterion is arbitrary and excludes cutaneous embolization, which is common, or embolism occurring before the insti- tution of therapy, which is common among IE patients who develop embolic events. Because of the observed decreases in embolic risk during the first 2 weeks of antibiotic therapy, the benefit of surgery in avoiding catastrophic embolic events is greatest early in the treatment course of IE. Early surgi- cal intervention may preclude a primary or recurrent major embolic event but exposes the patient to both immediate and lifelong risks of valve replacement if the valve cannot be pri- marily repaired. At this time, the strategy for surgical inter- vention to avoid systemic embolization in IE remains specific Baddour et al Infective Endocarditis in Adults 1469 to the individual patient, with benefit being greatest in the early phase of IE when embolic rates are highest and other predictors of a complicated course (ie, recurrent embolization; heart failure; aggressive, antibiotic-resistant organisms; or PVE) are present (Table 5). The benefits of early surgery were demonstrated in the prospective, randomized trial12 that was discussed earlier in this document. Because of several limita- tions of that trial, additional study is needed before routine application of early surgery solely to reduce embolic risk can be strongly advocated. Embolic events are important prognostic indicators of IE outcomes. In 1 analysis, an embolic event was 1 of 4 early pre- dictors of in-hospital death caused by IE.285 Other independent predictors of death by logistic regression modeling among 267 consecutive patients with definite or possible IE by modified Duke criteria were diabetes mellitus, S aureus infection, and Acute Physiology And Chronic Health Evaluation (APACHE) II score. Another controversial topic is whether imaging to detect emboli should be performed in all IE patients. The current paradigm includes dedicated, anatomic imaging if there are signs or symptoms suggestive of an embolic event. There is less agreement on imaging, which can pose risks because con- trast material is usually required, in patients without symp- toms or signs of emboli, some of whom may have silent or subclinical events. In particular, should MRI of the brain be obtained in all IE patients because cerebral emboli are so com- monplace? As previously mentioned in an earlier section (3D Echocardiography and Other Imaging Modalities), some have advocated this strategy in all patients who are to undergo valve surgery to identify those who may harbor embolic lesions that could pose a higher risk of intracranial bleeding with cardio- pulmonary bypass and heparin administration used for cardiac surgery. Anticoagulation Anticoagulation in IE patients is controversial, particularly in mechanical valve IE.286 Some authorities recommend con- tinuation of anticoagulant therapy in patients with mechani- cal valve IE. However, the general advice is to discontinue all forms of anticoagulation in patients with mechanical valve IE who have experienced a CNS embolic event for at least 2 This time should allow for thrombus organization and prevent the acute hemorrhagic transformation of embolic lesions. Reintroduction of anticoagulation in these patients should be done with great caution, beginning with intravenous unfractionated heparin titrated to an activated partial thrombo- plastin time range of 50 to 70 seconds and transitioning care- fully to adjusted dose warfarin. The novel oral anticoagulants are not approved for use with either mechanical valves or bio- prosthetic valves when risk factors for thromboembolism exist (eg, atrial fibrillation). The benefit of therapeutic anticoagulation has never been demonstrated convincingly in patients with NVE. In part related to findings that demonstrated a salutary effect of intra- venous aspirin therapy in established experimental S aureus a randomized trial compared oral aspirin 325 mg/d with placebo in 115 IE patients.288 No significant benefit was observed in aspirin-treated patients in terms of vegetation resolution and embolic events. Moreover, there was a trend toward more bleeding episodes in the aspirin-treated patients. Aspirin levels, a critical correlate of antimicrobial efficacy in an animal model, were not monitored in this study.289 Retrospective, observational studies290 296 have examined the impact, if any, of long-term antiplatelet therapy before the onset of IE on infection-related outcomes. Findings from these investigations have been mixed in terms of IE-related outcomes. Until definitive data are available, the initiation of aspirin or other antiplatelet agents as adjunctive therapy in IE is not recommended. In contrast, the continuation of long- term antiplatelet therapy at the time of development of IE with no bleeding complications may be considered. Recommendations 1. Discontinuation of all forms of anticoagulation in patients with mechanical valve IE who have expe- rienced a CNS embolic event for at least 2 weeks is reasonable (Class IIa; Level of Evidence C). 