Infect Dis Clin N Am 16 (2002) 507521

Current best practices and guidelines Assessment and management of complications in infective endocarditis
Daniel J. Sexton, MDa,*, Denis Spelman, MBBA, FRACP, PRCPA, MPHb
Department of Medicine, Division of Infectious Diseases, Box 3605, Duke University Medical Center, Durham, NC 27710, USA b Microbiology, Infectious Diseases, Infection Control and Hospital Epidemiology Units, Alfred Hospital, Melbourne 3181, Australia
a

Infective endocarditis (IE) is a disease of low frequency but high mortality and morbidity. The overall incidence of native valve endocarditis in the general population is estimated to be between 1.5 to 6 cases/100,000 per year [1,2]. Because of this low incidence most of the reported information in the medical literature on complications, outcomes, and treatment comes from case series rather than case-controlled studies; only a few randomized clinical trials have been conducted on the treatment of endocarditis. Thus, although reported incidence of complications of endocarditis in some case series has ranged as high as 57% [3], a number of factors make interpretation of such data dicult. First, referral bias is a signicant problem when analyzing results of even large case series. Cases referred to tertiary medical centers have rates of surgical intervention, complications, and death 2 to 3 times higher than cases that are seen and cared for in community hospitals [2,4]. Despite inconsistencies and diculties in interpreting the literature, the complications of endocarditis are well known to practicing clinicians. The most prevalent complications are congestive heart failure, paravalvular abscess formation, and embolism (especially stroke). In addition, endocarditis may be complicated by septic arthritis, vertebral osteomyelitis, pericarditis, metastatic abscesses, and an array of renal problems ranging from immune complex glomerulonephritis to renal abscesses. Finally, complications associated with medical treatment of endocarditis can result in signicant

* Corresponding author. E-mail address: sexto002@mc.duke.edu (D.J. Sexton). 0891-5520/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 9 1 - 5 5 2 0 ( 0 1 ) 0 0 0 1 1 - 3

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complications such as ototoxicity and nephrotoxicity, skin rashes, and serum sickness. This review focuses on the cardiac, embolic, neurologic, and renal complications of endocarditis and discusses how these complications inuence the clinical management of individual cases in daily practice. Congestive heart failure Congestive heart failure is the most common cause of death in patients with IE. Moreover, heart failure is the most compelling indication for surgery in patients with endocarditis. The predominant cause of heart failure in patients with endocarditis is valvular insuciency resulting from infection-induced valvular destruction. Although fragments of valvular vegetations may occasionally embolize into the coronary arteries and cause acute myocardial infarction and subsequent heart failure, the majority of patients who develop congestive heart failure secondary to endocarditis have primary valvular insuciency. In rare cases vegetations become large enough to cause functional stenosis, leading to heart failure. Because heart failure carries a dismal prognosis unless it is surgically corrected by valvular replacement, all patients with endocarditis should have an initial assessment of cardiac function. This assessment should include a careful clinical examination and an assessment for the presence or absence of symptoms of heart failure. The ndings of heart failure may be subtle. For example, resting tachycardia not attributable to fever or other causes may be the rst clue of a low ejection fraction. In addition to a careful clinical examination, all patients with IE should undergo echocardiography to assess their ejection fraction in addition to the status of their valvular function. Patients with aortic valve endocarditis are at risk of developing rapidly progressive heart failure or pulmonary edema if their valve suddenly becomes incompetent [5,6]. These patients may appear to be stable early in the course of their valve infection but then experience the abrupt onset of pulmonary edema and require emergency surgery for valve repair or replacement. Congestive heart failure may also occur in patients with mitral valve endocarditis due to rupture of one or more chordae tendinae. All patients with left-sided endocarditis should have regular and careful clinical assessment of their cardiac function with special attention to the presence of symptoms that are compatible with heart failure, such as orthopnea or dyspnea. It is inappropriate to make general categorical recommendations about whether or not all patients with mild symptoms of heart failure should have immediate surgery; each case must be evaluated individually. In most cases, the authors advocate surgery for all patients who do not respond promptly and completely to medical therapy within 24 hours. Surgery should be performed earlier rather than later in patients with heart failure and aortic regurgitation and those with infection due to Staphylococcus aureus. The authors also advise immediate surgery for patients with aortic valve endocarditis who have echocardiographic evidence of premature closure of

