In this situation, if the organism is susceptible to a fluoroquinolone, animal studies of therapy for foreign-body infection suggest that a fluoroquinolone can be used instead of gentamicin.184 Thus, although clinical data are not available to support the practice, selection for fluoroquino- lone resistance during treatment can occur, and prevalent fluo- roquinolone resistance among CoNS will limit its use, it may reasonable to use a fluoroquinolone in this setting. PVE, particularly when onset is within 12 months of cardiac valve implantation and an aortic valve prosthesis is involved, is frequently complicated by perivalvular or myo- cardial abscesses or valvular dysfunction.136 Surgery is often required in these patients and may be lifesaving. As noted above, CoNS may become resistant to rifampin during therapy for PVE. Because of the potential for changes in the patterns of antibiotic susceptibility during therapy, organisms recov- ered from surgical specimens or blood from patients who have had a bacteriological relapse should be carefully retested for complete antibiotic susceptibility profiles. Although published data on combinations of antimicrobial therapy are limited, we suggest that PVE caused by oxacillin- susceptible CoNS should be treated with nafcillin or oxacillin plus rifampin in combination with gentamicin for the first 2 weeks of therapy. A first-generation cephalosporin or vanco- mycin may be substituted for nafcillin/oxacillin for patients who are truly allergic to penicillin. Recommendations 1. Vancomycin and rifampin are recommended for a minimum of 6 weeks, with the use of gentamicin lim- ited to the first 2 weeks of therapy (Class I; Level of Evidence B). 2. If CoNS are resistant to gentamicin, then an amino- glycoside to which they are susceptible may be con- sidered (Class IIb; Level of Evidence C). 3. If CoNS are resistant to all aminoglycosides, then substitution with a fluoroquinolone may be consid- ered if the isolate is susceptible to a fluoroquinolone (Class IIb; Level of Evidence C). from patients who have had a bacteriological relapse should be carefully retested for complete antibiotic susceptibility profiles (Class I; Level of Evidence C). S aureus Because of the high mortality rate associated with S aureus combination antimicrobial therapy is recommended (Table 11). The use of combination therapy is based not on studies of in vitro synergy but rather on the efficacy of this therapy for treatment of CoNS PVE, as well as the results of treatment of experimental IE and infected devices. In animal studies, rifampin appears to be key in the complete steriliza- tion of foreign bodies infected by MRSA.184,185 For infection caused by MSSA, nafcillin or oxacillin together with rifampin is suggested; with MRSA, vancomycin and rifampin should be used. Gentamicin should be adminis- tered for the initial 2 weeks of therapy with either -lactam or vancomycin-containing regimens. If a strain is resistant to gentamicin, then a fluoroquinolone may be used if the strain is susceptible. Early cardiac surgical interventions play an important role in maximizing outcomes in S aureus PVE,186 especially in the presence of heart failure.11 Recommendations 1. Combination antimicrobial therapy is recom- mended (Class I; Level of Evidence C). Baddour et al Infective Endocarditis in Adults 1455 2. Gentamicin should be administered for the initial 2 weeks of therapy with either -lactam or vancomycin- containing regimens (Class I; Level of Evidence C). Enterococci Although there are >15 species within the Enterococcus genus, E faecalis and E faecium are the major species isolated from clinical sources in IE patients. Enterococci are the third leading cause of IE and account for 10% of cases in non- IDUs. E faecalis causes 97% of cases of IE; E faecium, 1% to 2%; and other species, 1%. Regimens recommended for enterococcal IE are shown in Tables 12 through 15. Enterococci should be routinely tested in vitro for susceptibility to penicillin or ampicillin and van- comycin (MIC determination) and for high-level resistance to gentamicin to predict synergistic interactions (see below). Because of the striking increase in resistance of enterococci to vancomycin, aminoglycosides, and penicillin, additional susceptibility tests may be necessary to identify alternative antimicrobial regimens. For strains of enterococci resistant to -lactams, vancomycin, or aminoglycosides, it is reason- able to test for susceptibility in vitro to daptomycin and line- zolid. Linezolid is bacteriostatic in vitro against enterococci, whereas daptomycin is bactericidal in vitro in susceptible strains. Although rarely identified, -lactamase producing enterococci may account for relapse of infection. Routine screening for -lactamase production is not sensitive enough, and specialized testing will be needed for detection. Compared with VGS and -hemolytic streptococci, enterococci are relatively resistant to penicillin, ampicillin, and vancomycin. These streptococci usually are killed by monotherapy with these antimicrobials, whereas enterococci are inhibited but not killed. Killing of susceptible strains of enterococci requires the synergistic action of penicillin, ampi- cillin, or vancomycin in combination with either gentamicin or streptomycin. Enterococci are relatively impermeable to aminogly- cosides. High concentrations of aminoglycosides in the extracellular environment are required to achieve sufficient concentrations of the drug at the site of the ribosomal target within the bacterial cell for bactericidal activity. These con- centrations are higher than can be achieved safely in patients; however, cell wall active agents such as penicillin, ampicillin, and vancomycin raise the permeability of the enterococcal cell so that a bactericidal effect can be achieved by relatively low concentrations of an aminoglycoside. If an enterococcal strain is resistant to the cell wall active agent or high concentrations of an aminoglycoside (500 g/mL gentamicin or 1000 g/mL streptomycin), then the combination of an aminoglycoside and the cell wall active agent will not result in bactericidal activity in vitro or in vivo (ie, in experimental IE models), nor will it predictably produce a microbiological cure in human enterococcal IE. Recommendations 1. Enterococci should be tested routinely in vitro for susceptibility to penicillin and vancomycin (MIC determination) and for high-level resistance to gen- tamicin to predict synergistic interactions (Class I; Level of Evidence A). 