It is reasonable for the counting of days for the duration of therapy to begin on the first day on which blood cultures are negative in cases in which blood cultures were initially positive. It is reasonable to obtain 2 sets of blood cultures every 24 to 48 hours until bloodstream infection is cleared. However, if a patient undergoes valve surgery and the resected valve tissue is culture positive or a perivalvular abscess is found, then an entire course of antimicrobial therapy is reasonable after valve surgery. If the resected tissue is culture negative, then it may be reasonable for the duration of postoperative treatment given less the number of days of treatment admin- istered for native valve infection before valve replacement. This, however, has been challenged by retrospectively col- lected data from 2 different medical centers116,117 that sug- gest that 2 weeks of antibiotic therapy may be sufficient in patients who undergo valve surgery and have negative valve tissue cultures, particularly in IE cases caused by VGS or Streptococcus gallolyticus (bovis). Whether a 2-week treatment course would be sufficient after valve sur- gery in patients with positive valve cultures either was not or included only 5 patients in the Histopathological evidence of bacteria with valve tissue Gram staining in patients with negative tissue cul- tures can represent killed organisms and is not a factor in defining the length of therapy after valve surgery.110 For patients with NVE who undergo valve resection with prosthetic valve replacement or repair with an annuloplasty ring, there is a lack of consensus as to whether the postopera- tive treatment regimen should be one that is recommended for prosthetic valve treatment rather than one that is recommended Baddour et al Infective Endocarditis in Adults 1445 for native valve treatment. In regimens that contain combi- nation antimicrobial therapy, it is reasonable to administer agents at the same time or temporally close together to maxi- mize the synergistic killing effect on an infecting pathogen. Recommendations 1. Infectious diseases consultation should be obtained to define an optimal empirical treatment regimen at the time of initiation of antimicrobial therapy (Class I; Level of Evidence B). 2. It is reasonable that the counting of days for the duration of antimicrobial therapy begin on the first day on which blood cultures are negative in cases in which blood cultures were initially positive (Class IIa; Level of Evidence C). 3. It is reasonable to obtain at least 2 sets of blood cul- tures every 24 to 48 hours until bloodstream infec- tion has cleared (Class IIa; Level of Evidence C). 4. If operative tissue cultures are positive, then an entire antimicrobial course is reasonable after valve surgery (Class IIa; Level of Evidence B). 5. If operative tissue cultures are negative, it may be reasonable to count the number of days of anti- microbial therapy administered before surgery in the overall duration of therapy (Class IIb; Level of Evidence C). 6. It is reasonable to time the administration of antimi- crobial therapy at the same time or temporally close together for regimens that include >1 antimicrobial agent (Class IIa; Level of Evidence C). Dog or cat exposure Bartonella sp Pasteurella sp Capnocytophaga sp Contact with contaminated milk or infected farm animals Brucella sp Coxiella burnetii Erysipelothrix sp Homeless, body lice Bartonella sp AIDS Salmonella sp S pneumoniae S aureus Pneumonia, meningitis S pneumoniae Solid organ transplantation S aureus Aspergillus fumigatus Enterococcus sp Candida sp Gastrointestinal lesions S gallolyticus (bovis) Enterococcus sp Clostridium septicum HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; IDU, injection drug use; and VGS, viridans group streptococci. Table 6. Epidemiological Clues That May be Helpful in Defining the Etiological Diagnosis of Culture-Negative Endocarditis Epidemiological Feature Common Microorganism IDU S aureus, including community-acquired oxacillin-resistant strains Coagulase-negative staphylococci -Hemolytic streptococci Fungi Aerobic Gram-negative bacilli, including Pseudomonas aeruginosa Polymicrobial Indwelling cardiovascular medical devices S aureus Coagulase-negative staphylococci Fungi Aerobic Gram-negative bacilli Corynebacterium sp Genitourinary disorders, infection, and manipulation, including pregnancy, delivery, and abortion Enterococcus sp Group B streptococci (S agalactiae) Listeria monocytogenes Aerobic Gram-negative bacilli Neisseria gonorrhoeae Chronic skin disorders, including recurrent infections S aureus -Hemolytic streptococci Poor dental health, dental procedures VGS Nutritionally variant streptococci Abiotrophia defectiva Granulicatella sp Gemella sp HACEK organisms Alcoholism, cirrhosis Bartonella sp Aeromonas sp Listeria sp S