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the mitral valve even if they are not experiencing congestive heart failure; in one study the operative mortality of such patients was 4 lower when valve surgery was done before rather than after signs of heart failure appeared [7]. Because heart failure occurs in a substantial portion of patients with leftsided endocarditis, patients should be evaluated by a cardiac surgeon early in the course of their illness. This evaluation has two purposes. First, it allows the surgeon to evaluate the patient before complications develop so they are better able to assess the true change in status should signs and symptoms of heart failure occur. Second, early evaluation allows the surgeon to develop a relationship with individual patients prior to the onset of an emergency condition requiring immediate intervention should such a problem occur. Early surgical consultation also allows for consideration of other issues such as whether or not preoperative coronary arteriography ought to be performed and whether there are any relative or denite contraindications to surgery such as neurologic or renal disease or bleeding disorders.

Paravalvular abscesses Paravalvular abscesses with or without extension into the adjacent cardiac conduction tissues are associated with death rates >75% unless surgical intervention occurs [8]. Paravalvular abscesses may manifest as various forms of heart block when adjacent tissues containing conduction bers become inamed or directly damaged by the infectious process. A recent prospective study at Duke University disclosed that 36 of 137 patients with native valve endocarditis had cardiac conduction abnormalities; 21 of these 36 patients had some form of infra-nodal block. The mortality rate of those with infranodal block (41%) was signicantly greater than those without an infra-nodal conduction abnormality (15%; P 0.04). Only 8 of 15 patients with echocardiographic evidence of paravalvular abscesses had evidence of infranodal block on EKG [9]. Because of the utility of electrocardiography in detecting paravalvular abscesses, a baseline EKG should be obtained on all patients with IE. Serial monitoring of EKGs is not generally necessary, although such monitoring should be done if there are any signs of complications such as persistent fever, signs or symptoms of heart failure, or any arrhythmia. Transthoracic echocardiography is insensitive for detection of paravalvular abscess formation, missing up to 50% of abscesses that are detected by transesophageal echocardiography [6,8,10]. Echocardiographic signs of paravalvular abscess formation include (1) anterior or posterior aortic root thickness >9 mm, (2) perivalvular density >14 mm in the interventricular septum, (3) sinus of Valsalva defects or aneurysms, and (4) abnormal rocking motility of prosthetic valves [6]. Paravalvular abscesses occur commonly in patients with prosthetic valve endocarditis, and abscess formation is more common in patients with mechanical prosthetic valve endocarditis than in patients with bioprosthetic valve endocarditis (Fig. 1) [11]. Paravalvular

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Fig. 1. Courtesy of Vance G. Fowler, Jr, MD, Duke University Medical Center, Durham, NC.

abscesses in patients with native aortic valve endocarditis are less likely to form stulae or pseudoaneuryms than paravalvular abscesses in patients with mitral valve endocarditis [12]; however, abscess formation is associated with high surgical mortality and may require complex and dicult surgical repairs [6,13,14]. The authors advise surgery for all patients with paravalvular abscesses. Despite being associated with high death rates unless surgery is undertaken, paravalvular abscesses are not invariably fatal if medical therapy is utilized. The authors have anecdotal experience of longterm survival of several patients with paravavular abscesses who either refused surgery or had contraindications to surgery. Echocardiography cannot always distinguish paravalvular abscesses from postoperative artifacts in patients with prosthetic heart valves. Occasionally a false-positive diagnosis of abscess can be made in patients with prosthetic valve endocarditis. Patients with uninfected prosthetic heart valves may have small paravalvular leaks or abnormalities of the paravalvular area detected by echocardiography. In such patients it is often helpful to compare echocardiograms obtained during the suspected episode of endocarditis with prior echocardiograms. Echocardiography is virtually the only preoperative technique to detect aortocardiac stulae (Fig. 2). Such stulae might occur when paravalvular infection extends into the sinuses of Valsalva or into the aorta or pulmonary arteries. Mortality rates may exceed 50% in such cases even when the diagnosis is made promptly and when surgery is attempted early in the course of this complication [15].

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Fig. 2. Courtesy of Vance G. Fowler, Jr, MD, Duke University Medical Center, Durham, NC.