2. In vitro susceptibility to daptomycin and linezolid should be obtained for strains that are resistant to -lactams, vancomycin, or aminoglycosides (Class I; Level of Evidence C). Table 11. Therapy for Endocarditis Involving a Prosthetic Valve or Other Prosthetic Material Caused by Staphylococci Regimen Dose* and Route Duration, wk Strength of Recommendation Comments Oxacillin-susceptible strains Nafcillin or oxacillin 12 g/24 h IV in 6 equally divided doses 6 Class I; Level of Evidence B Vancomycin should be used in patients with immediate-type hypersensitivity reactions to -lactam antibiotics (see Table 5 for dosing guidelines); cefazolin may be substituted for nafcillin or oxacillin in patients with non immediate-type hypersensitivity reactions to penicillins. Plus Rifampin 900 mg per 24 h IV or orally in 3 equally divided doses Plus Gentamicin 3 mg/kg per 24 h IV or IM in 2 or 3 equally divided doses Oxacillin-resistant strains Vancomycin 30 mg/kg 24 h in 2 equally divided doses 6 Class I; Level of Evidence B Adjust vancomycin to a trough concentration of 10 20 g/mL. (see text for gentamicin alternatives) Plus Rifampin 900 mg/24 h IV/PO in 3 equally divided doses Plus Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 equally divided doses IM indicates intramuscular; and IV, intravenous. *Doses recommended are for patients with normal renal function. Gentamicin should be administered in close proximity to vancomycin, nafcillin, or oxacillin dosing. See Table 7 for appropriate dose of gentamicin. Role of Aminoglycosides in the Treatment of Patients With Enterococcal IE: Special Considerations Aminoglycoside-containing regimens have been a cornerstone of antimicrobial therapy for enterococcal IE187 and have been recommended as standard therapy in previous (1995) AHA Since the publication of the latest (2005) AHA statement on antimicrobial therapy of patients with IE,12 the frequency of aminoglycoside-resistant strains of enterococci has increased significantly. In addition, a number of studies have been published on the dosing of aminoglycosides, the duration of aminoglycoside therapy, and the possible role of non aminoglycoside-containing regimens for the treatment of E faecalis IE.189 191 Approximately 97% of cases of enterococcal IE are caused by E faecalis, and the majority of these remain susceptible to -lactams and vancomycin, but aminoglycoside resistance is increasing in frequency. In the study by Gavald et al,190 approximately half of the patients had IE caused by high- level aminoglycoside-resistant strains of E faecalis. In the study by Fern ndez-Hidalgo et al,191 26% of the 272 patients had high-level aminoglycoside-resistant strains of E faecalis. Therefore, aminoglycoside-containing regimens would not be effective therapy for these patients. A number of factors should be considered in the selec- tion of aminoglycoside-containing regimens. Compared with other patients with IE, in general, patients with enterococcal IE are older; are often debilitated; may have complicated, underlying urological conditions, including pre-existing renal failure; may have healthcare-associated infections; and have significant other underlying comorbidities common in older In these patients, gentamicin-associated neph- rotoxicity may significantly complicate a standard 4- to 6-week course of therapy and could result in serious, possibly life-threatening, complications such as renal failure requiring hemodialysis. In these situations, the potential risk of attempt- ing to complete a 4- to 6-week course of gentamicin therapy may exceed the benefit.193 In patients with VGS IE treated with multiple divided doses of gentamicin, single daily-dose therapy with genta- micin resulted in similar response rates and was well tol- erated (see treatment of VGS IE above). Studies of single daily dosing of gentamicin compared with divided doses in enterococcal experimental IE and in humans have yielded conflicting results. These results may reflect different PK of aminoglycosides in animals compared with humans. Studies in humans of the dosing interval of gentamicin were not controlled or standardized. Dosing of gentamicin ranged from once daily to 3 times daily; therefore, the data were insufficient to compare the efficacy of once-daily doses with divided doses. Until more convincing data demonstrate that once-daily dosing of gentamicin is as effective as multiple dosing, in patients with normal renal function, gentami- cin should be administered in daily multiple divided doses ) rather than a daily single dose to patients with enterococcal IE. In patients with normal renal function, it is reasonable to administer gentamicin every 8 hours with the dose adjusted to achieve a 1-hour serum con- centration of 3 g/mL and a trough concentration of <1 g/ mL. Increasing the dose of gentamicin in these patients did not result in enhanced efficacy but did increase the risk of Many patients with enterococcal IE are managed in a nontertiary care facility, and the laboratory may not have the capability for rapid determination of serum gentamicin concentrations or may not have a clinical pharmacist avail- able to assist in optimal dosing adjustments. These and other factors have prompted studies to evaluate the efficacy of non gentamicin-containing regimens for the treatment of Table 12. Therapy for Endocarditis Involving a Native or Prosthetic Valve or Other Prosthetic Material Resulting From Enterococcus Species Caused by Strains Susceptible to Penicillin and Gentamicin in Patients Who Can Tolerate -Lactam Therapy* Regimen Dose and Route Duration, wk Strength of Recommendation Comments Either Class IIa; Level of Evidence B Native valve: 4-wk therapy recommended for patients with symptoms of illness <3 mo; 6-wk therapy recommended for native valve symptoms >3 mo and for patients with prosthetic valve or prosthetic material. Recommended for patients with creatinine clearance >50 mL/min. Ampicillin sodium 2 g IV every 4 h 4 6 4 6 Class IIa; Level of Evidence B Or Aqueous penicillin G sodium 18 30 million U/24 h IV either continuously or in 6 equally divided doses Plus Gentamicin sulfate 3 mg/kg ideal body weight in 2 3 equally divided doses Or Double -lactam Ampicillin 2 g IV every 4 h 6 Class IIa; Level of Evidence B Recommended for patients with initial creatinine clearance <50 mL/min or who develop creatinine clearance <50 mL/min during therapy with gentamicin-containing regimen. Plus Ceftriaxone 2 g IV every 12 h 6 IV indicates intravenous. *For patients unable to tolerate a -lactam, see Table 14. Doses recommended are for patients with normal renal and hepatic function. Dose of gentamicin should be adjusted to achieve a peak serum concentration of 3 to 4 g/mL and a trough concentration of <1 g/mL. Baddour et al Infective Endocarditis in Adults 1457 The decision of whether to use an ami- noglycoside-containing regimen must