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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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).


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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 (during initial hospitalization and before completion of a full course of antibiotics) is indicated in patients with IE who present with valve dysfunction resulting in symptoms or signs of heart failure (Class I; Level of Evidence B). 2. Early surgery should be considered particularly in patients with IE caused by fungi or highly resistant organisms (eg, vancomycin-resistant Enterococcus, multidrug-resistant Gram-negative bacilli) (Class I; Level of Evidence B). 3. Early surgery is indicated in patients with IE com- plicated by heart block, annular or aortic abscess, or destructive penetrating lesions (Class I; Level of Evidence B). 4. Early surgery is indicated for evidence of persistent infection (manifested by persistent bacteremia or fever lasting >5 7 days and provided that other sites of infection and fever have been excluded) after the start of appropriate antimicrobial therapy (Class I; Level of Evidence B). 5. Early surgery is reasonable in patients who present with recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy (Class IIa; Level of Evidence B). 6. Early surgery is reasonable in patients with severe valve regurgitation and mobile vegetations >10 mm (Class IIa, Level of Evidence B). 7. Early surgery may be considered in patients with mobile vegetations >10 mm, particularly when involving the anterior leaflet of the mitral valve and associated with other relative indications for sur- gery (Class IIb; Level of Evidence C). Early Valve Surgery in PVE: Recommendations 1. Early surgery is indicated in patients with symp- toms or signs of heart failure resulting from valve dehiscence, intracardiac fistula, or severe prosthetic valve dysfunction (Class I; Level of Evidence B). 2.


Early surgery is indicated in patients with symp- toms or signs of heart failure resulting from valve dehiscence, intracardiac fistula, or severe prosthetic valve dysfunction (Class I; Level of Evidence B). 2. Early surgery should be done in patients who have persistent bacteremia despite appropriate antibi- otic therapy for 5 to 7 days in whom other sites of infection have been excluded (Class I; Level of Evidence B). 3. Early surgery is indicated when IE is compli- cated by heart block, annular or aortic abscess, or destructive penetrating lesions (Class I; Level of Evidence B). 4. Early surgery is indicated in patients with PVE caused by fungi or highly resistant organisms (Class I; Level of Evidence B). 5. Early surgery is reasonable for patients with PVE who have recurrent emboli despite appropriate anti- biotic treatment (Class IIa; Level of Evidence B). 6. Early surgery is reasonable for patients with relaps- ing PVE (Class IIa; Level of Evidence C). 7. Early surgery may be considered in patients with mobile vegetations >10 mm (Class IIb; Level of Evidence C). Valve Surgery in Patients With Right-Sided IE Although outcomes are better for patients with right-sided IE compared with patients with left-sided infection, surgi- cal intervention is occasionally considered in the former group. Because many of the patients with right-sided IE develop infection as a result of IDU (see the Right-Sided IE in IDUs section), the general approach is to treat these patients Table 17.


Because many of the patients with right-sided IE develop infection as a result of IDU (see the Right-Sided IE in IDUs section), the general approach is to treat these patients Table 17. Direct Evidence Supporting an Association Between Valve Surgery and Lower Mortality From Observational Studies: Level of Evidence B Study Mortality IE Group PE vs SA Lalani et al10 In-hospital mortality NVE PE Bannay et al15 5-y mortality NVE+PVE PE Kiefer et al11 In-hospital and 1-y mortality CHF (NVE+PVE) PE Lalani et al10 In-hospital mortality Paravalvular complications (NVE) SA Bannay et al15 5-y mortality Intracardiac abscess (NVE+PVE) SA Lalani et al10 In-hospital mortality Systemic embolization (NVE) SA Bannay et al15 5-y mortality Systemic embolization (NVE+PVE) SA Lalani et al10 In-hospital mortality S aureus (NVE) SA Bannay et al15 5-y mortality CHF (NVE+PVE) SA Lalani et al259 In-hospital and 1-y mortality PVE with the highest propensity to undergo surgery SA CHF indicates congestive heart failure; NVE, native valve infective endocarditis; PE, primary end point; PVE, prosthetic valve infective endocarditis; and SA, subgroup analysis. All studies have adjusted for selection and survivor bias and confounding. Valve surgery was performed during the active phase of the disease (during initial hospitalization before completion of a full therapeutic course of antibiotics). Baddour et al Infective Endocarditis in Adults 1467 medically and to avoid placement of valve prostheses because of the subsequent risk of device infection with continued IDU. Surgical intervention is reasonable for patients with the fol- lowing complications: right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy, sustained infection caused by difficult-to-treat organisms (ie, fungi, multidrug resistant bacteria) or lack of response to appropriate antimicrobial therapy, and tricuspid valve vegeta- tions that are 20 mm in diameter and recurrent pulmonary embolism despite antimicrobial therapy.