pneumoniae -Hemolytic streptococci Burn S aureus Aerobic Gram-negative bacilli, including P aeruginosa Fungi Diabetes mellitus S aureus -Hemolytic streptococci S pneumoniae Early ( 1 y) prosthetic valve placement Coagulase-negative staphylococci S aureus Aerobic Gram-negative bacilli Fungi Corynebacterium sp Legionella sp Late (>1 y) prosthetic valve placement Coagulase-negative staphylococci S aureus Viridans group streptococci Enterococcus species Fungi Corynebacterium sp (Continued) Table 6. Continued Epidemiological Feature Common Microorganism Overview of VGS, Streptococcus gallolyticus (Formerly Known as Streptococcus bovis), Abiotrophia defectiva, and Granulicatella Species VGS are common pathogenic agents in community-acquired NVE in patients who are not IDUs. The taxonomy of VGS is evolving. The species that most commonly cause IE are S sanguis, S oralis (mitis), S salivarius, S mutans, and Gemella morbillorum (formerly called S morbillorum). Members of the S anginosus group (S intermedius, angi- nosus, and constellatus) also have been referred to as the S milleri group, and this has caused some confusion. In contrast to other -hemolytic streptococcal species, the S anginosus group tends to form abscesses and to cause hematogenously disseminated infection (eg, myocardial and visceral abscesses, septic arthritis, and vertebral osteomy- elitis). In addition, although the S anginosus group usually is sensitive to penicillin, some strains may exhibit variable penicillin resistance. The recommendations that follow are intended to assist clinicians in selecting appropriate antimi- crobial therapy for patients with IE caused by VGS and S gallolyticus (bovis, a nonenterococcal penicillin-susceptible group D Streptococcus). S gallolyticus (bovis) expresses the group D antigen, but it can be distinguished from group D Enterococcus by appropriate biochemical tests. Patients with either S gallolyticus (bovis) bacteremia or IE should undergo a colonoscopy to determine whether malignancy or other mucosal lesions are present. Certain VGS have biological characteristics that may com- plicate diagnosis and therapy. A defectiva and Granulicatella species (G elegans, G adiacens, G paraadiacens, and G balaenopterae), formerly known as nutritionally variant strep- tococci, are detected by automated blood culture systems but may yield pleomorphic forms by Gram stain and will not grow on subculture unless chocolate agar or other media supple- mented with pyridoxal or cysteine is used. Treatment regimens outlined for VGS, A. defectiva, and Granulicatella species are subdivided into categories based on penicillin MIC data. Native Valve Highly Penicillin-Susceptible VGS and S gallolyticus (bovis) (MIC 0.12 g/mL) Bacteriological cure rates 98% may be anticipated in patients who complete 4 weeks of therapy with parenteral penicillin or ceftriaxone for IE caused by highly penicillin-susceptible VGS or S gallolyticus (bovis)118,119 (Table 7). Ampicillin is a reasonable alternative to penicillin and has been used when penicillin is not available because of supply deficiencies. The addition of gentamicin sulfate to penicillin exerts a synergistic killing effect in vitro on VGS and S gallolyticus (bovis). The combination of penicillin or ceftriaxone with gentamicin results in synergistic killing in animal models of VGS or S gallolyticus (bovis) experimental IE. In selected patients, treatment with a 2-week regimen with either penicil- lin or ceftriaxone combined with an aminoglycoside resulted in cure rates that are similar to those after monotherapy with penicillin or ceftriaxone administered for 4 weeks.83,120 Studies performed in Europe, South America, and the United States demonstrated that the combination of once-daily ceftriaxone with either netilmicin or gentamicin administered once daily was equivalent in efficacy to 2 weeks of therapy with peni- cillin with an aminoglycoside administered in daily divided The 2-week regimen of penicillin or ceftriaxone combined with single daily-dose gentamicin is reasonable for uncomplicated cases of IE caused by highly penicillin-suscep- tible VGS or S gallolyticus (bovis) in patients at low risk for adverse events caused by gentamicin therapy (Table 7). This 2-week regimen is not recommended for patients with known extracardiac infection or those with a creatinine clearance of <20 mL/min. Although the two, 4-week -lactam containing regi- mens shown in Table 7 produce similar outcomes, each regi- men has advantages and disadvantages. Monotherapy with either penicillin or ceftriaxone for 4 weeks avoids the use of gentamicin, which is potentially ototoxic and nephrotoxic. Compared with penicillin, the advantage of once-daily cef- triaxone is its simplicity for use in therapy administered to Both penicillin and ceftriaxone are overall well tolerated but, like