2. Initiation of aspirin or other antiplatelet agents as adjunctive therapy in IE is not recommended (Class III; Level of Evidence B). 3. The continuation of long-term antiplatelet therapy at the time of development of IE with no bleeding complications may be considered (Class IIb; Level of Evidence B). Periannular Extension of Infection Extension of IE beyond the valve annulus predicts a higher mortality rate, more frequent development of heart fail- ure, and more frequent need for cardiac surgery.284,297,298 Perivalvular cavities form when annular infections break through and spread into contiguous tissue. In aortic NVE, this generally occurs through the weakest portion of the annulus, which is near the membranous septum and atrio- The anatomic vulnerability of this area explains both why abscesses occur in this location and why heart block is a frequent sequela.300 Periannular exten- sion is common, occurring in 10% to 40% of all NVE and complicating aortic IE more commonly than mitral or tri- Periannular infection is of even greater con- cern with PVE, occurring in 56% to 100% of patients.298,302 Perivalvular abscesses are particularly common with pros- thetic valves because the annulus, rather than the leaflet, is the usual primary site of infection, especially in early PVE and on bioprosthetic valves.302 Under the influence of systemic intravascular pressures, abscesses may progress to fistulous tracts that create intracar- diac or pericardial shunts. The mortality rate was 41% in a of patients with aorto-cavitary fistulization despite surgical intervention in 87%. Multivariate analysis demon- strated that factors associated with an increased risk of death included moderate to severe heart failure, PVE, and urgent or emergency surgical intervention. In some cases, progressive periannular infection totally disrupts the ventricular-aortic continuity or the mitral-aortic trigone. Such structural lesions and intracardiac fistulas may be catastrophic; even if their hemodynamic impact is tolerated, these lesions will not heal with medical treatment alone and require urgent operative intervention. Clinical parameters for the diagnosis of perivalvular extension of IE are inadequate. Persistent bacteremia or fever, recurrent emboli, heart block, heart failure, or a new patho- logical murmur in a patient with IE on appropriate antibiotics may suggest extension.303 Only aortic valve involvement and current IDU have been prospectively identified as independent risk factors for perivalvular abscess.297 On ECG, new atrio- ventricular block has a positive predictive value of 88% for abscess formation but low (45%) sensitivity.298 Patients at risk for perivalvular extension of IE require prompt evaluation. The size of vegetations is not helpful for predicting perivalvular extension.297 The sensitivity of TTE for detecting perivalvular abscess is low (18% to 63% in pro- spective and retrospective studies, respectively).305,306 TEE dramatically improves the sensitivity for defining periannular extension of IE (76% to 100%) while retaining excellent spec- ificity (95%) and positive and negative predictive values (87% When combined with spectral and color Doppler techniques, TEE can demonstrate the distinc- tive flow patterns of fistulas and pseudoaneurysms and can rule out communications from unruptured abscess cavities. Because of these combined capabilities, TEE is recommended for the initial assessment of any patient suspected of having perivalvular extension of IE. A small number of patients with periannular extension of infection or myocardial abscess may be treated successfully without surgical intervention.307,308 These patients potentially include those who have smaller (<1 cm) abscesses and who do not have complications such as heart block, echocardiographic evidence of progression of abscess during therapy, valvular dehiscence, or insufficiency. Such patients should be monitored closely with serial TEE; TEE should be repeated at intervals of 2, 4, and 8 weeks after completion of antimicrobial therapy. Surgery for patients with perivalvular extension of IE is directed toward eradication of the infection and correction of hemodynamic abnormalities. Drainage of abscess cavities, excision of necrotic tissue, and closure of fistulous tracts often accompany valve replacement or repair surgery.309 Although valve replacement is usually required, its successful performance may be compromised by extensive destruction of the periannular supporting tissues. Under these conditions, human aortic homo- grafts, when available, can be used to replace the damaged aor- tic valve and to reconstruct the damaged aorta.310,311 Homografts have a constant but low incidence rate of IE.312 Some groups have advocated the use of stentless or mini-stented aortic valve prostheses with debridement in the same clinical scenario, par- ticularly if homografts are not readily available.313 Recommendation 1. TEE is recommended for the