Surgical intervention is reasonable for patients with the fol- lowing complications: right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy, sustained infection caused by difficult-to-treat organisms (ie, fungi, multidrug resistant bacteria) or lack of response to appropriate antimicrobial therapy, and tricuspid valve vegeta- tions that are 20 mm in diameter and recurrent pulmonary embolism despite antimicrobial therapy. Valve repair rather than replacement should be performed when feasible. If valve replacement is performed, then an individualized choice of prosthesis by the surgeon is reasonable.263,264 Recommendations 1. Surgical intervention is reasonable for patients with certain complications (Class IIa; Level of Evidence C). 2. Valve repair rather than replacement should be per- formed when feasible (Class I; Level of Evidence C). 3. If valve replacement is performed, then an individu- alized choice of prosthesis by the surgeon is reason- able (Class IIa; Level of Evidence C). 4. It is reasonable to avoid surgery when possible in patients who are IDUs (Class IIa; Level of Evidence C). Valve Surgery in Patients With Prior Emboli/ Hemorrhage/Stroke The timing of valve surgery in IE patients with stroke remains controversial. Stroke is an independent risk factor for post- operative mortality in IE patients. After stroke, neurological deterioration can occur as a result of hemorrhagic transforma- tion with anticoagulation during cardiopulmonary bypass or exacerbation of cerebral ischemia attributable to hypotension during cardiac surgery. The risk of intracranial hemorrhage is dependent on several factors, including extent and size of infarction, whether it is ischemic or hemorrhagic, and the exact timing of surgery. One clinical quandary is whether early valve surgery can be safely performed within 7 days after a stroke or if it is better to postpone surgery for at least 1 week. No randomized trials have addressed this conundrum.


One clinical quandary is whether early valve surgery can be safely performed within 7 days after a stroke or if it is better to postpone surgery for at least 1 week. No randomized trials have addressed this conundrum. The high rates of postoperative mor- bidity and mortality seen in earlier studies265 267 have resulted in a reluctance to refer patients with IE and acute stroke for imme- diate valve surgery. However, these initial studies included a limited number of patients, and risk adjustments were not per- formed. The largest early series of operated patients with cere- bral complications included 181 patients.267 Hospital mortality rates as a function of the interval between evidence of cerebral infarction to cardiac surgery were 66.3% when surgery was per- formed within 24 hours of stroke and gradually decreased every week to 7.0% with surgery >4 weeks after stroke. Investigations have suggested better outcomes for IE patients with ischemic stroke who undergo early cardiac sur- Ruttmann et al270 analyzed 65 patients who under- went cardiac surgery after cardioembolic (embolic) stroke (median time, 4 days; range, 0 38 days). Surgery in this time frame was not associated with worse patient outcomes. Fifty of the 61 patients (81.9%) with CT-verified preopera- tive stroke survived cardiac surgery. Latency between the neurological event and cardiac surgery was not a significant factor with respect to the perioperative neurological compli- cation rate or the postoperative neurological recovery rate. Full neurological recovery was achieved in 70% of 50 stroke patients. Other studies6 8 suggest that the risk of neurologi- cal deterioration during cardiac surgery after a stroke is lower than previously assumed, particularly in patients with silent cerebrovascular emboli.


Other studies6 8 suggest that the risk of neurologi- cal deterioration during cardiac surgery after a stroke is lower than previously assumed, particularly in patients with silent cerebrovascular emboli. The first study to evaluate the timing of surgery after stroke in IE that included a risk adjustment for differences in patient characteristics comprised 198 patients.273 Fifty-eight patients who underwent surgery within 1 week of stroke were compared with 140 patients who underwent surgery 8 days after stroke. Hospital mortality was numerically but not significantly higher in the early surgery group (22.4% versus 12%). After adjustment for other risk factors such as age, paravalvular abscess, and heart failure, the risk of hos- pital mortality remained nonsignificantly higher in the early surgery group (odds ratio, 2.308; 95% confidence interval, 0.942 5.652). Differences in 1-year mortality were less pro- nounced, with an adjusted hazard ratio of 1.138 (95% con- fidence interval, 0.802 1.650). In-hospital mortality in the early surgery group was comparable to that of the medically treated patients. After hemorrhagic stroke, the risk of exacerbation by sur- gery is prohibitively high in the first month but can extend beyond 1 month in some patients, possibly because of the presence of undetected mycotic aneurysms (MAs). In a mul- ticenter study of patients with hemorrhagic stroke, mortality was higher when surgery was performed within 4 weeks of the hemorrhagic event compared with later surgery (75% versus These data support the following recommendations: Valve surgery may be performed in IE patients with stroke or sub- clinical cerebral emboli without delay if intracranial hemor- rhage has been excluded by imaging studies and neurological damage is not severe (ie, coma). In patients with major isch- emic stroke or intracranial hemorrhage, it is reasonable to delay valve surgery for at least 4 weeks. Recommendations 1.