all antimicrobials, have the potential for causing adverse drug events; some of the more common ones include rash, fever, diarrhea, and neutropenia. Liver function abnormalities can be seen with ceftriaxone use and are sometimes associated with sludging of drug in the For patients who are unable to tolerate penicillin or ceftriax- one, vancomycin is a reasonably effective alternative. Prolonged intravenous use of vancomycin may be complicated by throm- bophlebitis, rash, fever, neutropenia, and rarely ototoxic reac- tions. The likelihood of red man syndrome is reduced with an infusion of vancomycin over 1 hour. Desired trough vancomy- cin levels should range between 10 and 15 g/mL. Recommendations 1. Both aqueous crystalline penicillin G and ceftriax- one are reasonable options for a 4-week treatment duration (Class IIa; Level of Evidence B). 2. A 2-week treatment regimen that includes gentami- cin is reasonable in patients with uncomplicated IE, rapid response to therapy, and no underlying renal disease (Class IIa; Level of Evidence B). 3. Vancomycin for a 4-week treatment duration is a reasonable alternative in patients who cannot tol- erate penicillin or ceftriaxone therapy (Class IIa; Level of Evidence B). 4. The desired trough vancomycin level should range between 10 and 15 g/mL (Class I; Level of Evidence C). Relatively Penicillin-Resistant VGS and S gallolyticus (bovis) (MIC >0.12 <0.5 g/mL) Penicillin resistance in vitro occurs among some strains of VGS and S gallolyticus (bovis). To date, however, the num- ber of IE cases that have been reported as a result of VGS or S gallolyticus (bovis) strains that harbor any degree of penicil- lin resistance is small.123 126 Therefore, it is difficult to define the optimal treatment strategies for this group of patients. Baddour et al Infective Endocarditis in Adults 1447 Table 8 shows regimens for treatment of NVE caused by rel- atively penicillin-resistant strains (MIC >0.12 <0.5 g/mL). For patients with VGS or S gallolyticus (bovis) IE caused by these relatively resistant strains, it is reasonable to admin- ister penicillin for 4 weeks, together with single daily-dose gentamicin for the first 2 weeks of treatment. Ampicillin is a reasonable alternative to penicillin if shortages of penicillin exist. If the isolate is ceftriaxone susceptible, then ceftriaxone alone may be considered (Class IIb; Level of Evidence C). Vancomycin alone may be a reasonable alternative if the patient is intolerant of -lactam therapy (Class IIb; Level of Evidence C). Consultation with an infectious diseases special- ist is encouraged in both of these scenarios. Recommendations 1. It is reasonable to administer penicillin for 4 weeks with single daily-dose gentamicin for the first 2 weeks of therapy (Class IIa; Level of Evidence B). 2. If the isolate is ceftriaxone susceptible, then ceftri- axone alone may be considered (Class IIb; Level of Evidence C). 3. Vancomycin alone may be a reasonable alternative in patients who are intolerant of -lactam therapy (Class IIa; Level of Evidence C). A defectiva and Granulicatella Species and VGS With a Penicillin MIC 0.5 g/mL The determination of antimicrobial susceptibilities of A defec- tiva and Granulicatella species (both formerly known as nutri- tionally variant streptococci) is often technically difficult, and the results may not be accurate. Moreover, IE caused by these microorganisms is uncommon and has been more difficult to cure microbiologically compared with IE caused by a strain of For these reasons, in patients with IE caused by A defectiva and Granulicatella species, it is reasonable to administer a combination regimen that includes ampicillin (12 g/d in divided doses) or penicillin (18 30 mil- lion U/D in divided doses or by continuous infusion) plus gen- in 2 3 divided doses) with infectious diseases consultation to determine length of therapy. Findings from an animal model of experimental endocarditis suggest that if vancomycin is chosen for use in patients intolerant of penicillin or ampicillin, then the addition of gentamicin is not Ceftriaxone combined with gentamicin may be a reasonable alternative treatment option125,126 for VGS isolates that are susceptible to ceftriaxone on the basis of the Clinical and Laboratory Standards Institute definition and are resistant to penicillin (MIC 0.5 g/mL, as defined in this statement). Currently, there is no reported clinical experience with the combination of ampicillin plus ceftriaxone for IE caused by these organisms. Table 7. Therapy of NVE Caused by Highly Penicillin-Susceptible VGS and Streptococcus gallolyticus (bovis) Regimen Dose* and Route Duration, wk Strength of Recommendation Comments Aqueous crystalline penicillin G sodium 12 18 million U/24 h IV either continuously or in 4 or 6 equally divided doses 4 Class IIa; Level of Evidence B