be individualized for each patient. The rationale and recommendations for spe- cific aminoglycoside-containing regimens for the treatment of enterococcal IE based on in vitro susceptibilities are dis- cussed in the following groups of patients and in Tables 12 through 15. Recommendations 1. Gentamicin should be administered in daily mul- tiple divided doses (total, 3 mg kg 1 ) rather than a single daily dose to patients with enterococ- cal IE and normal renal function (Class I; Level of Evidence B). with the dose adjusted to achieve a 1-hour serum con- centration of 3 g/mL and a trough concentration of <1 g/mL (Class IIa; Level of Evidence B). Enterococcal Endocarditis Susceptible to Penicillin, Vancomycin, and Aminoglycosides Antimicrobial regimens outlined in Table 12 are reasonable for treatment of patients with IE caused by these organisms. In a prospective study, the duration of antimicrobial therapy in native valve E faecalis IE was based on the duration of infec- tion before diagnosis and onset of effective therapy.196 Patients with <3 months duration of symptoms were treated success- fully with 4 weeks of antimicrobial therapy. Patients with 3 months duration of symptoms were successfully treated with 6 weeks of therapy. The duration of therapy for NVE is based on this work, and the regimens that may be considered are listed in Table 12. In patients with PVE, 6 weeks of antimicro- bial therapy is reasonable. Patients with preexisting mild (creatinine clearance, 30 50 mL/min) or severe (creatinine clearance, <30 mL/min) renal failure may not be able to safely complete a 4- to 6-week course of gentamicin therapy because of gentamicin-associated nephrotoxicity. Alternative regimens that should be considered include the use of streptomycin instead of gentamicin, short- course gentamicin therapy (2 3 weeks), and use of a non ami- noglycoside-containing double -lactam regimen. The risks and benefits of the alternative regimens are as follows. Streptomycin Therapy Although there are no published studies comparing the effi- cacy of regimens containing streptomycin or gentamicin, a similar cure rate was reported in a single noncomparative The main advantage is that streptomycin is less neph- rotoxic than gentamicin. There are several disadvantages of using streptomycin-containing regimens, including a lack of familiarity among clinicians with streptomycin, a higher risk of ototoxicity, which may not be reversible, and drug avail- ability limitations. In addition, most laboratories do not rou- tinely perform serum streptomycin assays and may not have access to a clinical pharmacist to assist in dosing adjustments. Streptomycin use should be avoided in patients with creati- nine clearance <50 mL/min. If the strain of enterococcus is susceptible to both gentamicin and streptomycin, it is reason- able to use gentamicin rather than streptomycin for therapy. When gentamicin therapy is not an option, then a double - lactam regimen (see later section) is reasonable. Short-Course ( 2-Week) Gentamicin Therapy Olaison and Schadewitz189 in Sweden reported a 5-year pro- spective study of 78 cases of enterococcal IE treated with a -lactam and an aminoglycoside. The older age of these patients was a factor in their inability to tolerate prolonged aminoglycoside therapy. The median duration of aminogly- coside therapy was 15 days, and the microbiological cure and survival rates were similar to those for patients who received longer courses of gentamicin therapy. The major advantage of short-course aminoglycoside therapy is reduced risk of aminoglycoside-associated nephrotoxicity. The disadvan- tage is that this is a single nonrandomized, noncomparative study. The results of a Danish pilot study185 that represented a before and after study, which was based on 2007 guidelines that recommended a 2-week treatment course of gentamicin for enterococcal IE in combination with -lactam therapy for 4 to 6 weeks, confirmed the results seen in the Swedish Double -Lactam Regimens for E faecalis IE Most strains of E faecalis are inhibited but not killed in vitro by penicillin or ampicillin, with MICs usually 2 to 4 g/ mL penicillin; ampicillin MICs are usually 1 dilution lower. Cephalosporins and antistaphylococcal penicillins (oxacillin, nafcillin) have minimal or no in vitro activity against entero- cocci. The in vitro activity of carbapenems is variable, with imipenem being most active. Because there are few therapeutic alternatives to amino- glycoside-containing regimens, combinations of -lactams were tested in vitro and in animal models of enterococcal experimental IE. The combination of ampicillin and imipe- nem acted synergistically in vitro and was effective therapy of multidrug-resistant enterococcal experimental IE.198 This study led to additional studies of experimental IE that dem- onstrated that the combination of ampicillin-ceftriaxone was effective therapy for gentamicin-susceptible or high-level gentamicin-resistant E faecalis experimental IE.199 The likely mechanism of double -lactam combinations against entero- cocci is saturation of different penicillin-binding proteins. These in vitro and in vivo studies provided the rationale for double -lactam therapeutic trials in humans with E faecalis IE caused by gentamicin-susceptible or high-level gentami- cin-resistant strains. A large, multicenter study by Spanish and Italian investigators compared ampicillin-ceftriaxone with ampicillin-gentamicin therapy of E faecalis IE.191 Patients with high-level aminoglycoside-resistant strains were not treated with ampicillin-gentamicin. A smaller study by this group compared ceftriaxone-ampicillin therapy of aminogly- coside-susceptible with high-level aminoglycoside-resistant E Both of these studies had significant limitations: They were observational, largely retrospective, and nonran- domized; the regimens were not standardized among the dif- ferent centers; discontinuation of gentamicin therapy was at the discretion of the investigators and not always the result of gentamicin-associated nephrotoxicity; and the serum con- centrations of gentamicin were not assessed or reported in all study sites. Despite these limitations, these 2 studies provide impor- tant data. First, these are the largest series of E faecalis IE reported to date, 43 patients in 1 study190 and 272 in the other Second, high-level aminoglycoside-resistant E faeca- lis IE treated with ampicillin-ceftriaxone therapy was present in 50% of the patients in the smaller study and 33% of patients in the larger study. Third, none of the patients in either study developed nephrotoxicity with ampicillin-ceftriaxone ther- patients developed nephrotoxicity (P<0.001). Fourth, in the larger