initial assessment of any patient suspected of having perivalvular exten- sion of IE (Class I; Level of Evidence B). Metastatic Foci of Infection Similar to embolic complications, metastatic foci of infec- tion frequently occur in IE and can greatly affect management strategies, in particular timing of valve surgery, duration of antimicrobial therapy, and need for invasive interventions (usually surgical or interventional radiological drainage). Much like embolic events, metastatic foci of infection either can remain asymptomatic or may cause major clinical signs or symptoms. In the latter case, sustained fever can be a valu- able clue, particularly when bloodstream infection has been cleared or in cases when bloodstream infection persists despite adequate antimicrobial coverage. In addition, distinguish- ing bland infarction caused by an embolus from a metastatic focus (abscess) sometimes can be difficult. In patients who are symptomatic, a diagnostic evaluation including radiologi- cal, ultrasonographic, and invasive procedures such as joint aspiration for both diagnostic and therapeutic reasons is rec- ommended. Invasive procedures such as percutaneous drain- age of soft tissue or organ abscess may be needed. Surgical intervention, as mentioned above, may be required for radi- cal infection cure. For example, splenic abscesses generally require splenectomy or a drainage procedure because the usefulness of antimicrobial therapy is in preventing disease extension in the spleen and treating systemic infection rather than eliminating abscesses.314 Whether percutaneous aspira- tion or drainage of splenic abscesses can be performed safely and effectively should be decided by an experienced team of clinicians. Identification and management of metastatic foci of infec- tion are critically important in patients who require valve surgery. When feasible, all invasive procedures for the initial management of metastatic foci of infection should be done before valve surgery to reduce the likelihood of infecting a placed prosthetic valve or annuloplasty ring. Cerebrovascular imaging may be considered in all patients with left-sided IE who have no CNS signs or symptoms (see the Intracranial MAs section below). There are currently no other recommendations for routinely evaluating all patients with IE for metastatic foci of infection, although many clinicians rec- ommend such routine screening for all cases of S aureus IE. Rather, a directed workup is advocated on the basis of local- izing signs or symptoms. Depending on the site of interest, the choice of diagnostic procedure (eg, CT, MRI, ultrasonogra- phy) varies, and the selection should be individualized for each patient. The choice of procedure may require consultation with experts. It is strongly recommended that a discussion of which laboratory (microbiology, pathology including cytology) stud- ies will be needed once tissue or fluid aspirate specimens are available takes place before an invasive procedure is performed. Recommendation 1. The choice of diagnostic procedure (eg, CT, MRI, ultrasonography) varies and the selection should be individualized for each patient (Class I; Level of Evidence C). Mycotic Aneurysms MAs are uncommon complications of IE that result from sep- tic embolization of vegetations to the arterial vasa vasorum or the intraluminal space, with subsequent spread of infec- tion through the intima and outward through the vessel wall. Baddour et al Infective Endocarditis in Adults 1471 Arterial branching points favor the impaction of emboli and are the most common sites of development of MAs. MAs caused by IE occur most frequently in the intracranial arteries, followed by the visceral arteries and the arteries of the upper and lower extremities. A detailed analysis of the complex management of MAs has been included in a separate AHA Scientific Statement that addresses vascular infections and is pending publication; please refer to this document for additional information. Intracranial MAs Intracranial MAs (ICMAs) represent a relatively small but extremely dangerous subset of neurological complications. The overall mortality rate among IE patients with ICMAs is 60%. Among patients with unruptured ICMAs, the mortality rate is 30%; in patients with ruptured ICMAs, the mortality rate approaches 80%.315,316 The reported occurrence of ICMAs is probably underestimated because some ICMAs remain asymptomatic and resolve with antimicrobial therapy. Streptococci and S aureus account for and ICMAs are seen with increased frequency among IDUs with IE.318 The dis- tal middle cerebral artery branches are most often involved, especially the bifurcations. Multiple ICMAs occur in 20% ; mortality rates are similar for multiple and single distal ICMAs. The mortality rate for patients with proximal ICMAs is >50%.321 The clinical presentation of patients with ICMAs is highly variable. Patients may develop severe headache, altered sen- sorium, or focal neurological deficits such as hemianopsia or cranial