Preferred in most patients >65 y or patients with impairment of eighth cranial nerve function or renal function. Ampicillin 2 g IV every 4 h is a reasonable alternative to penicillin if a penicillin shortage exists. Or Ceftriaxone sodium 2 g/24 h IV/IM in 1 dose 4 Class IIa; Level of Evidence B Aqueous crystalline penicillin G sodium 12 18 million U/24 h IV either continuously or in 6 equally divided doses 2 Class IIa; Level of Evidence B 2-wk regimen not intended for patients with known cardiac or extracardiac abscess or for those with creatinine clearance of <20 mL/min, impaired eighth cranial nerve function, or Abiotrophia, Granulicatella, or Gemella spp infection; gentamicin dose should be adjusted to achieve peak serum concentration of 3 4 g/mL and trough serum concentration of <1 g/mL when 3 divided doses are used; there are no optimal drug concentrations for single daily dosing. Or Ceftriaxone sodium 2 g/24 h IV or IM in 1 dose 2 Class IIa; Level of Evidence B Plus Gentamicin sulfate 3 mg/kg per 24 h IV or IM in 1 dose 2 Vancomycin hydrochloride 30 mg/kg per 24 h IV in 2 equally divided doses 4 Class IIa; Level of Evidence B Vancomycin therapy is reasonable only for patients unable to tolerate penicillin or ceftriaxone; vancomycin dose should be adjusted to a trough concentration range of 10 15 g/mL. IM indicates intramuscular; IV, intravenous; NVE, native valve infective endocarditis; and VGS, viridans group streptococci. Minimum inhibitory concentration is 0.12 g/mL. The subdivisions differ from Clinical and Laboratory Standards Institute recommended break points that are used to define penicillin susceptibility. *Doses recommended are for patients with normal renal function. Data for once-daily dosing of aminoglycosides for children exist, but no data for treatment of IE exist. Other potentially nephrotoxic drugs (eg, nonsteroidal anti-inflammatory drugs) should be used with caution in patients receiving gentamicin therapy. Although it is preferred that gentamicin (3 mg/kg) be given as a single daily dose to adult patients with endocarditis caused by viridans group streptococci, as a second option, gentamicin can be administered daily in 3 equally divided doses. Vancomycin dosages should be infused during the course of at least 1 hour to reduce the risk of histamine-release red man syndrome. Recommendations 1. It is reasonable to treat patients with IE caused by A defectiva, Granulicatella species, and VGS with a penicillin MIC 0.5 g/mL with a combination of ampicillin or penicillin plus gentamicin as done for enterococcal IE with infectious diseases con- sultation (Class IIa; Level of Evidence C). 2. If vancomycin is used in patients intolerant of ampi- cillin or penicillin, then the addition of gentamicin is not needed (Class III; Level of Evidence C). 3. Ceftriaxone combined with gentamicin may be a reasonable alternative treatment option for VGS isolates with a penicillin MIC 0.5 g/mL that are susceptible to ceftriaxone (Class IIb; Level of Evidence C). Prosthetic Valve or Valvular Prosthetic Material Endocarditis of Prosthetic Valves or Other Prosthetic Material Caused by VGS and S gallolyticus (bovis) For patients with IE complicating prosthetic valves or other prosthetic material caused by a highly penicillin- susceptible strain (MIC 0.12 g/mL), it is reasonable to administer 6 weeks of therapy with penicillin or cef- triaxone with or without gentamicin for the first 2 weeks (Table 9). It is reasonable to administer 6 weeks of therapy with a combination of penicillin or ceftriaxone and gen- tamicin in patients with IE caused by a strain that is rela- tively or highly resistant to penicillin MIC >0.12 g/mL. Vancomycin is useful only for patients who are unable to tolerate penicillin, ceftriaxone, or gentamicin. Ampicillin is an acceptable alternative to penicillin if shortages of penicillin exist. Recommendations 1. Aqueous crystalline penicillin G or ceftriaxone for 6 weeks with or without gentamicin for the first 2 weeks is reasonable (Class IIa; Level of Evidence B). 2. It is reasonable to extend gentamicin to 6 weeks if the MIC is >0.12 g/mL for the infecting strain (Class IIa; Level of Evidence C). 