study, the median age was 70 years in both treatment groups; however, patients in the ampicillin-ceftriaxone group were generally sicker and had more comorbid conditions (eg, chronic renal failure [P=0.004], neoplasm [P=0.015], and nosocomial acquisition of infection [P=0.006]). Fifth, in 1 study, PVE was present in 59 (37%) and 30 (34%) of patients treated with ampicillin-ceftriaxone and ampicillin- gentamicin, respectively, with similar success rates. Sixth, in the larger study, there were no significant differences between ampicillin-ceftriaxone and ampicillin-gentamicin in the need for surgery, complications (except for fewer cases of renal fail- ure in the ampicillin-ceftriaxone group), relapse, or mortality. Finally, the overall microbiological cure and success rates for ampicillin-ceftriaxone therapy in both studies were similar to rates in previously reported studies in patients treated with The major advantages of the ampicillin-ceftriaxone regi- men are the lower risk of nephrotoxicity and the lack of need for measuring aminoglycoside serum concentrations. The potential disadvantage is the possibility of hypersensitivity reactions to 2 separate -lactams. Because it would likely not be possible to discriminate between hypersensitivities related to ampicillin or to ceftriaxone, both drugs might have to be discontinued with substitution of vancomycin-gentamicin therapy. At this time, the writing group does not have a prefer- ence for one regimen over the other but rather advocates an individualized approach to regimen selection for each patient. Recommendations 1. Therapy that includes either ampicillin or aqueous crystalline penicillin G plus gentamicin or ampicil- lin plus ceftriaxone is reasonable (Class IIa; Level of Evidence B). 2. Either 4 or 6 weeks of therapy is reasonable for NVE, depending on the duration of IE symptoms before the initiation of therapy if ampicillin or peni- cillin plus gentamicin is used (Class IIa; Level of Evidence B). 3. Six weeks of therapy is reasonable if ampicillin plus ceftriaxone is selected as the treatment regimen, regardless of symptom duration (Class IIa; Level of Evidence B). 4. Six weeks of antimicrobial therapy is reasonable for PVE (Class IIa; Level of Evidence B). 5. Streptomycin should be avoided in patients with creatinine clearance <50 mL/min (Class III; Level of Evidence B). 6. If the strain of Enterococcus is susceptible to both gentamicin and streptomycin, it is reasonable to use gentamicin rather than streptomycin for therapy (Class IIa; Level of Evidence C). 7. When gentamicin therapy is not an option, then a double -lactam regimen (see later section) is rea- sonable (Class IIa; Level of Evidence B). E faecalis IE Susceptible to Penicillin, Resistant to Aminoglycosides, or Gentamicin Resistant and Streptomycin Susceptible Aminoglycoside resistance in enterococci is most commonly the result of the acquisition of plasmid-mediated aminoglyco- side-modifying enzymes. E faecalis strains resistant to high levels of gentamicin are resistant to most other aminoglyco- sides, although some of them are susceptible to streptomycin. The regimens for E faecalis IE with strains that are penicil- lin-susceptible and aminoglycoside-resistant are shown in Table 13. Ceftriaxone-ampicillin therapy is reasonable and is given for 6 weeks. The rationale for double -lactam therapy is outlined above. For gentamicin-resistant and streptomycin-susceptible E faecalis, ampicillin-ceftriaxone is reasonable. The 2005 AHA recommended streptomycin for patients with gentamicin-resistant strains of enterococci. The limitations of streptomycin use are summarized above. The total number of cases published in the European studies far exceeds the rela- tively small number of reported streptomycin-treated patients with enterococcal IE. Although there are no published data comparing ampicillin-ceftriaxone with streptomycin-con- taining regimens, we believe that ampicillin-ceftriaxone is reasonable for these patients. Disadvantages of streptomycin- containing regimens are outlined above. Recommendations 1. Ceftriaxone-ampicillin combination therapy is reasonable for IE caused by aminoglycoside- resistant enterococcal strains (Class IIa; Level of Evidence B). 2. For gentamicin-resistant and streptomycin-suscep- tible Enterococcus species, ampicillin-ceftriaxone combination therapy is reasonable (Class IIa; Level of Evidence B). Vancomycin Therapy for Enterococcal IE in Patients Unable to Tolerate -Lactams or Patients With E faecalis Resistant to Penicillin The regimens that are reasonable for these patients are shown in Table 14.Vancomycin should be administered only if a patient is unable to tolerate penicillin or ampicillin. Combinations of pen- icillin or ampicillin with gentamicin are preferable to combined vancomycin-gentamicin because of the potential increased risk of ototoxicity and nephrotoxicity with the vancomycin-genta- micin combination. Moreover, combinations of penicillin or ampicillin and gentamicin are more active than combinations of vancomycin and gentamicin in vitro and in animal models of experimental IE. It is reasonable that patients with NVE receive 6 weeks of vancomycin-gentamicin therapy and that patients with PVE receive at least 6 weeks of therapy. Baddour et al Infective Endocarditis in Adults 1459 Rarely,strainsofEfaecalisproduceaninducible -lactamase. These -lactamase producing strains are susceptible to ampicil- lin-sulbactam and to vancomycin. Intrinsic penicillin resistance is uncommon in E faecalis but is common in E faecium. It is reasonable to treat patients with E faecalis IE caused by strains that are intrinsically resistant to penicillin with a combination of vancomycin plus gentamicin. Recommendations for treatment of IE caused by these strains are shown in Table 14. Recommendations 1. Vancomycin should be administered only if a patient is unable to tolerate penicillin or ampicillin (Class I; Level of Evidence B). 2. It is reasonable that patients with NVE receive 6 weeks of vancomycin-gentamicin therapy and that patients with PVE receive at least 6 weeks of ther- apy (Class IIa; Level of Evidence B). 