Stroke The most common neurologic complication of endocarditis is stroke. This complication, especially when due to a hemorrhagic stroke in a patient with acute bacterial endocarditis, can be devastating. Strokes contribute signicantly to mortality and long-term sequelae due to IE. In a recent study using stringent criteria for stroke to evaluate over 700 consecutive patients with endocarditis, approximately 18% of patients with mitral valve endocarditis developed stroke, and 10% of patients with aortic valve endocarditis had a stroke. In over half of these cases, stroke was the initial presenting symptom of endocarditis or was present at the time the initial diagnosis of endocarditis was made [16]. Similar ndings were reported in another recent study from a teaching hospital in Finland; embolic stroke occurred in 23 of 218 (11%) episodes of endocarditis; in 76% of cases neurologic symptoms were evident before antimicrobial therapy was initiated [17]. A substantial percentage of patients who develop stoke due to endocarditis have concurrent heart failure. Valve replacement surgery in patients with stroke is particularly dicult because surgery requires the use of a cardiopulmonary bypass, which increases the risk of exacerbating a pre-existing stroke by converting an ischemic infarct into a hemorrhagic infarct. In addition, although most experts agree that recurrent emboli constitute an indication for valve replacement surgery, it is often extremely dicult to determine the number and timing of embolic events. As detection of embolic damage

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might occur well after the embolism occurred, it might be impossible to ascertain whether a second or third episode of embolism has occurred during therapy. Because the timing of embolic events can have a substantial impact on both immediate and later decisions to undergo valvular surgery, all patients with endocarditis and neurologic symptoms should undergo imaging studies to determine the exact location and type of neurologic damage. A recent embolic stroke, particularly if it is hemorrhagic, is a relative contraindication to valve replacement surgery. Most authorities prefer to delay surgery for at least 10 to 14 days after the initial symptoms of stroke, although this is not an absolute rule, and some authors have concluded that surgery can be safely done without delay in patients with endocarditis and ischemic infarcts <1 to 2 cm in diameter that are detected by cerebral computed tomography [18]. In one multi-center retrospective study the rate of exacerbation of cerebral complications was 10% in patients who underwent surgery more than 15 days after cerebral infarction and 2.3% in those who had valve surgery a month or more after their stroke [19]. In patients who have concurrent heart failure and stroke, the relative benets of early valve replacement surgery must be weighed against the risks of extending or exacerbating a pre-existing stroke. Therapeutic decisions in such patients should include consultation from neurologists, thoracic surgeons, and infectious disease specialists. In many cases a precise numerical risk of death or further neurologic damage from surgery cannot be given. To resolve this dilemma clinical judgment should weigh individual circumstances such as the severity of heart failure, the presence of concurrent neurologic symptoms, and whether the infarct is recent, ischemic, or hemorrhagic before decisions about surgical or medical therapy are made. In summary, it is best to delay surgery for at least two weeks in patients with endocarditis and stroke, but if heart failure is severe, the risk of exacerbating pre-existing neurological damage may be less than the risk of the patient dying of heart failure. Most patients who present neurologic decits during an acute episode of endocarditis have embolic strokes, but occasionally patients may present with stroke syndrome due to a leaking or ruptured mycotic aneurysm. In such cases neurosurgical intervention, including placement of coils or ligation of the aneurysm, may be indicated. Because most patients with mycotic aneurysms present with hemorrhagic strokes, arteriography may be useful in selected patientsparticularly those in which the location of the neurologic decit is suggestive of mycotic aneurysm. Intra-cranial mycotic aneurysms most commonly involve the middle cerebral arteries, especially distally or the distal branches, although the posterior and anterior cerebral arteries can also be involved [20]. Three quarters of intracerebral mycotic aneurysms involve the middle cerebral artery, and up to 29% are multiple [20]. In addition to the clinical illness, anatomical localization can help distinguish between a mycotic and a congenital aneurysm; a mycotic aneurysm usually involves distal branch points of a cerebral vessel