3. Vancomycin can be useful in patients intolerant of penicillin, ceftriaxone, or gentamicin (Class IIa; Level of Evidence B). Streptococcus pneumoniae, Streptococcus pyogenes, and Groups B, C, F, and G -Hemolytic Streptococci IE caused by these streptococci is uncommon. There are few published reports of large case series evaluating management strategies for IE caused by these microorganisms. Results of logistic regression analysis of clinical variables from cases of pneumococcal IE demonstrated the potential value of valve replacement in preventing early death in 1 investigation.129 For patients with NVE caused by highly penicillin-susceptible S pneumoniae, it is reasonable to administer 4 weeks of anti- microbial therapy with penicillin, cefazolin, or ceftriaxone. Vancomycin is reasonable only for patients who are unable to tolerate -lactam therapy. Six weeks of therapy is reasonable for patients with prosthetic valve endocarditis (PVE). Pneumococci with intermediate penicillin resistance (MIC >0.1 1.0 g/mL) or high penicillin resistance (MIC 2.0 g/mL) are recovered uncommonly from patients with Moreover, cross-resistance of pneumococci to other antimicrobial agents such as cephalosporins, mac- rolides, fluoroquinolones, carbapenems, and even vanco- mycin is increasing in frequency. In 1 multicenter study131 with a relatively large number of patients with IE caused by Table 8. Therapy of NVE Caused by Strains of VGS and Streptococcus gallolyticus (bovis) Relatively Resistant to Penicillin Regimen Dose* and Route Duration, wk Strength of Recommendation Comments Aqueous crystalline penicillin G sodium 24 million U/24 h IV either continuously or in 4 6 equally divided doses 4 Class IIa; Level of Evidence B It is reasonable to treat patients with IE caused penicillin-resistant (MIC 0.5 g/mL) VGS strains with a combination of ampicillin or penicillin plus gentamicin as done for enterococcal IE with infectious diseases consultation (Class IIa; Level of Evidence C). Ampicillin 2 g IV every 4 h is a reasonable alternative to penicillin if a penicillin shortage exists. Plus Gentamicin sulfate 3 mg/kg per 24 h IV or IM in 1 dose 2 Ceftriaxone may be a reasonable alternative treatment option for VGS isolates that are susceptible to ceftriaxone (Class IIb; Level of Evidence C). Vancomycin hydrochloride 30 mg/kg per 24 h IV in 2 equally divided doses 4 Class IIa; Level of Evidence C Vancomycin therapy is reasonable only for patients unable to tolerate penicillin or ceftriaxone therapy. IE indicates infective endocarditis; IM, intramuscular; IV, intravenous; MIC, minimum inhibitory concentration; NVE, native valve infective endocarditis; and VGS, viridans group streptococci. MIC is >0.12 to <0.5 g/mL for penicillin. The subdivisions differ from Clinical and Laboratory Standards Institute recommended break points that are used to define penicillin susceptibility.) *Doses recommended are for patients with normal renal function. See Table 7 for appropriate dose of gentamicin. Although it is preferred that gentamicin (3 mg/kg) be given as a single daily dose to adult patients with endocarditis caused by viridans group streptococci, as a second option, gentamicin can be administered daily in 3 equally divided doses. See Table 7 for appropriate dosage of vancomycin. Baddour et al Infective Endocarditis in Adults 1449 S pneumoniae resistant to penicillin (MIC, 0.1 4 g/mL), patients were evaluated and compared with 39 patients who were infected with penicillin-susceptible strains. Several key observations were made. Infection by penicillin-resis- tant strains did not worsen prognosis. High-dose penicillin or a third-generation cephalosporin is reasonable in patients with penicillin-resistant IE without meningitis. In patients with IE and meningitis, high doses of cefotaxime are rea- sonable. If the isolate is resistant (MIC 2 g/mL) to cefo- taxime, then the addition of vancomycin and rifampin may be considered. Ceftriaxone may be considered instead of cefotaxime in the previous recommendations. These find- ings are based on current levels of resistance, and increasing MICs could dictate revisions in future treatment selections. Accordingly, the treatment of patients with pneumococcal IE should be coordinated in consultation with an infectious diseases specialist. For S pyogenes IE, penicillin G administered intrave- nously for 4 to 6 weeks is reasonable treatment on the basis of limited published data. Ceftriaxone is a reasonable alternative to penicillin. Vancomycin is reasonable only for patients who are unable to tolerate a -lactam antibiotic. In general, strains of group B, C, F, and G streptococci are slightly more resistant to penicillin than are strains of group A streptococci. In these patients, the addition of gentamicin to penicillin or to ceftriaxone for at least the first 2 weeks of a 4- to 6-week course of antimicrobial therapy for group B, C, and G streptococcal IE may be considered.132,133 There is a clini- that early cardiac surgical intervention has improved overall survival rates among treated patients with -hemolytic streptococcal IE compared with patients treated decades ago. Because of the relative infrequency of IE caused by these microorganisms, consultation with an infectious dis- eases specialist during treatment is recommended. Recommendations 1. Four weeks of antimicrobial therapy with penicillin, cefazolin, or ceftriaxone is reasonable for IE caused by S pneumoniae; vancomycin can be useful for patients intolerant of -lactam therapy (Class IIa; Level of Evidence C). 