3. Patients with E faecalis IE caused by strains that are intrinsically resistant to penicillin should be treated with a combination of vancomycin plus gentamicin (Class I; Level of Evidence B). Enterococcal Endocarditis Resistant to Penicillin, Aminoglycosides, and Vancomycin The rapid emergence of vancomycin-resistant enterococci has become a global issue of major clinical importance. Most of these strains are E faecium, and as many as 95% of strains express multidrug resistance to vancomycin, aminoglyco- sides, and penicillins. Only about 3% of E faecalis strains are multidrug resistant, and many vancomycin-resistant E faecalis are penicillin susceptible. Fortunately, E faecium IE is uncom- mon. Most of the reports of multidrug-resistant E faecium IE are single case reports, reports of a small number of collected cases, or cases reported in new drug trials.200 Enterococci are considered to be resistant to vancomycin if MICs are >4 g/mL. Linezolid and daptomycin are the only 2 antimicrobial agents currently available in the United States that may be useful for the treatment of multidrug-resistant E faecium IE. Quinupristin-dalfopristin may be active in vitro but only against strains of E faecium and is inactive against E faecalis. Quinupristin-dalfopristin is rarely used because of severe side effects, including intractable muscle pain. Tigecycline is active in vitro against some strains of multidrug-resistant enterococci, but there are minimal published data on its use clinically. The same can be said for tedizolid, which has been released. Table 15 lists possible therapeutic options for the treat- ment of multidrug-resistant enterococcal IE. These patients should be managed by specialists in infectious diseases, car- diology, cardiovascular surgery, clinical pharmacy, and, if necessary, pediatrics. Antimicrobial regimens are discussed as follows. Linezolid Linezolid is a synthetic drug that is the first member of the oxazolidinone class. It acts by inhibiting ribosomal protein Table 13. Therapy for Endocarditis Involving a Native or Prosthetic Valve or Other Prosthetic Material Resulting From Enterococcus species Caused by a Strain Susceptible to Penicillin and Resistant to Aminoglycosides or Streptomycin-Susceptible Gentamicin-Resistant in Patients Able to Tolerate -Lactam Therapy* Regimen Dose and Route Duration, wk Strength of Recommendation Comments Double -lactam Ampicillin 2 g IV every 4 h 6 Class IIa; Level of Evidence B Double -lactam is reasonable for patients with normal or impaired renal function abnormal cranial nerve VIII function or if the laboratory is unable to provide rapid results of streptomycin serum concentration; native valve infection with symptoms of infection <3-mo duration may be treated for 4 wk with the streptomycin-containing regimen. PVE, NVE with symptoms >3 mo, or treatment with a double -lactam regimen require a minimum of 6 wk of therapy. Plus Ceftriaxone 2 g IV every 12 h Alternative for streptomycin susceptible/gentamicin resistant Either 4 6 Class IIa; Level of Evidence B Use is reasonable only for patients with availability of rapid streptomycin serum concentrations. Patients with creatinine clearance <50 mL/min or who develop creatinine clearance <50 mL/min during treatment should be treated with double - lactam regimen. Patients with abnormal cranial nerve VIII function should be treated with double -lactam regimen. Ampicillin sodium 2 g IV every 4 h Or Aqueous penicillin G sodium 18 30 million U/24 h IV either continuously or in 6 equally divided doses Plus Streptomycin sulfate 15 mg/kg ideal body weight per 24h IV or IM in 2 equally divided doses IM indicates intramuscular; IV, intravenous; NVE, native valve infective endocarditis; and PVE, prosthetic valve infective endocarditis. *For patients unable to tolerate a -lactam, see Table 14. Doses recommended for patients with normal renal and hepatic function. Streptomycin dose should be adjusted to obtain a serum peak concentration of 20 to 35 g/mL and a trough concentration of <10 g/mL. synthesis and is approved for use by the FDA in adults and children. It is not approved by the FDA for treatment of IE. Linezolid is bacteriostatic in vitro against enterococci, and susceptibility of enterococci to linezolid ranges from 97% to 99%, including strains that are multidrug resistant. Enterococci with MIC >2 g/mL are considered to be resistant to linezolid. However, linezolid-resistant strains have devel- oped during treatment.201 In a small number of patients, linezolid was effective ther- apy of vancomycin-resistant E faecium IE.174 Birmingham et reported cure in 17 of 22 courses of therapy (77%) for E faecium IE. Mave et al203 reported cure in 2 of 3 patients with E faecium IE with linezolid. Other case reports of cure of E faecium IE of native valve204 or prosthetic valve205 were reported. However, linezolid treatment failures of E faecium IE also were reported.206 The advantages of linezolid therapy include high bio- availability of the oral formulation, approval for pediatric patients, and a lack of many therapeutic alternatives. The disadvantages are toxicity (mild to severe neutropenia and thrombocytopenia that is reversible); peripheral and optic neuritis, which is more often seen with longer durations of therapy and may not be reversible; multidrug interactions, especially serotonin uptake inhibitors; and emergence of resistance during treatment. The previous high cost should decrease with generic availability soon. Cardiac valve replacement surgery may be necessary in patients who do not respond to linezolid therapy. Daptomycin Daptomycin is a cyclic lipopeptide antibiotic that has bacteri- cidal activity in vitro against susceptible strains of enterococci. Enterococci are considered daptomycin susceptible with MIC <4 g/mL. Although >90% of enterococci are reportedly susceptible in vitro to daptomycin, the emergence of dapto- mycin resistance is an increasing problem.207 Daptomycin is FDA approved for treatment of S aureus infections but not for enterococcal infections. Daptomycin is not approved for use in pediatric patients. The number of published cases of vancomycin-resistant E faecium IE treated with daptomycin is extremely small, so management conclusions are difficult to define, and the success rate has varied among reported cases. Levine and reported daptomycin cure in 6 of 9 patients with E faecium IE; both daptomycin-treated patients with E faecium IE reported by Segreti et al209 died. Multiple other case reports describe daptomycin failures, some as a result of emergence of daptomycin-resistance during treatment.210,211 Other inves- tigators have suggested that higher doses of daptomycin ); daptomycin combined with gentamicin, ampicillin, ceftaroline, rifampin, or tigecycline; or various combinations of these should be used instead of daptomycin A number of in vitro evaluations214 216 sug- gested that ampicillin and ceftaroline in combination with daptomycin demonstrate the greatest synergistic activity com- pared with other -lactam daptomycin combinations. Mave et al203 compared daptomycin with linezolid for vancomycin-resistant Enterococcus bacteremia. Five patients had E faecium IE; 1 of 2 daptomycin-treated patients and 2 of 3 linezolid-treated patients survived. The