In patients with major isch- emic stroke or intracranial hemorrhage, it is reasonable to delay valve surgery for at least 4 weeks. Recommendations 1. Valve surgery may be considered in IE patients with stroke or subclinical cerebral emboli and residual vegetation without delay if intracranial hemorrhage has been excluded by imaging studies and neurolog- ical damage is not severe (ie, coma) (Class IIb; Level of Evidence B). 2. In patients with major ischemic stroke or intra- cranial hemorrhage, it is reasonable to delay valve surgery for at least 4 weeks (Class IIa; Level of Evidence B). Risk of Embolization Systemic embolization occurs in 22% to 50% of cases of Rates can be higher if noninvasive imaging, including MRI and CT scanning, is routinely done to detect asymptomatic (silent) emboli. Emboli often involve major arterial beds, including the brain, lungs, coronary arteries, spleen, bowel, and extremities. Up to 65% of embolic events involve the CNS, and >90% of CNS emboli lodge in the distri- bution of the middle cerebral artery.277 The highest incidence of embolic complications is seen with mitral valve IE (and more with anterior rather than posterior mitral leaflet involve- ment) and with IE caused by S aureus, Candida, and HACEK organisms. Emboli can occur before diagnosis, during therapy, or after therapy is completed, although most emboli occur within the first 2 to 4 weeks of antimicrobial therapy.58,278 Of note, 2 inde- pendent studies have confirmed that the rate of embolic events decreases dramatically during and after the first 2 to 3 weeks of successful antibiotic therapy. In a study from 1991, the embolic rate dropped from 13 to <1.2 embolic events per 1000 patient-days during that time.58 Vilacosta et al278 confirmed the reduced frequency of embolization after 2 weeks of therapy.


In a study from 1991, the embolic rate dropped from 13 to <1.2 embolic events per 1000 patient-days during that time.58 Vilacosta et al278 confirmed the reduced frequency of embolization after 2 weeks of therapy. Moreover, the latter study reemphasized the increased risk of embolization with increasing vegetation size during therapy, mitral valve involvement, and staphylococcal pathogenesis. In a survey that included the International Collaboration on Endocarditis cohort, Dickerman and colleagues280 focused on the incidence of stroke in a multicenter IE population and demonstrated that acute stroke rates fell significantly after initiation of antibiotic therapy regardless of valve involved or pathogen identified. Moreover, only 3.1% of the cohort suf- fered stroke after the first week of antimicrobial therapy; this finding has led to the opinion that stroke prevention as a sole indication for valve surgery after 1 week of appropriate antibi- otic therapy is not warranted. Prediction of individual patient risk for embolization is extremely difficult. Many studies have attempted to use echocardiography to identify a high-risk subset of IE patients who might benefit from early surgery to avoid embolization. Several studies with TTE have demonstrated a trend toward higher embolic rates with left-sided vegetations >1 cm in De Castro and colleagues276 compared TTE with multiplane TEE and found that neither technique was help- ful in defining embolic risk in patients with vegetations. In a based on TEE, mitral vegetations >1 cm in diameter were associated with the greatest frequency of embolism. The association was strengthened when the analysis was limited to those patients who had not yet experienced a clinical embolic event.


The association was strengthened when the analysis was limited to those patients who had not yet experienced a clinical embolic event. Another prospective TEE study, however, found no clear correlation of vegetation size with embolization.59 Nevertheless, the same investigators later reported the results of a new prospective study of 118 patients who underwent TEE and found that, on multivariable analysis, risk factors associated with embolic risk included vegetation size >10 mm and mitral valve involvement.56 Overall, these data are com- patible with previous observations that indicate that, in gen- eral, mitral vegetations of any size are associated with a higher risk of embolization (25%) than aortic vegetations (10%). As noted above, the highest embolic risk (37%) has been seen in the subset of patients with mitral vegetations attached to the anterior rather than the posterior mitral leaflet.59,63 This sug- gests that the mechanical effects of broad and abrupt leaflet excursion, occurring twice per heartbeat, may contribute to the propensity of a vegetation in this location to fragment and embolize. In another study, the effect of vegetation size on embolic potential was dependent on the infecting organism, with large vegetations independently predicting embolic events only in the setting of streptococcal IE.60 In contrast, as confirmed above byVilacosta et al,278 staphylococcal or fungal IE appears to carry a high incidence rate of embolization independently of vegetation size. Prognosis based on echocardiographic findings was exam- ined in a large, multicenter, prospective investigation. On the basis of TEE findings in 384 consecutive adult patients with definite IE, vegetation length >15 mm was a predictor of 1-year mortality (adjusted relative risk, 1.8; 95% confidence The role of echocardiography in predicting embolic events has been controversial.