2. Six weeks of therapy is reasonable for PVE caused by S pneumoniae (Class IIa; Level of Evidence C). 3. High-dose penicillin or a third-generation cepha- losporin is reasonable in patients with IE caused by penicillin-resistant S pneumoniae without men- ingitis; if meningitis is present, then high doses of Table 9. Therapy for Endocarditis Involving a Prosthetic Valve or Other Prosthetic Material Caused by VGS and Streptococcus gallolyticus (bovis) Regimen Dose* and Route Duration, wk Strength of Recommendation Comments Penicillin-susceptible strain Aqueous crystalline penicillin G sodium 24 million U/24 h IV either continuously or in 4 6 equally divided doses 6 Class IIa; Level of Evidence B Penicillin or ceftriaxone together with gentamicin has not demonstrated superior cure rates compared with monotherapy with penicillin or ceftriaxone for patients with highly susceptible strain; gentamicin therapy should not be administered to patients with creatinine clearance <30 mL/min. Or Ceftriaxone 2 g/24 h IV or IM in 1 dose 6 Class IIa; Level of Evidence B With or without Gentamicin sulfate 3 mg/kg per 24 h IV or IM in 1 dose 2 Ampicillin 2 g IV every 4 h is a reasonable alternative to penicillin if a penicillin shortage exists. Vancomycin hydrochloride 30 mg/kg per 24 h IV in 2 equally divided doses 6 Class IIa; Level of Evidence B Vancomycin is reasonable only for patients unable to tolerate penicillin or ceftriaxone. Penicillin relatively or fully resistant strain (MIC >0.12 g/mL) Aqueous crystalline penicillin sodium 24 million U/24 h IV either continuously or in 4 6 equally divided doses 6 Class IIa; Level of Evidence B Ampicillin 2 g IV every 4 h is a reasonable alternative to penicillin if a penicillin shortage exists. Or Ceftriaxone 2 g/24 h IV/IM in 1 dose 6 Class IIa; Level of Evidence B Plus Gentamicin sulfate 3 mg/kg per 24 h IV/IM in 1 dose 6 Vancomycin hydrochloride 30 mg/kg per 24 h IV in 2 equally divided doses 6 Class IIa; Level of Evidence B Vancomycin is reasonable only for patients unable to tolerate penicillin or ceftriaxone. IM indicates intramuscular; IV, intravenous; MIC indicates minimum inhibitory concentration; and VGS, viridans group streptococci. *Doses recommended are for patients with normal renal function. See Table 7 for appropriate dose of gentamicin. Although it is preferred that gentamicin (3 mg/kg) be given as a single daily dose to adult patients with endocarditis resulting from VGS, as a second option, gentamicin can be administered daily in 3 equally divided doses. See text and Table 7 for appropriate dose of vancomycin. cefotaxime (or ceftriaxone) are reasonable (Class IIa; Level of Evidence C). 4. The addition of vancomycin and rifampin to cefo- taxime (or ceftriaxone) may be considered in patients with IE caused by S pneumoniae that are resistant to cefotaxime (MIC >2 g/mL) (Class IIb; Level of Evidence C). 5. Because of the complexities of IE caused by S pneu- moniae, consultation with an infectious diseases spe- cialist is recommended (Class I; Level of Evidence C). 6. For IE caused by S pyogenes, 4 to 6 weeks of therapy with aqueous crystalline penicillin G or ceftriaxone is reasonable; vancomycin is reasonable only in patients intolerant of -lactam therapy (Class IIa; Level of Evidence C). 7. For IE caused by group B, C, or G streptococci, the addition of gentamicin to aqueous crystalline peni- cillin G or ceftriaxone for at least the first 2 weeks of a 4- to 6-week treatment course may be considered (Class IIb; Level of Evidence C). 8. Consultation with an infectious diseases specialist to guide treatment is recommended in patients with IE caused by -hemolytic streptococci (Class I; Level of Evidence C). Staphylococci IE may be caused by staphylococci that are coagulase positive (S aureus) or coagulase negative (S epidermidis, S lugdunen- sis, and various other species). Although coagulase-positive staphylococci were traditionally believed to cause primarily NVE and coagulase-negative staphylococci (CoNS) were associated with PVE, considerable overlap now exists. For example, in a multicenter, prospective, observational investi- gation involving >1000 consecutive patients with definite IE from >20 countries, S aureus was the most common cause of PVE (25.8% of 214 cases), whereas 64 cases of NVE (8%) resulted from CoNS.136 In addition, the prevalence of CoNS NVE appears to be increasing.137 Thus, it is important to con- sider both pathogen groups when a patient with suspected IE has a preliminary blood culture that suggests staphylococci by Gram stain interpretation. S aureus S aureus is the most common cause of IE in much of the devel- Data from >70 million hospitalizations in the United States suggest that rates of S aureus IE have increased significantly relative to other