number of cases of vancomycin-resistant Enterococcus bacteremia was too small to draw significant conclusions about treatment response rates. In summary, there are insufficient data to recommend monotherapy with daptomycin for the treatment of multidrug- resistant enterococcal IE. If daptomycin therapy is selected, may be considered. Consideration may be given to combinations of therapy with daptomycin, including ampicillin or ceftaroline, particularly in patients infected with strains with relatively high MICs to daptomycin within the susceptible range (<4 g/mL). Other less active (in vitro) combinations with daptomycin include gentamicin, rifampin, or tigecycline. Table 14. Vancomycin-Containing Regimens for Vancomycin- and Aminoglycoside-Susceptible Penicillin-Resistant Enterococcus Species for Native or Prosthetic Valve (or Other Prosthetic Material) IE in Patients Unable to Tolerate -Lactam Regimen Dose* and Route Duration, wk Strength of Recommendation Comments Unable to tolerate -lactams Vancomycin 30 mg/kg per 24 h IV in 2 equally divided doses 6 Class IIa; Level of Evidence B Plus Gentamicin 3 mg/kg per 24 h IV or IM in 3 equally divided doses Penicillin resistance; intrinsic or -lactamase producer Vancomycin 30 mg/kg per 24 h IV in 2 equally divided doses 6 Class IIb; Level of Evidence C For -lactamase producing strain, if able to tolerate a -lactam antibiotic, ampicillin-sulbactam plus aminoglycoside therapy may be used. Plus Gentamicin 3 mg/kg per 24 h IV or IM in 3 equally divided doses IE indicates infective endocarditis; IM, intramuscular; and IV, intravenous. *Doses recommended are for adults with normal renal function. Dose of vancomycin should be adjusted to obtain a serum trough concentration of 10 to 20 g/mL. Dose of gentamicin should be adjusted to obtain serum peak and trough concentrations of 3 to 4 and <1 g/mL, respectively. Ampicillin-sulbactam dosing is 3 g/6 hour IV. Baddour et al Infective Endocarditis in Adults 1461 Recommendations 1. Patients with IE attributable to Enterococcus spe- cies resistant to penicillin, aminoglycosides, and vancomycin should be managed by specialists in infectious diseases, cardiology, cardiovascular sur- gery, clinical pharmacy, and, if necessary, pediatrics (Class I; Level of Evidence C). 2. If daptomycin therapy is selected, then doses of 10 may be considered (Class IIb; Level of Evidence C). 3. Combination therapy with daptomycin and ampi- cillin or ceftaroline may be considered, especially in patients with persistent bacteremia or enterococcal strains with high MICs (ie, 3 g/mL) to daptomy- cin within the susceptible range (Class IIb; Level of Evidence C). HACEK Microorganisms IE caused by fastidious Gram-negative bacilli of the HACEK group (HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) accounts for 5% to 10% of community-acquired NVE in patients who are not IDUs.218 These microorganisms grow slowly in standard blood cul- ture media, and recovery may require prolonged incubation. Typically, only a small fraction of blood culture bottles in patients with HACEK IE demonstrate growth. Bacteremia caused by HACEK microorganisms in the absence of an obvi- ous focus of infection is highly suggestive of IE even without typical physical findings of IE. Previously, the HACEK group of microorganisms was uniformly susceptible to ampicillin. However, -lactamase producing strains of HACEK are appearing with increased frequency; rarely, resistance to ampicillin can occur in Moreover, difficulty in per- forming antimicrobial susceptibility testing as a result of failure of growth in in vitro susceptibility testing is common- place. In 1 survey, 60% of isolates did not grow adequately in control wells, and no valid in vitro susceptibility results were Therefore, unless growth is adequate for in vitro screening, then HACEK microorganisms should be consid- ered ampicillin resistant, and penicillin and ampicillin should not be used to treat patients with IE in these cases. Almost all strains of the HACEK group are susceptible to ceftriaxone (or other third- or fourth-generation cephalosporins). Ceftriaxone has commonly been used to treat HACEK IE220 and is reason- able for treatment (Table 16). The duration of therapy for NVE of 4 weeks is reasonable; for PVE, the duration of therapy of 6 weeks is reasonable. Gentamicin is no longer recommended because of its nephrotoxicity risks. The HACEK group is usually susceptible in vitro to fluo- On the basis of these susceptibility data, a flu- oroquinolone (ciprofloxacin, levofloxacin, or moxifloxacin) may be considered as an alternative agent in patients unable to tolerate ceftriaxone (or other third- or fourth-generation cephalosporins) therapy. There are only a few case reports of HACEK IE treated with a fluoroquinolone, however. In addi- tion, ampicillin-sulbactam may be considered a treatment option, although HACEK resistance to this agent in vitro has Accordingly, patients with HACEK IE who cannot tolerate ceftriaxone therapy should be treated in con- sultation with an infectious diseases specialist. Recommendations 1. Unless growth is adequate in vitro to obtain suscep- tibility testing results, HACEK microorganisms are considered ampicillin resistant, and penicillin and ampicillin should not be used for the treatment of patients with IE (Class III; Level of Evidence C). 2. Ceftriaxone is reasonable for treatment of HACEK IE (Class IIa; Level of Evidence B). 3. The duration of therapy for HACEK NVE of 4 weeks is reasonable (Class IIa; Level of Evidence B); for HACEK PVE, the duration of therapy of 6 weeks is reasonable (Class IIa; Level of Evidence C). 4. Gentamicin is not recommended because of its nephrotoxicity risks (Class III; Level of Evidence C). 5. A fluoroquinolone (ciprofloxacin, levofloxacin, or moxifloxacin) may be considered an alternative agent for patients unable to tolerate ceftriaxone (or other third- or fourth-generation cephalosporins) (Class IIb; Level of Evidence C). 6. Ampicillin-sulbactam may be considered a treat- ment option for HACEK IE (Class IIb; Level of Evidence C). 