neuropathies. Neurological signs and symptoms are nonspecific and may suggest a mass lesion or an embolic Some ICMAs leak slowly before rupture and pro- duce mild meningeal irritation. Frequently, the spinal fluid in these patients is sterile, and it usually contains erythrocytes, leukocytes, and elevated protein. In other patients, there are no clinically recognized premonitory findings before sudden subarachnoid or intraventricular hemorrhage.315 Symptomatic cerebral emboli frequently but not invari- ably precede the finding of an ICMA.315 Therefore, imaging procedures to detect ICMAs are indicated in IE patients with localized or severe headaches; sterile meningitis, especially if erythrocytes or xanthochromia is present; or focal neurologi- cal signs. Several imaging modalities can be used to identify ICMAs; currently, there is no preferred initial imaging study that can be recommended.322 Techniques include cardiac (mul- tislice) CT angiography with 3D reconstruction, digital subtrac- tion angiography, and magnetic resonance angiography with 3D reconstruction. In cases when there is a high clinical suspi- cion of ICMAs and a negative initial screening with 1 of these modalities, then conventional angiography is reasonable to per- form. Cerebral MRI may be considered in all patients with left- sided IE who have no CNS signs or symptoms. MRI findings may assist in subsequent medical and surgical management.322 Recommendations 1. Cerebrospinal imaging should be performed to detect ICMA or CNS bleeding in all patients with IE or contiguous spread of infection who develop severe, localized headache, neurological deficits, or meningeal signs (Class I; Level of Evidence B). 2. Cerebrovascular imaging may be considered in all patients with left-sided IE who have no CNS signs or symptoms (Class IIb; Level of Evidence C). 3. CT angiography, magnetic resonance angiography, or digital subtraction angiography is reasonable as an initial imaging test for detection of ICMA (Class IIa, Level of Evidence B). 4. Conventional angiography for detection of sus- pected ICMA is reasonable in patients with negative CT angiography, magnetic resonance angiography, or digital subtraction angiography (Class IIa; Level of Evidence B). Extracranial MAs Intrathoracic or intra-abdominal MAs often are asymptomatic until leakage or rupture occurs. Presumably, most extracranial MAs will rupture if not excised. The appearance of a tender, pulsatile mass in a patient with IE suggests an extracranial MA. Hematemesis, hematobilia, and jaundice suggest rupture of a hepatic artery MA; arterial hypertension and hematuria sug- gest rupture of a renal MA; and massive bloody diarrhea sug- gests the rupture of an extracranial MA into the small or large bowel. Either CT scanning or multislice CT angiography with 3D reconstruction is indicated for initial imaging. TEE is useful in identifying MAs of the sinus of Valsalva and thoracic aorta. Recommendations 1. Either CT scanning or multislice CT angiography with 3D reconstruction is indicated for initial imag- ing (Class I; Level of Evidence B). 2. TEE is useful in identifying MAs of the sinus of Valsalva and thoracic aorta (Class I; Level of Evidence B). Outpatient Therapy Outpatient parenteral antibiotic therapy (OPAT) is efficacious, safe, and cost-effective for a variety of infections,323 325 includ- ing IE that requires prolonged parenteral therapy in hospital- ized patients who otherwise no longer require inpatient care but do require continued parenteral antimicrobial therapy. Antibiotic regimens recommended for IE vary widely and often require 4 weeks of therapy, generally given by the intra- venous route. Absorption of orally administered antimicrobial agents may be unreliable, and such a strategy is generally not recommended as sole therapy for IE. Several other aspects of OPAT such as drug stability at room temperature; frequency of drug dosing; access to ancillary equipment, including ambula- tory pumps; insurance coverage; and whether the patient has a history of IDU can all affect the ultimate use of OPAT. The timing for transition from inpatient antibiotic therapy to OPAT and patient exclusion criteria have been critically evaluated by Andrews and von Reyn.326 These guidelines are based on the local availability of medical care in the outpa- tient setting and risk factors and timing of potential adverse outcomes that would be best managed in the inpatient setting. Before OPAT is considered, most patients with IE should first be evaluated and stabilized in the hospital; only rarely can some patients be treated entirely as outpatients. Patients selected for OPAT should be at low risk for the complications of IE, the most frequent of which are heart failure and systemic emboli. The period of greatest risk for systemic emboli is before or within the first 1 to 2 weeks of antimicrobial therapy, although serious complications such as heart failure and rupture of MAs may develop weeks to months after the initiation of