causes of IE.3 This increase is primarily a consequence of healthcare contact (eg, intra- vascular catheters, surgical wounds, indwelling prosthetic and is especially prevalent in North Increasing rates of oxacillin-resistant S aureus or MRSA isolates in both hospital and community settings and the recovery of clinical S aureus isolates both partially resistant to vancomycin have complicated the treatment of S aureus IE. An increasing body of evidence suggests an association between high (but still susceptible on the basis of the Clinical and Laboratory Standards Institute definition) vancomycin MICs in S aureus and worse clinical outcome in both MRSA infections treated with vancomycin140 and MRSA bacteremia treated with antistaphylococcal peni- Importantly, this association between higher vanco- mycin MIC in infecting MSSA and worse clinical outcomes among patients treated with antistaphylococcal penicillins (not vancomycin) was externally validated in a large cohort of patients with MSSA IE.142 These data suggest that host- or pathogen-specific factors, rather than higher MICs of the infecting pathogen to vancomycin, contribute to the poor out- comes in these patients (because the latter patients were not treated with a glycopeptide). In non-IDUs, S aureus IE involves primarily the left side of the heart and is associated with mortality rates ranging from 25% to 40%. S aureus IE in IDUs often involves the tricuspid valve. Cure rates for right-sided S aureus IE in IDUs are high (>85%) and may be achieved with relatively short courses of either parenteral or oral treatment (2 4 weeks; see below). Complicated IE manifested, for example, by deep tis- sue abscesses or osteoarticular infection may require more prolonged therapy. Coagulase-Negative Staphylococci As noted above, in addition to their importance in PVE, CoNS now cause a significant but relatively small proportion of NVE Risk factors for CoNS IE are similar to those for S aureus and include typical risk factors associated with exten- sive healthcare contact. Of interest, data suggest that the over- all outcomes for patients with CoNS IE and S aureus IE are Most CoNS are resistant to methicillin. These resis- tant organisms are particularly prominent among patients with healthcare-associated staphylococcal IE. Methicillin-resistant strains also are clinically resistant to cephalosporins and car- bapenems, although this fact is not always reflected accurately in the results of standard in vitro tests. An important subset of patients with CoNS IE has been identified: those with infection caused by S lugdunensis. This species of CoNS tends to cause a substantially more virulent form of IE, with a high rate of perivalvular extension of infec- tion and metastatic infection. This organism is uniformly sus- ceptible in vitro to most antibiotics.143 145 Most experts believe that IE caused by this organism can be treated with standard regimens based on the in vitro susceptibility profiles of the strain. The patient also should be monitored carefully for the development of periannular extension or extracardiac spread of infection. Although microbiological differentiation of S lugdunensis requires specific biochemical assays, the poor outcomes associated with S lugdunensis underscore the impor- tance of performing these specialized assays. Initial screening can be done with pyrrolidonyl aminopeptidase hydrolysis test- ing, and isolates that test positive should be further identified by a multisubstrate identification system, matrix-assisted laser desorption ionization time of flight, or other methods, includ- Recommendation 1. Ongoing vigilance for IE complications, including perivalvular extension of infection and extracardiac foci of infection, is reasonable (Class IIa; Level of Evidence C). Baddour et al Infective Endocarditis in Adults 1451 IE Caused by Staphylococci in the Absence of Prosthetic Valves or Other Prosthetic Material Right-Sided IE in IDUs The addition of gentamicin to nafcillin or oxacillin has tradi- tionally been a standard approach for the treatment of right- sided IE. For example, in IDUs with uncomplicated right-sided S aureus IE (no evidence of renal failure, extrapulmonary metastatic infections, aortic or mitral valve involvement, meningitis, or infection by MRSA), combined short-course (2 weeks) -lactam plus aminoglycoside therapy was highly effective in several studies.91,92,148 In 1 study, 92 patients pro- vided such combination therapy had excellent outcomes, even HIV-infected patients and those who had large tricuspid valve vegetations (>10 mm in diameter). In contrast, short-course regimens with glycopeptides (teicoplanin or vancomycin) plus gentamicin appeared to be less effective for right-sided S aureus IE caused by either MSSA or MRSA strains.148 These glycopeptides may be less effective