7. Patients with HACEK IE who do not tolerate cef- triaxone therapy should be treated in consultation with an infectious diseases specialist (Class I; Level of Evidence C). Table 15. Therapy for Endocarditis Involving a Native or Prosthetic Valve or Other Prosthetic Material Resulting From Enterococcus Species Caused by Strains Resistant to Penicillin, Aminoglycosides, and Vancomycin Regimen Dose* and Route Duration, wk Strength of Recommendation Comments Linezolid 600 mg IV or orally every 12 h >6 Class IIb; Level of Evidence C Linezolid use may be associated with potentially severe bone marrow suppression, neuropathy, and numerous drug interactions. Patients with IE caused by these strains should be treated by a care team including specialists in infectious diseases, cardiology, cardiac surgery, clinical pharmacy, and, in children, pediatrics. Cardiac valve replacement may be necessary for cure. Or Daptomycin 10 12 mg/kg per dose >6 Class IIb; Level of Evidence C IE indicates infective endocarditis, and IV, intravenous. *Doses recommended are for patients with normal renal and hepatic function. Non-HACEK Gram-Negative Bacilli IE caused by non-HACEK Gram-negative aerobic bacilli (Enterobacteriaceae and Pseudomonas species) is rare. In that included 2761 patients seen in 61 hospitals in 28 countries, only 49 cases (1.8%) were attributable to non-HACEK Gram-negative aerobic bacilli. It is noteworthy that healthcare exposure was asso- ciated with the development of IE caused by this group of organisms in 57% of patients. In contrast, IDU, a prominent risk factor for the development of this IE syndrome in ear- lier years, was recognized in only 4% of cases in the mul- tinational survey that included cases seen between 2000 and 2005. Escherichia coli and Pseudomonas aeruginosa accounted for 51% of cases, and 59% had PVE. Although management included cardiac surgery in 51% of cases, the in-hospital mortality rate was 24%. Despitethe very rare occurrence ofIE causedby Salmonella species in North America, this syndrome deserves specific mention because it occurs with some frequency in other geo- Salmonella species have a proclivity to infect cardiovascular structures in adults. Therefore, all patients with bloodstream infection resulting from Salmonella species should be evaluated for complicating cardiovascular infec- tions, including IE, myocarditis, pericarditis, and endarteritis. Although many serotypes have been implicated, most cases are caused by S choleraesuis, S typhimurium, and S enteritidis.222 Cardiac surgery in combination with prolonged courses of combined antibiotic therapy is reasonable for most patients with IE caused by non-HACEK Gram-negative aerobic bacilli, particularly in the setting of left-sided valvular involvement. Prospective trial data are lacking to define the optimal antimicrobial regimen for the treatment of IE caused by non- HACEK Gram-negative aerobic bacilli. Input from special- ists in infectious diseases who are experienced in the medical management of IE should be obtained to define an antibiotic regimen in each case. This is particularly important in IE caused by non-HACEK Gram-negative aerobic bacilli for sev- eral reasons. First, as stated previously, healthcare exposure is commonly seen in these cases; thus, multidrug resistance often characterizes these pathogens. Second, therapy may include agents with increased toxicity risks such as aminogly- cosides (given in high dosages) and colistin. Third, because regimens that include >1 agent are often selected for use, the risks of drug-drug interactions and increased drug-related adverse events are problematic. Fourth, mortality is high in these infections, and medical-surgical approaches are often required for optimal management and favorable outcomes. Combination antibiotic therapy with a -lactam (penicillins, cephalosporins, or carbapenems) and either an aminoglycoside or fluoroquinolone for 6 weeks is reasonable.221 Consultation with an infectious diseases expert in IE should be sought because of the various mechanisms of antibiotic resistance that can be found in the non-HACEK Gram-negative aerobic bacilli. For example, several of these bacteria may harbor inducible -lactamases that could require supplemental laboratory screening, in addition to routine in vitro susceptibility testing. Medical therapy may be successful in right-sided P aerugi- nosa IE in 50% to 75% of cases. If the disease is refractory to anti- biotics, then partial tricuspid valvulectomy or vegetectomy 223 without valve replacement is indicated.224 Typically, these patients have been IDUs, and because of their high recidivism risk, avoid- ance of placement of prosthetic valves is desirable. Recommendations 1. Cardiac surgery is reasonable in combination with prolonged courses of combined antibiotic therapy for most patients with IE caused by non-HACEK Gram-negative aerobic bacilli, particularly P aeru- ginosa (Class IIb; Level of Evidence B). Table 16. Therapy for Endocarditis Involving a Native or Prosthetic Valve or Other Prosthetic Material Caused by HACEK Microorganisms Regimen Dose and Route Duration, wk Strength of Recommendation Comments Ceftriaxone sodium* 2 g/24 h IV or IM in 1 dose 4, NVE; Class IIa; Level of Evidence B Preferred therapy: cefotaxime or another third- or fourth-generation cephalosporin may be substituted. Or Ampicillin sodium 2 g IV every 4 h Class IIa; Level of Evidence B Ampicillin sodium may be an option if the growth of the isolate is sufficient to permit in vitro susceptibility results. Or equally divided doses Class IIb; Level of Evidence C Fluoroquinolone therapy may be considered for patients unable to tolerate cephalosporin and ampicillin therapy; levofloxacin or moxifloxacin may be substituted; fluoroquinolones generally is not recommended for patients <18 y old. Treatment for 6 wk is reasonable in patients with PVE (Class IIa; Level of Evidence C). HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; IM, intramuscular; IV, intravenous; NVE, native valve infective endocarditis; and PVE, prosthetic valve infective endocarditis. *Patients should be informed that intramuscular injection of ceftriaxone is painful. Dose recommended for patients with normal renal function. Fluoroquinolones are highly active in vitro against HACEK microorganisms. Published data on the use of fluoroquinolones for endocarditis caused by HACEK are minimal. Baddour et al Infective Endocarditis in Adults 1463 2. Combination antibiotic therapy with a -lactam (penicillins, cephalosporins, or carbapenems) and either an aminoglycoside or fluoroquinolone for 6 weeks is reasonable (Class IIa; Level of Evidence C). 