antimicro- bial therapy. The presence of poorly controlled heart failure, neurological findings that may result from systemic emboli or bleeding MAs, cardiac conduction abnormalities, valve ring abscesses (usually detected by TEE), persistent fever, or persis- tently positive blood cultures should preclude OPAT. The risk for drug-related side effects usually increases with a prolonged drug exposure (eg, vestibular, auditory, and nephrotoxicity resulting from aminoglycosides; leukopenia caused by -lactams and vancomycin; and nephrotoxicity resulting from the combination of vancomycin and gentami- cin) and requires close monitoring by the home infusion team consisting of representatives from nursing and pharmacy and clinicians with expertise in IE management. The following criteria are essential for an effective OPAT program: A reliable support system at home and easy access to a hospital for prompt re-evaluation by an experienced clinician if a complication such as recurrence of fever, symptoms of a cardiac arrhythmia, heart failure, or a neurological event develops Regular visits by a home infusion nurse who carefully monitors the patient for early detection of complications, failure to respond to therapy, problems with adherence to therapy, or complications (eg, catheter-related infection, catheter leakage or displacement, venous thrombosis) directly related to the antibiotics or intravenous access Regular visits with an experienced clinician to assess clinical status during the OPAT Recommendations 1. Patients with IE should first be evaluated and sta- bilized in the hospital before being considered for outpatient therapy (Class I; Level of Evidence C). 2. Patients selected for OPAT should be at low risk for the complications of IE, the most frequent of which are heart failure and systemic emboli (Class I; Level of Evidence C). Care at Completion of Antimicrobial Therapy Short-Term Follow-Up The majority of patients with IE are cured with appro- priate medical and, if necessary, surgical treatment. Echocardiography is reasonable before or synchronous with completion of antimicrobial therapy to establish a new baseline for subsequent comparison (Table 18). A referral to a program to assist in the cessation of drug use should be made for IDUs. Patients should be educated about the signs of endocarditis and urged to seek immediate medical attention should they occur. If feasible, a thorough dental evaluation is reasonable, especially in patients deemed likely to require valve replace- ment, with all active sources of oral infection eradicated. All indwelling intravenous catheters used to infuse antimicrobial treatment should be removed promptly at the end of therapy. Routine blood cultures are no longer recommended after the completion of antimicrobial therapy because the likelihood of a positive culture result in a patient who is otherwise without evidence of active infection is low. In the short-term follow-up, patients should be moni- tored for development of several complications (Table 18). A relapse of IE is a primary concern. Patients should be aware that relapses can occur and that new onset of fever, chills, or other evidence of systemic toxicity mandates immediate eval- uation, including a thorough history and physical examination and 3 sets of blood cultures. Every effort should be made to determine the cause of signs or symptoms of infection. In addition, prescribing empirical antimicrobial therapy should be avoided for an undefined febrile illness unless the patient s clinical condition (eg, sepsis) warrants empirical therapy. It is reasonable for patients who have completed therapy to undergo an examination after completing antibiotic therapy. Developing or worsening heart failure is a second com- plication that should be considered during short-term follow- up. Although new onset of heart failure caused by valvular dysfunction is unlikely during this period, valve function can deteriorate as a result of ongoing infection or mechanical stress unrelated to infection. In addition to physical examina- tion, echocardiographic findings can support this diagnosis. If heart failure develops or worsens, the patient should be evalu- ated immediately for cardiac surgery. Antibiotic toxicity still can occur after the completion of treatment and is the third complication that should be consid- ered during short-term follow-up. Two drug-related adverse events are concerns. The first is delayed ototoxicity because of the previous use of aminoglycosides. Audiological and Table 18. Care During and After Completion of Antimicrobial Treatment Initiation before or at completion of therapy Echocardiography to establish new baseline Drug rehabilitation referral for patients who use illicit injection drugs Education on the signs of endocarditis and need for antibiotic prophylaxis for certain dental/surgical/invasive procedures Thorough dental evaluation and treatment if not performed earlier in evaluation Prompt removal of intravenous catheter at completion