On the basis of TEE findings in 384 consecutive adult patients with definite IE, vegetation length >15 mm was a predictor of 1-year mortality (adjusted relative risk, 1.8; 95% confidence The role of echocardiography in predicting embolic events has been controversial. In 1 survey282 that included 4 echocar- diographers who were blinded to clinical data, interobserver agreement was mixed on the characterization of vegetations. Agreement was high for the presence of vegetation (98%) and involved site (97%); interobserver agreement was consider- ably less for vegetation size (73%), mobility (57%), shape (37%), and attachment (40%). However, all of the series that included >100 patients who underwent TEE showed a positive relationship between embolic events and vegetation size. Moreover, the study with the largest number of patients (n=176) that assessed the value of TEE and included silent embolism detected by CT scanning demonstrated that the risk of embolic events was highly related to vegetation size and mobility but not to other known risk factors associated with embolism in IE.283 The conflicting results on the relationship between echocardiography and embolic risk can be explained at least partially by the poor standardization of diagnostic cri- teria for IE in older series, inclusion or not of silent embolism, inclusion or not of previous embolism, echocardiographic method used, lack of focus on future embolic events after TEE, and sample size.


Moreover, the study with the largest number of patients (n=176) that assessed the value of TEE and included silent embolism detected by CT scanning demonstrated that the risk of embolic events was highly related to vegetation size and mobility but not to other known risk factors associated with embolism in IE.283 The conflicting results on the relationship between echocardiography and embolic risk can be explained at least partially by the poor standardization of diagnostic cri- teria for IE in older series, inclusion or not of silent embolism, inclusion or not of previous embolism, echocardiographic method used, lack of focus on future embolic events after TEE, and sample size. An increase in vegetation size over 4 to 8 weeks of therapy as documented by TEE appears to predict embolic events.282 In addition, a second, albeit infrequent, peak of late embolic events has been observed to occur 15 to 30 weeks after the diagnosis of IE and has been associated with nonhealing veg- etations (failure of a vegetation to stabilize or diminish in size) as defined by echocardiography.63 The traditional indication for valvular surgery for IE to avoid embolization has been 2 major embolic events.284 This criterion is arbitrary and excludes cutaneous embolization, which is common, or embolism occurring before the insti- tution of therapy, which is common among IE patients who develop embolic events. Because of the observed decreases in embolic risk during the first 2 weeks of antibiotic therapy, the benefit of surgery in avoiding catastrophic embolic events is greatest early in the treatment course of IE. Early surgi- cal intervention may preclude a primary or recurrent major embolic event but exposes the patient to both immediate and lifelong risks of valve replacement if the valve cannot be pri- marily repaired.


Early surgi- cal intervention may preclude a primary or recurrent major embolic event but exposes the patient to both immediate and lifelong risks of valve replacement if the valve cannot be pri- marily repaired. At this time, the strategy for surgical inter- vention to avoid systemic embolization in IE remains specific Baddour et al Infective Endocarditis in Adults 1469 to the individual patient, with benefit being greatest in the early phase of IE when embolic rates are highest and other predictors of a complicated course (ie, recurrent embolization; heart failure; aggressive, antibiotic-resistant organisms; or PVE) are present (Table 5). The benefits of early surgery were demonstrated in the prospective, randomized trial12 that was discussed earlier in this document. Because of several limita- tions of that trial, additional study is needed before routine application of early surgery solely to reduce embolic risk can be strongly advocated. Embolic events are important prognostic indicators of IE outcomes. In 1 analysis, an embolic event was 1 of 4 early pre- dictors of in-hospital death caused by IE.285 Other independent predictors of death by logistic regression modeling among 267 consecutive patients with definite or possible IE by modified Duke criteria were diabetes mellitus, S aureus infection, and Acute Physiology And Chronic Health Evaluation (APACHE) II score. Another controversial topic is whether imaging to detect emboli should be performed in all IE patients. The current paradigm includes dedicated, anatomic imaging if there are signs or symptoms suggestive of an embolic event. There is less agreement on imaging, which can pose risks because con- trast material is usually required, in patients without symp- toms or signs of emboli, some of whom may have silent or subclinical events. In particular, should MRI of the brain be obtained in all IE patients because cerebral emboli are so com- monplace?