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and therefore tends to bleed into the subarachnoid space, whereas a congenital aneurysm occurs proximally close to the Circle of Willis. A mycotic aneurysm complicating endocarditis can present as stroke or subarachnoid hemorrhage. CT imaging may show a variety of ndings. In one series of 14 patients, CT demonstrated intracerebral hematoma in 5 patients, infarcts in 4 patients, subarachnoid hemorrhage in 4 patients; aneurysms were seen in only 2 patients [20]. In this group of 14 patients angiography displayed 18 aneurysms, with single aneurysms in 10 patients and multiple aneurysms in 4 patients [20,21]. Angiography remains the best diagnostic test to detect and assess mycotic aneurysms. Angiography may reveal a mycotic aneurysm as the cause of hemorrhage or infarction as well as unsuspected or uncomplicated aneurysms. There is uncertainty regarding which patients with endocarditis should undergo angiographic examination, however. Many aneurysms respond to medical therapy alone [22] and few patients are considered to be surgical candidates. Some experts believe that mycotic aneurysms in patients with endocarditis due to S. aureus are more likely to bleed [23], but to the authors knowledge this opinion has not been adequately proven in a prospective or retrospective analysis of cases. Angiography should be performed when a patient presents with a subarachnoid hemorrhage to establish the presence and localization of an aneurysm and help to decide whether or not surgery is likely to be of benet. Angiography should also be considered in patients with persistent focal headaches or cranial nerve palsies, which may portend an expanding unruptured aneurysm. Follow-up angiography, recommended by some authors, may outline the course of such an aneurysm (resolution, decrease in size, or enlargement) or detect new aneurysms [20]. Surgical treatment of aneurysms may involve craniotomy and ligation, clipping, or excision of an aneurysm. Surgical intervention is not usually undertaken unless there is bleeding, severe headache, or cranial nerve palsies [23]. A less invasive endovascular approach has been used as an alternative to surgery for some aneurysms. Procedures using coils [24] or hyperselective catheterization of a vessel and the use of a small amount of glue to occlude both the aneurysm and the parent vessel [25] have been described. Such approaches have been used as an alternative to denitive surgery when the latter is contraindicated or with distal or peripheral localization of the aneurysm. Uncontrolled infection and infection with resistant organisms Active endocarditis due to fungal endocarditis or organisms that are resistant to standard antimicrobial agents may be a relative indication for early surgery even in the absence of other complications such as recurrent embolism, heart failure, or a paravalvular abscess. Fungal endocarditis is rarely curable with medical therapy [26]; thus the authors believe that most

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of such patients should go undergo valve replacement surgery. In addition, patients with infection due to organisms such as vancomycin- or gentamicinresistant enterococci or methicillin-resistant S. aureus may require early surgery since outcomes with medical therapy are often poor. Careful microbiologic and clinical assessment of all patients with endocarditis due to resistant organisms is helpful in deciding when surgery is necessary. Whenever blood cultures remain positive for more than seven days of therapy or other signs of persistent infection (such as persistent fever, leukocytosis, or other signs) are present, surgical repair of the valve or valve replacement should be undertaken earlier rather than later. Metastatic abscesses Patients with IE can develop metastatic abscesses in virtually any organ or location in the body (Fig. 3). Most patients with IE who have splenic abscesses do not have abdominal pain or splenomegaly, but the majority has persistent fever during or following treatment for endocarditis. Whenever persistent fever occurs in patients with endocarditis a search for a metastatic abscess utilizing a focused clinical examination and imaging methods such as CT scans or Indium-tagged white cell scans should be undertaken. Although some metastatic abscesses can drain percutaneously, splenic abscesses generally require splenectomy for cure. In one study of 27 patients with splenic abscesses the mortality was 100% in patients who did not undergo splenectomy compared to only 18% in patients who had the procedure [27]. Patients with endocarditis who also have prosthetic joints are particularly

Fig. 3. Courtesy of Vance G. Fowler, Jr, MD, Duke University Medical Center, Durham, NC.

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likely to develop metastatic infections [28]. Documenting the presence of a metastatic infection in such patients may be extremely dicult, particularly in patients who are already receiving eective antimicrobial therapy for their endocarditis. Patients with prosthetic joint infection may have unapparent infection of their prosthesis early during the course of endocarditis but later manifest the classic signs of joint infection after cure of their infection. Because most such patients do not develop recurrent bacteremia, the authors generally do not advise early removal of the prosthetic components in patients with known or possible prosthetic joint infection during acute episodes of endocarditis. Such patients should, however, undergo debridement and removal of all components if any obvious purulent uid collection occurs within the joint space or if denite signs of deep infection (such as stula formation or marked loosening of prosthetic components) occur. In one recent prospective study of 53 patients with S. aureus bacteremia who simultaneously had prosthetic joints, 34% developed infection of the prosthetic joint during or following the episode of bacteremia [28]. Some patients with IE also have simultaneous vertebral osteomyelitis. The management of this infection and its complications is largely the same as in patients with vertebral osteomyelitis without endocarditiswith one important exception. If a patient with endocarditis due to a known organism has signs, symptoms, and radiological changes of simultaneous vertebral osteomyelitis, it is usually not necessary to conrm the etiology of the bony infection with a needle aspirate or bone biopsy.