of antimicrobial therapy Short-term follow-up At least 3 sets of blood cultures from separate sites for any febrile illness and before initiation of antibiotic therapy Physical examination for evidence of heart failure Evaluation for toxicity resulting from current/previous antimicrobial therapy Long-term follow-up At least 3 sets of blood cultures from separate sites for any febrile illness and before initiation of antibiotic therapy Evaluation of valvular and ventricular function (echocardiography) Scrupulous oral hygiene and frequent dental professional office visits Baddour et al Infective Endocarditis in Adults 1473 vestibular toxicity can develop despite the maintenance of appropriate serum drug concentrations during treatment. For patients receiving long-term aminoglycosides, particu- larly those with underlying renal or otic disorders, serial audiograms may be considered during therapy if feasible and available. No tools are routinely available for monitor- ing vestibular function, and patients should be told to report the onset of any symptoms of vestibular toxicity during or after treatment. The second antibiotic-related adverse event is Clostridium difficile infection. Onset of diarrhea can be delayed as long as 4 weeks after the last dose of antibiotic. The hope is that prompt recognition and treatment of this infectious complica- tion will diminish the likelihood of severe complications. Recommendations 1. Echocardiography is reasonable before or synchro- nous with completion of antimicrobial therapy to establish a new baseline for subsequent compari- son (Class IIa; Level of Evidence C). 2. A referral to a program to assist in the cessation of drug use should be made for IDUs (Class I; Level of Evidence C). 3. Patients should be educated about the signs of endocarditis and urged to seek immediate medi- cal attention should they develop (Class I; Level of Evidence C). 4. A thorough dental evaluation is reasonable, espe- cially in patients deemed likely to require valve replacement, with all active sources of oral infec- tion eradicated (Class IIa; Level of Evidence C). 5. Routine blood cultures are not recommended after the completion of antimicrobial therapy because the likelihood of a positive culture result in a patient who is otherwise without evidence of active infection is low (Class III; Level of Evidence C). 6. All indwelling intravenous catheters used to infuse antimicrobial treatment should be removed promptly at the end of therapy (Class I; Level of Evidence C). 7. For patients receiving long-term aminoglycosides, particularly those with underlying renal or otic disorders, serial audiograms may be considered during therapy if available (Class IIb; Level of Evidence C). 8. In the short-term follow-up, patients should be monitored for the development of several com- plications, including IE relapse and heart failure (Class I; Level of Evidence C). 9. Patients should be aware that relapses can occur and that new onset of fever, chills, or other evidence of systemic toxicity mandates immediate evalu- ation, including a thorough history and physical examination and 3 sets of blood cultures (Class I; Level of Evidence C). 10. Because of concerns for IE relapse, a thorough evalua- tion should be done to determine the cause of infection signs and symptoms (Class I; Level of Evidence C). 11. Empirical antimicrobial therapy for suspected infection should be avoided unless the patient s clinical condition (eg, sepsis) warrants it (Class III; Level of Evidence C). 12. It is reasonable to have patients who have completed therapy and do not have symptoms of systemic tox- icity undergo an examination after completing anti- biotic therapy (Class IIa; Level of Evidence C). 13. Developing or worsening heart failure is a common complication that should be monitored for during short-term follow-up (Class I; Level of Evidence C). 14. If heart failure develops or worsens, the patient should be evaluated immediately for cardiac sur- gery (Class I; Level of Evidence B). 15. Antibiotic toxicity still can occur after the comple- tion of treatment and is a complication that should be considered during short-term follow-up (Class I; Level of Evidence C). 16. No tools are routinely available for monitoring vestibular function, and patients should be told to report the onset of any symptoms of vestibular toxicity during or after treatment (Class I; Level of Evidence C). Long-Term Follow-Up Months to years after completion of medical therapy for IE, patients should have ongoing observation for and education about recurrent infection and delayed onset of worsening valve dysfunction (Table 18). Daily dental hygiene should be stressed, with serial evaluations by a dentist who is familiar with this patient population. Patients should be questioned about symptoms of heart failure, and a thorough physi- cal examination should be done. Additional evaluation with echocardiography is indicated in selected patients with posi- tive findings from history