In particular, should MRI of the brain be obtained in all IE patients because cerebral emboli are so com- monplace? As previously mentioned in an earlier section (3D Echocardiography and Other Imaging Modalities), some have advocated this strategy in all patients who are to undergo valve surgery to identify those who may harbor embolic lesions that could pose a higher risk of intracranial bleeding with cardio- pulmonary bypass and heparin administration used for cardiac surgery. Anticoagulation Anticoagulation in IE patients is controversial, particularly in mechanical valve IE.286 Some authorities recommend con- tinuation of anticoagulant therapy in patients with mechani- cal valve IE. However, the general advice is to discontinue all forms of anticoagulation in patients with mechanical valve IE who have experienced a CNS embolic event for at least 2 This time should allow for thrombus organization and prevent the acute hemorrhagic transformation of embolic lesions. Reintroduction of anticoagulation in these patients should be done with great caution, beginning with intravenous unfractionated heparin titrated to an activated partial thrombo- plastin time range of 50 to 70 seconds and transitioning care- fully to adjusted dose warfarin. The novel oral anticoagulants are not approved for use with either mechanical valves or bio- prosthetic valves when risk factors for thromboembolism exist (eg, atrial fibrillation). The benefit of therapeutic anticoagulation has never been demonstrated convincingly in patients with NVE. In part related to findings that demonstrated a salutary effect of intra- venous aspirin therapy in established experimental S aureus a randomized trial compared oral aspirin 325 mg/d with placebo in 115 IE patients.288 No significant benefit was observed in aspirin-treated patients in terms of vegetation resolution and embolic events. Moreover, there was a trend toward more bleeding episodes in the aspirin-treated patients.


Moreover, there was a trend toward more bleeding episodes in the aspirin-treated patients. Aspirin levels, a critical correlate of antimicrobial efficacy in an animal model, were not monitored in this study.289 Retrospective, observational studies290 296 have examined the impact, if any, of long-term antiplatelet therapy before the onset of IE on infection-related outcomes. Findings from these investigations have been mixed in terms of IE-related outcomes. Until definitive data are available, the initiation of aspirin or other antiplatelet agents as adjunctive therapy in IE is not recommended. In contrast, the continuation of long- term antiplatelet therapy at the time of development of IE with no bleeding complications may be considered. Recommendations 1. Discontinuation of all forms of anticoagulation in patients with mechanical valve IE who have expe- rienced a CNS embolic event for at least 2 weeks is reasonable (Class IIa; Level of Evidence C). 2. Initiation of aspirin or other antiplatelet agents as adjunctive therapy in IE is not recommended (Class III; Level of Evidence B). 3. The continuation of long-term antiplatelet therapy at the time of development of IE with no bleeding complications may be considered (Class IIb; Level of Evidence B). Periannular Extension of Infection Extension of IE beyond the valve annulus predicts a higher mortality rate, more frequent development of heart fail- ure, and more frequent need for cardiac surgery.284,297,298 Perivalvular cavities form when annular infections break through and spread into contiguous tissue.


Periannular Extension of Infection Extension of IE beyond the valve annulus predicts a higher mortality rate, more frequent development of heart fail- ure, and more frequent need for cardiac surgery.284,297,298 Perivalvular cavities form when annular infections break through and spread into contiguous tissue. In aortic NVE, this generally occurs through the weakest portion of the annulus, which is near the membranous septum and atrio- The anatomic vulnerability of this area explains both why abscesses occur in this location and why heart block is a frequent sequela.300 Periannular exten- sion is common, occurring in 10% to 40% of all NVE and complicating aortic IE more commonly than mitral or tri- Periannular infection is of even greater con- cern with PVE, occurring in 56% to 100% of patients.298,302 Perivalvular abscesses are particularly common with pros- thetic valves because the annulus, rather than the leaflet, is the usual primary site of infection, especially in early PVE and on bioprosthetic valves.302 Under the influence of systemic intravascular pressures, abscesses may progress to fistulous tracts that create intracar- diac or pericardial shunts. The mortality rate was 41% in a of patients with aorto-cavitary fistulization despite surgical intervention in 87%. Multivariate analysis demon- strated that factors associated with an increased risk of death included moderate to severe heart failure, PVE, and urgent or emergency surgical intervention. In some cases, progressive periannular infection totally disrupts the ventricular-aortic continuity or the mitral-aortic trigone. Such structural lesions and intracardiac fistulas may be catastrophic; even if their hemodynamic impact is tolerated, these lesions will not heal with medical treatment alone and require urgent operative intervention. Clinical parameters for the diagnosis of perivalvular extension of IE are inadequate.