Renal complications Renal complications may occur in any form of endocarditis but are particularly frequent in patients with IE due to S. aureus. Hematuria, glomerulonephritis, or renal infarction may occur in as many as 40% to 50% of patients with staphylococcal IE [2931] and are due to embolic and immunecomplexmediated processes. Majumdar et al. examined renal biopsy or postmortem specimens from 62 patients with IE, the majority of which has S. aureus infection. Renal infarction (31%), acute glomerulonephritis (26%), acute intestinal nephritis (10%), and renal cortical necrosis (10%) were the most common histopathic ndings. The most common cause of glomerulonephritis in these patients was non-immune-mediated vasculitis [32].

Evaluation of the clinical response in patients with endocarditis Because persistent infection is one indication for valve replacement, it is important to assess whether or not an individual patient with endocarditis is responding appropriately to antimicrobial therapy. Patients with staphylococcal endocarditis may have persistent bacteremia for up to 7 days despite appropriate therapy with ultimately eective antimicrobial therapy.

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In general, the authors do not assume that treatment failure has occurred unless fever persists >7 days or blood cultures are positive beyond the rst week of antimicrobial therapy. When blood cultures are positive for a prolonged period during antimicrobial therapy, a search for metastatic infection or other complications (including a mycotic aneurysm) should be undertaken before assuming that the cause of the persistent fever is failure of treatment of the valvular infection itself. Moreover, all such patients should undergo transesophageal echocardiography to exclude a paravalvular abscess as the cause of the persistent bacteremia. Persistent fever will occasionally occur in patients undergoing treatment for endocarditis. This problem can be particularly vexing when a search for paravalvular abscess, metastatic infection, and persistent bacteremia is negative and the standard indications for valvular surgery are absent. The list of potential causes for persistent fever in such patients is lengthy and includes nosocomial infection, myocardial abscesses, pulmonary emboli, drugs, cerebral mycotic aneurysms, and pericarditis. In one study involving 26 patients with 27 episodes of endocarditis and fever of unknown origin persisting greater than 13 days, ve patients ultimately died from endocarditis-related complications, and in 7 of 27 episodes a myocardial abscess was eventually found to be the cause of the persistent fever [33].

Special problems Recurrent endocarditis is a frequent problem in patients with intravenous drug abuse. A number of issues should be candidly discussed and examined when patients with IE who are known, active users of intravenous drugs simultaneously have absolute or relative indications for valve replacement surgery. The authors advise that all patients with IE who are actively using intravenous drugs agree to undergo drug rehabilitation as one pre-requisite for undergoing valve surgery. Patients who are refractory drug abusers with a second, third, or fourth episode of endocarditis needing valve replacement surgery pose special ethical and practical problems, especially if they already have a prosthetic valve. In such cases, consultation with an ethics committee or second opinions from other cardiovascular surgeons, infectious disease specialists, or cardiologists may be useful in deciding whether additional valve surgery is warranted. Although valvular replacement has been the standard surgical procedure in patients with endocarditis who have heart failure, recurrent emboli, paravalvular abscess, or uncontrolled infection, valvuloplasty, valve debridement, or valve repair can occasionally be performed. Valve repair surgery is more often possible when the aected valve is the mitral or tricuspid valve [12]. Curative surgical management involves the excision of infected tissue with drainage and debridement of any abscess cavity. This can occasionally only be accomplished by entering the cardiac chambers for removal of