3. Consultation with an infectious diseases expert in IE should be sought because of the various mechanisms of antibiotic resistance that can be found in the non- HACEK Gram-negative aerobic bacilli (Class I; Level of Evidence C). Culture-Negative Endocarditis Positive blood cultures are a major diagnostic criterion in IE and key to identifying an pathogenic agent and an optimal Continuous bacteremia and a high frequency of positive blood cultures are typical hallmarks of this infection. The intensity of bacteremia may not be great, however, with <50 colony-forming units per 1 mL blood detected in the majority of patients in an investigation.227 Failure to culture microorganisms that cause IE can be a major problem that complicates diagnosis and timely, effec- tive treatment. Although most previous studies have put the frequency of blood culture negative IE at 5% to 10%, a European study of IE that included 820 cases indicated that 20% of patients with confirmed IE had all negative blood This may be attributable to inadequate microbio- logical techniques, infection with highly fastidious bacteria or fungi, noncultivatable agents, or the previous administration of antimicrobial agents before blood cultures were obtained. Administration of antimicrobial agents to IE patients before blood cultures are obtained reduces the recovery rate of bac- teria by 35% to 40%.228 232 The antimicrobial susceptibility of the organism, the dose, and the duration and nature of pre- vious antimicrobial therapy together determine the length of time that blood cultures will remain negative.232 IE patients with blood cultures that are initially negative after only a few days of antibiotic therapy may have positive blood cultures after several days without antibiotics. The blood cultures of patients who receive longer courses of high-dose bactericidal antimicrobials may remain negative for weeks. Selection of medical therapy for patients with culture- negative IE is difficult. On the one hand, there is a need to provide empirical antimicrobials for all likely pathogens. On the other hand, certain therapeutic agents, including amino- glycosides, have potentially toxic effects that dictate limita- tion or avoidance of use if at all possible. Moreover, some of the laboratory-based diagnostic techniques to define fas- tidious or unusual pathogens are not available in most clinical laboratories and require considerable time for completion of testing if specimens are sent to a referral laboratory.233 During this period, patients are often treated empirically for the more common bacterial causes of IE, which can result in exposure to potentially toxic therapy that could be avoided with earlier pathogen identification. An evaluation of epidemiological factors (Table 6), history of prior infections including cardiovascular infections, expo- sure to antimicrobials, clinical course, severity, and extracar- diac sites of infection of the current infection should be done in all IE cases. During the period between the collection of blood cultures and the determination of a pathogen or if blood cultures are ultimately deemed culture negative, empirical therapy is generally required. Consultation with an infectious diseases specialist to define the most appropriate choice of therapy is recommended. Collection of additional clinical and laboratory data often dictates subsequent revisions in initial empirical therapy that will be administered over the treatment course. For patients with acute (days) clinical presentations of native valve infection, coverage for S aureus, -hemolytic streptococci, and aerobic Gram-negative bacilli is reasonable. Empirical coverage could include vancomycin and cefepime as an initial regimen. For patients with a subacute (weeks) presentation of NVE, empirical coverage of S aureus, VGS, HACEK, and enterococci is reasonable. One treatment option could include vancomycin and ampicillin-sulbactam to pro- vide some coverage for these organisms. Subsequent regimen revision can be done when a pathogen is recovered from blood cultures. For patients with culture-negative PVE, coverage for staphylococci, enterococci, and aerobic Gram-negative bacilli is reasonable if the onset of symptoms is within 1 year of prosthetic valve placement. A regimen could include vanco- mycin, rifampin, gentamicin, and cefepime. 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. One initial treatment option could include vancomycin and ceftriaxone. If subsequent blood culture results or other laboratory methodologies define a pathogen, then empirical therapy should be revised to focused therapy that is recommended for the specific pathogen identified. True culture-negative IE can be caused by uncommon or rare pathogens that do not grow in routinely used blood The organisms that have garnered the most attention are Bartonella species, Chlamydia species, C burnetii, Brucella species, Legionella species, Tropheryma whipplei, Candida, and non-Candida fungi (particularly Aspergillus species). The last 2 groups of organisms are espe- cially relevant to PV recipients. With the use of special diag- nostic techniques, Bartonella species, C burnetii, and Brucella species have been identified in the majority of cases of cul- ture-negative IE caused by fastidious organisms. Additional laboratory screening is required to identify the causes of In some cases, serological and special blood culture techniques can be helpful. In other cases, tissue (usually valve) screening is required. Diagnostic methods for resected valve tissue include microbiological, histopathologi- cal, and molecular techniques, the last of which includes gene amplification with PCR methods. Unfortunately, most clinical laboratories do not perform molecular screening, and speci- mens must be sent to reference laboratories. The most prevalent pathogen among these uncommon causes of culture-negative IE in this group has varied glob- ally according to published data.236 Incidence data from population-based surveys for IE caused by these organisms are lacking in the United States. In PVE cases, the timing of infection onset can also be important in defining pathogens.235 Limitations such as referral bias and sampling bias may have affected the findings.235 237 Results of a large prospective analysis of referred samples from culture-negative IE performed by a well-recognized reference laboratory deserve additional comment.236 First, there was identification of a pathogen in 62.7% of 759 cases; in 2.5%, a noninfectious origin (see below) was confirmed. Second, serological results were positive in 47.7% of cases, primarily for Coxiella and Bartonella species infection. Third, PCR identified a pathogen in two thirds of the valves studied. Fourth, no cause was defined in 35% of cases. Treatment of the wide variety of microorganisms that cause culture-negative IE without prior antibiotic exposure has been described anecdotally, and regimens of choice are based on limited data and can be found in other publications. Noninfectious causes of valvular vegetations can produce a syndrome similar to culture-negative IE. Perhaps the one that has received the most attention is anti-phospholipid anti- body (APA) syndrome,238 which has been described as both a primary and a secondary syndrome and is associated with the presence of APA. 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. 