Clinical parameters for the diagnosis of perivalvular extension of IE are inadequate. Persistent bacteremia or fever, recurrent emboli, heart block, heart failure, or a new patho- logical murmur in a patient with IE on appropriate antibiotics may suggest extension.303 Only aortic valve involvement and current IDU have been prospectively identified as independent risk factors for perivalvular abscess.297 On ECG, new atrio- ventricular block has a positive predictive value of 88% for abscess formation but low (45%) sensitivity.298 Patients at risk for perivalvular extension of IE require prompt evaluation. The size of vegetations is not helpful for predicting perivalvular extension.297 The sensitivity of TTE for detecting perivalvular abscess is low (18% to 63% in pro- spective and retrospective studies, respectively).305,306 TEE dramatically improves the sensitivity for defining periannular extension of IE (76% to 100%) while retaining excellent spec- ificity (95%) and positive and negative predictive values (87% When combined with spectral and color Doppler techniques, TEE can demonstrate the distinc- tive flow patterns of fistulas and pseudoaneurysms and can rule out communications from unruptured abscess cavities. Because of these combined capabilities, TEE is recommended for the initial assessment of any patient suspected of having perivalvular extension of IE. A small number of patients with periannular extension of infection or myocardial abscess may be treated successfully without surgical intervention.307,308 These patients potentially include those who have smaller (<1 cm) abscesses and who do not have complications such as heart block, echocardiographic evidence of progression of abscess during therapy, valvular dehiscence, or insufficiency. Such patients should be monitored closely with serial TEE; TEE should be repeated at intervals of 2, 4, and 8 weeks after completion of antimicrobial therapy. Surgery for patients with perivalvular extension of IE is directed toward eradication of the infection and correction of hemodynamic abnormalities.


Surgery for patients with perivalvular extension of IE is directed toward eradication of the infection and correction of hemodynamic abnormalities. Drainage of abscess cavities, excision of necrotic tissue, and closure of fistulous tracts often accompany valve replacement or repair surgery.309 Although valve replacement is usually required, its successful performance may be compromised by extensive destruction of the periannular supporting tissues. Under these conditions, human aortic homo- grafts, when available, can be used to replace the damaged aor- tic valve and to reconstruct the damaged aorta.310,311 Homografts have a constant but low incidence rate of IE.312 Some groups have advocated the use of stentless or mini-stented aortic valve prostheses with debridement in the same clinical scenario, par- ticularly if homografts are not readily available.313 Recommendation 1. TEE is recommended for the initial assessment of any patient suspected of having perivalvular exten- sion of IE (Class I; Level of Evidence B). Metastatic Foci of Infection Similar to embolic complications, metastatic foci of infec- tion frequently occur in IE and can greatly affect management strategies, in particular timing of valve surgery, duration of antimicrobial therapy, and need for invasive interventions (usually surgical or interventional radiological drainage). Much like embolic events, metastatic foci of infection either can remain asymptomatic or may cause major clinical signs or symptoms. In the latter case, sustained fever can be a valu- able clue, particularly when bloodstream infection has been cleared or in cases when bloodstream infection persists despite adequate antimicrobial coverage. In addition, distinguish- ing bland infarction caused by an embolus from a metastatic focus (abscess) sometimes can be difficult. In patients who are symptomatic, a diagnostic evaluation including radiologi- cal, ultrasonographic, and invasive procedures such as joint aspiration for both diagnostic and therapeutic reasons is rec- ommended.


In patients who are symptomatic, a diagnostic evaluation including radiologi- cal, ultrasonographic, and invasive procedures such as joint aspiration for both diagnostic and therapeutic reasons is rec- ommended. Invasive procedures such as percutaneous drain- age of soft tissue or organ abscess may be needed. Surgical intervention, as mentioned above, may be required for radi- cal infection cure. For example, splenic abscesses generally require splenectomy or a drainage procedure because the usefulness of antimicrobial therapy is in preventing disease extension in the spleen and treating systemic infection rather than eliminating abscesses.314 Whether percutaneous aspira- tion or drainage of splenic abscesses can be performed safely and effectively should be decided by an experienced team of clinicians. Identification and management of metastatic foci of infec- tion are critically important in patients who require valve surgery. When feasible, all invasive procedures for the initial management of metastatic foci of infection should be done before valve surgery to reduce the likelihood of infecting a placed prosthetic valve or annuloplasty ring. Cerebrovascular imaging may be considered in all patients with left-sided IE who have no CNS signs or symptoms (see the Intracranial MAs section below). There are currently no other recommendations for routinely evaluating all patients with IE for metastatic foci of infection, although many clinicians rec- ommend such routine screening for all cases of S aureus IE. Rather, a directed workup is advocated on the basis of local- izing signs or symptoms. Depending on the site of interest, the choice of diagnostic procedure (eg, CT, MRI, ultrasonogra- phy) varies, and the selection should be individualized for each patient. The choice of procedure may require consultation with experts.