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conduction tissue. Repair of cardiac valves is the optimal therapy. If this cannot be done, valve replacement with avoidance of any prosthetic material implantation is advocated. Repair of the aortic valve is often dicult; replacement is usual, with the choice of AVR device governed by the extent of the infection. If infection is conned to the aortic valve, any of a variety of replacement devices may be used. If infection extends beyond the valve, replacement of the aortic root as well as the valve may be necessary. With the mitral or tricuspid valves, vegetectomy may be performed with excision of a small segment of valve leaet to which the vegetation is attached, with the created defect corrected by an annuloplasty stitch [34]. Perforated leaets may be closed using pericardium or homograft valve tissue. If infection extends beyond the leaets into the annulus, valve replacement is necessary. There has been a long-standing controversy regarding whether or not vegetation size as measured by echocardiography is a prognostic indicator for embolism or an indication for surgery. A recent study of 178 patients with endocarditis concluded that a signicantly higher percentage of patients with vegetations >1 cm in length had cerebral embolism and that patients with vegetations >1.5 cm that were highly mobile may be considered as candidates for early operation, irrespective of the presence of valve destruction, heart failure, or response to antimicrobial therapy [35]. Other studies have reported similar ndings [36]. Some investigators have reported no relationship between vegetation size and risk of embolism [37] while other investigators have concluded that patients with vegetations >1 cm have poorer responses to medical therapy [38]. The conclusions of all studies concerning vegetation size and outcome are hampered by a number of methodologic problems. First, most studies correlating embolism with vegetation size included large numbers of patients who had echocardiography after the embolism occurred. Second, selection bias hampered many prior studies; some patients underwent echocardiography because a neurologic event had occurred. Third, measuring the length or width of vegetations by echocardiography is not a completely reliable way to assess vegetation volume or mass because the shapes of vegetations are irregular and innitely variable. Finally, vegetation size in prior outcome studies was assessed at highly variable times during the course of illnessusually either before or soon after eective antimicrobial therapy was started. For these reasons the authors do not consider vegetation size alone to be a strong indication for surgery even though it is likely that large vegetations are harder to sterilize and may be associated with more embolic and direct cardiac complications. The use of anticoagulant therapy in patients with IE remains a controversial area. It has been the authors practice (and that of most others) to continue administration of anticoagulants during therapy of mechanical prosthetic valve endocarditis. This approach has been questioned recently, however [39]. Witchitz et al reported that anticoagulant therapy was an independent predictor of mortality in patients with prosthetic valve endocarditis caused

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by S. aureus [40]. Tornos et al subsequently reported that 11 of 15 patients with prosthetic valve endocarditis due to S. aureus died due to central nervous system complications while none of 35 patients with native valve S. aureus endocarditis died of similar complications. The authors attribute these dierences to the use of anticoagulant therapy in the former group and concluded that anticoagulant therapy should be discontinued in all patients with S. aureus endocarditis until the septic phase of the illness has resolved [39]. Medical treatment The principles of medical therapy of IE are relatively simple. First, bactericidal therapy must be used; in general agents that are bacteriostatic (such as clindamycin and macrolide antibiotics) are not eective. Second, prolonged therapy used in doses that give predictable and therapeutic serum levels is necessary. Only a few studies examining the eectiveness of courses of therapy <4 weeks in duration have been published [4143]. The American Heart Association guidelines for the treatment of IE provide an excellent summary of the available literature on the treatment of endocarditis and also provide detailed information on recommended and alternative therapeutic regimens [44]. Although vancomycin is an alternative treatment for patients with staphylococcal endocarditis who are allergic to b-lactams, vancomycin has been shown to be less rapidly bactericidal against staphylococci both in vitro and in vivo than semi-synthetic penicillins and rst-generation cephalosporins [43,45]. In one study involving a small number of patients with staphylococcal endocarditis, vancomycin was less eective than b-lactam therapy [46,47]. For the preceding reasons it is advisable to use semi-synthetic penicillins or rst-generation cephalosporins whenever possible in patients with endocarditis due to methicillin-sensitive S. aureus. In general, monotherapy for endocarditis due to methicillin-sensitive strains of S. aureus is adequate, even though combination therapy with an aminoglycoside and a semisynthetic penicillin may result in faster sterilization of blood cultures and vegetations in animals with experimental endocarditis. The clinical benet of such combination therapy is marginal to nil whereas the toxicity of adding an aminoglycoside is considerable and proven. It is advisable to perform skin testing in patients with a questionable history of immediate-type hypersensitivity to penicillin; such an approach has been shown by decision analysis to be superior to therapy with vancomycin without skin testing [48]. References
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