and physical examination. Patients should be instructed to seek immediate medical evaluation for persistent fever (Table 18). This is necessary because IE can mimic a variety of febrile illnesses. Blood cultures should be obtained. Antibiotic therapy should not be initiated for treat- ment of undefined febrile illnesses without blood cultures being obtained first. Antibiotics prescribed for nonspecific or unproved febrile syndromes are a major cause of (blood) culture-negative IE, and this practice should be strongly discouraged. Recommendations 1. Months to years after completion of medical ther- apy for IE, patients should have ongoing observa- tion for and education about recurrent infection and delayed onset of worsening valve dysfunction (Class I; Level of Evidence C). 2. Daily dental hygiene should be stressed, with serial evaluations by a dentist who is familiar with this patient population (Class I; Level of Evidence C). 3. Patients should be questioned about symptoms of heart failure, and a thorough physical examination should be done (Class I; Level of Evidence C). 4. Additional evaluations with echocardiography should be obtained in selected patients with posi- tive findings from history and physical examina- tion (Class I; Level of Evidence C). 5. Patients should be instructed to seek immediate medical evaluation for fever, and blood cultures should be obtained (Class I; Level of Evidence C). 6. Antimicrobial therapy should not be initiated for the treatment of undefined febrile illnesses unless the patient s condition (eg, sepsis) warrants it (Class III; Level of Evidence C). Dental Management A large, prospective study demonstrated a strong associa- tion between 3 indexes of oral hygiene and gingival disease and the incidence of bacteremia from IE-related species.327 Poor oral hygiene results in gingivitis, which often leads to periodontitis, and it is likely that these 2 periodontal dis- eases are associated with community-acquired IE. Current evidence suggests that poor oral hygiene and periodon- tal diseases, not dental office procedures, are likely to be responsible for the vast majority of cases of IE that originate in the mouth.328 Regardless of the source of infection, inpatients with IE should be thoroughly evaluated by a dentist familiar with the potential role of the mouth in these cases. The optimal timing for this evaluation may be after the patient s cardiac status has stabilized and early enough that all invasive dental procedures can be accomplished during intravenous antibiotic therapy. The clinical examination should rule out periodontal inflammation and pocketing around the teeth and caries that will eventually result in pulpal infection. A full series of intra- oral radiographs is required for the identification of caries and periodontal disease (eg, bone loss, tooth fractures). All of this is aimed at reducing the incidence and magnitude of bactere- mia from any manipulation of the gingival tissues, including normal daily events such as brushing teeth and chewing food. Treatment invariably involves a thorough dental cleaning by a hygienist who will review with patients the importance of maintaining scrupulous oral hygiene. Dental disease is almost entirely preventable if patients are compliant with 4 measures. First, the cause of both peri- odontal disease and caries is bacterial plaque accumulation on teeth, and prevention is dependent on keeping teeth free of plaque. Second, patients must understand that dietary mea- sures are critically important in preventing the formation of plaque, especially in areas on the teeth that are difficult to keep clean. The degree to which sugar and other refined carbohydrates are eliminated from the diet will have a major impact on the growth of pathogenic bacterial species, some of which are responsible for IE. Third, routine follow-up with their family dentist is necessary for close monitoring of oral hygiene and the early identification and eradication of oral disease. Finally, the daily use of a high-concentration fluori- dated toothpaste will help to ensure that the acid from plaque does not decalcify tooth structures and result in caries.A focus on all 4 measures should help to reduce the incidence of bac- teremia and the risk for recurrent IE. Recommendations 1. Inpatients with IE should be thoroughly evaluated by a dentist to identify and eliminate oral diseases that predispose to bacteremia and may therefore contribute to the risk for recurrent IE (Class I; Level of Evidence C). 2. The clinical examination should focus on periodon- tal inflammation and pocketing around teeth and caries that may result in pulpal infection and subse- quent abscess (Class I; Level of Evidence C). 3. A full series of intraoral radiographs will allow the identification of caries and periodontal disease and other disease (eg, tooth fractures) not evident from the physical examination. This should occur when the patient is able to travel to a dental facility (Class I; Level of Evidence C). 