Depending on the site of interest, the choice of diagnostic procedure (eg, CT, MRI, ultrasonogra- phy) varies, and the selection should be individualized for each patient. The choice of procedure may require consultation with experts. It is strongly recommended that a discussion of which laboratory (microbiology, pathology including cytology) stud- ies will be needed once tissue or fluid aspirate specimens are available takes place before an invasive procedure is performed. Recommendation 1. The choice of diagnostic procedure (eg, CT, MRI, ultrasonography) varies and the selection should be individualized for each patient (Class I; Level of Evidence C). Mycotic Aneurysms MAs are uncommon complications of IE that result from sep- tic embolization of vegetations to the arterial vasa vasorum or the intraluminal space, with subsequent spread of infec- tion through the intima and outward through the vessel wall. Baddour et al Infective Endocarditis in Adults 1471 Arterial branching points favor the impaction of emboli and are the most common sites of development of MAs. MAs caused by IE occur most frequently in the intracranial arteries, followed by the visceral arteries and the arteries of the upper and lower extremities. A detailed analysis of the complex management of MAs has been included in a separate AHA Scientific Statement that addresses vascular infections and is pending publication; please refer to this document for additional information. Intracranial MAs Intracranial MAs (ICMAs) represent a relatively small but extremely dangerous subset of neurological complications. The overall mortality rate among IE patients with ICMAs is 60%. Among patients with unruptured ICMAs, the mortality rate is 30%; in patients with ruptured ICMAs, the mortality rate approaches 80%.315,316 The reported occurrence of ICMAs is probably underestimated because some ICMAs remain asymptomatic and resolve with antimicrobial therapy.


Among patients with unruptured ICMAs, the mortality rate is 30%; in patients with ruptured ICMAs, the mortality rate approaches 80%.315,316 The reported occurrence of ICMAs is probably underestimated because some ICMAs remain asymptomatic and resolve with antimicrobial therapy. Streptococci and S aureus account for and ICMAs are seen with increased frequency among IDUs with IE.318 The dis- tal middle cerebral artery branches are most often involved, especially the bifurcations. Multiple ICMAs occur in 20% ; mortality rates are similar for multiple and single distal ICMAs. The mortality rate for patients with proximal ICMAs is >50%.321 The clinical presentation of patients with ICMAs is highly variable. Patients may develop severe headache, altered sen- sorium, or focal neurological deficits such as hemianopsia or cranial neuropathies. Neurological signs and symptoms are nonspecific and may suggest a mass lesion or an embolic Some ICMAs leak slowly before rupture and pro- duce mild meningeal irritation. Frequently, the spinal fluid in these patients is sterile, and it usually contains erythrocytes, leukocytes, and elevated protein. In other patients, there are no clinically recognized premonitory findings before sudden subarachnoid or intraventricular hemorrhage.315 Symptomatic cerebral emboli frequently but not invari- ably precede the finding of an ICMA.315 Therefore, imaging procedures to detect ICMAs are indicated in IE patients with localized or severe headaches; sterile meningitis, especially if erythrocytes or xanthochromia is present; or focal neurologi- cal signs. Several imaging modalities can be used to identify ICMAs; currently, there is no preferred initial imaging study that can be recommended.322 Techniques include cardiac (mul- tislice) CT angiography with 3D reconstruction, digital subtrac- tion angiography, and magnetic resonance angiography with 3D reconstruction. In cases when there is a high clinical suspi- cion of ICMAs and a negative initial screening with 1 of these modalities, then conventional angiography is reasonable to per- form.


In cases when there is a high clinical suspi- cion of ICMAs and a negative initial screening with 1 of these modalities, then conventional angiography is reasonable to per- form. Cerebral MRI may be considered in all patients with left- sided IE who have no CNS signs or symptoms. MRI findings may assist in subsequent medical and surgical management.322 Recommendations 1. Cerebrospinal imaging should be performed to detect ICMA or CNS bleeding in all patients with IE or contiguous spread of infection who develop severe, localized headache, neurological deficits, or meningeal signs (Class I; Level of Evidence B). 2. Cerebrovascular imaging may be considered in all patients with left-sided IE who have no CNS signs or symptoms (Class IIb; Level of Evidence C). 3. CT angiography, magnetic resonance angiography, or digital subtraction angiography is reasonable as an initial imaging test for detection of ICMA (Class IIa, Level of Evidence B). 4. Conventional angiography for detection of sus- pected ICMA is reasonable in patients with negative CT angiography, magnetic resonance angiography, or digital subtraction angiography (Class IIa; Level of Evidence B). Extracranial MAs Intrathoracic or intra-abdominal MAs often are asymptomatic until leakage or rupture occurs. Presumably, most extracranial MAs will rupture if not excised. The appearance of a tender, pulsatile mass in a patient with IE suggests an extracranial MA. Hematemesis, hematobilia, and jaundice suggest rupture of a hepatic artery MA; arterial hypertension and hematuria sug- gest rupture of a renal MA; and massive bloody diarrhea sug- gests the rupture of an extracranial MA into the small or large bowel. Either CT scanning or multislice CT angiography with 3D reconstruction is indicated for initial imaging. TEE is useful in identifying MAs of the sinus of Valsalva and thoracic aorta. Recommendations 1.


TEE is useful in identifying MAs of the sinus of Valsalva and thoracic aorta. Recommendations 1. Either CT scanning or multislice CT angiography with 3D reconstruction is indicated for initial imag- ing (Class I; Level of Evidence B). 2. TEE is useful in identifying MAs of the sinus of Valsalva and thoracic aorta (Class I; Level of Evidence B). Outpatient Therapy Outpatient parenteral antibiotic therapy (OPAT) is efficacious, safe, and cost-effective for a variety of infections,323 325 includ- ing IE that requires prolonged parenteral therapy in hospital- ized patients who otherwise no longer require inpatient care but do require continued parenteral antimicrobial therapy. Antibiotic regimens recommended for IE vary widely and often require 4 weeks of therapy, generally given by the intra- venous route. Absorption of orally administered antimicrobial agents may be unreliable, and such a strategy is generally not recommended as sole therapy for IE. Several other aspects of OPAT such as drug stability at room temperature; frequency of drug dosing; access to ancillary equipment, including ambula- tory pumps; insurance coverage; and whether the patient has a history of IDU can all affect the ultimate use of OPAT. The timing for transition from inpatient antibiotic therapy to OPAT and patient exclusion criteria have been critically evaluated by Andrews and von Reyn.326 These guidelines are based on the local availability of medical care in the outpa- tient setting and risk factors and timing of potential adverse outcomes that would be best managed in the inpatient setting. Before OPAT is considered, most patients with IE should first be evaluated and stabilized in the hospital; only rarely can some patients be treated entirely as outpatients. Patients selected for OPAT should be at low risk for the complications of IE, the most frequent of which are heart failure and systemic emboli.


Patients selected for OPAT should be at low risk for the complications of IE, the most frequent of which are heart failure and systemic emboli. The period of greatest risk for systemic emboli is before or within the first 1 to 2 weeks of antimicrobial therapy, although serious complications such as heart failure and rupture of MAs may develop weeks to months after the initiation of antimicro- bial therapy. The presence of poorly controlled heart failure, neurological findings that may result from systemic emboli or bleeding MAs, cardiac conduction abnormalities, valve ring abscesses (usually detected by TEE), persistent fever, or persis- tently positive blood cultures should preclude OPAT. The risk for drug-related side effects usually increases with a prolonged drug exposure (eg, vestibular, auditory, and nephrotoxicity resulting from aminoglycosides; leukopenia caused by -lactams and vancomycin; and nephrotoxicity resulting from the combination of vancomycin and gentami- cin) and requires close monitoring by the home infusion team consisting of representatives from nursing and pharmacy and clinicians with expertise in IE management. The following criteria are essential for an effective OPAT program: A reliable support system at home and easy access to a hospital for prompt re-evaluation by an experienced clinician if a complication such as recurrence of fever, symptoms of a cardiac arrhythmia, heart failure, or a neurological event develops Regular visits by a home infusion nurse who carefully monitors the patient for early detection of complications, failure to respond to therapy, problems with adherence to therapy, or complications (eg, catheter-related infection, catheter leakage or displacement, venous thrombosis) directly related to the antibiotics or intravenous access Regular visits with an experienced clinician to assess clinical status during the OPAT Recommendations 1.