because of limited bacte- ricidal activity, poor penetration into vegetations, or increased drug clearance among IDUs. A growing body of evidence suggests that the addition of adjunctive aminoglycoside therapy not only is unnecessary for patients with uncomplicated right-sided native valve S aureus IE but may cause harm. For example, 1 study showed that a 2-week monotherapy regimen of intravenous cloxacillin was equivalent to cloxacillin plus gentamicin administered for 2 In 2006, the US Food and Drug Administration (FDA) approved the use of daptomycin (6 mg kg 1 ) for the treatment of S aureus bacteremia and right-sided S aureus IE.13 In a reg- istrational open-label, multinational, clinical trial for the treat- ment of S aureus bacteremia or right-sided IE comparing the efficacy of daptomycin monotherapy with therapy that included low-dose (1 mg/kg IV every 8 hours or adjusted on the basis of renal function) gentamicin for the first 4 days, patients did equally well in either treatment arm. In the predefined subgroup of those with MRSA bacteremia, daptomycin demonstrated a 44.4% success rate compared with 31.8% for standard therapy; this difference was not statistically significant (absolute differ- ence, 12.6%, 95% confidence interval, 7.4 to 32.6; P=0.28). Of note, in a post hoc analysis of this landmark clinical trial,149 the addition of even such low-dose, short-course gentamicin in 1 arm of the study was significantly associated with renal toxic- ity, which occurred early and often, and the clinical association between gentamicin dose and duration was minimal. Thus, current evidence suggests that either parenteral -lactam or daptomycin short-course therapy is adequate for the treatment of uncomplicated MSSA right-sided IE. In contrast, glycopeptide therapy for MRSA right-sided IE may require more prolonged treatment regimens. For both MSSA and MRSA infections, use of adjunctive gentamicin for the treatment of S aureus bacteremia or right-sided NVE is discouraged Recommendation 1. Gentamicin is not recommended for treatment of right-sided staphylococcal NVE (Class III; Level of Evidence B). In patients for whom parenteral antibiotic therapy is problem- atic, oral treatment may be a reasonable option. Two studies have evaluated the use of predominantly oral 4-week antibiotic regimens (featuring ciprofloxacin plus rifampin) for the ther- apy of uncomplicated right-sided MSSA IE in IDUs.150,151 In each study, including one in which >70% of patients were HIV cure rates were >90%. However, the relatively high rate of quinolone resistance among contemporary S aureus strains has made this alternative treatment strategy problematic. IE in Non-IDUs Older anecdotal case reports in non-IDUs with S aureus IE suggested that the use of combined gentamicin-methicillin therapy may be of benefit in patients who fail to respond to monotherapy with methicillin.152 This issue was addressed in a multicenter, prospective trial comparing nafcillin alone for 6 weeks with nafcillin plus gentamicin (for the initial 2 weeks) in the treatment of predominantly left-sided IE caused by S Nafcillin-gentamicin therapy reduced the duration of bacteremia by 1 day compared with nafcillin monotherapy. However, combination therapy did not reduce mortality or the frequency of cardiac complications. Furthermore, combina- tion therapy increased the frequency of gentamicin-associated nephrotoxicity. As noted above,149 the risk of clinically sig- nificant nephrotoxicity with even short courses of adjunctive low-dose gentamicin for S aureus bacteremia and right-sided IE can be substantial. In addition, gentamicin should not be used with vancomycin in patients with MRSA NVE because of the nephrotoxicity risk.13,149 In cases of brain abscess com- plicating MSSA IE, nafcillin is the preferred agent rather than cefazolin, which has inadequate blood-brain barrier penetra- bility. If the patient cannot tolerate nafcillin therapy, then van- comycin should be used. Vancomycin is often included with cefazolin as empirical coverage for patients with IE caused by S aureus while await- ing susceptibility results.An analysis of the literature, however, compared the use of empirical combination of vancomycin and antistaphylococcal -lactam therapy with vancomycin alone and demonstrated the superiority of -lactam containing regi- mens over vancomycin monotherapy for bacteremic MSSA infections, including IE.154 This differential outcome included studies in which there was an early shift from empirical van- comycin to -lactam therapy as soon as blood cultures yielded MSSA (not MRSA). The meta-analysis included small, retro- spective studies, however, which limits support for initial com- bination therapy by some experts. Therefore, the usefulness of empiric combination therapy in patients with S aureus bactere- mia until oxacillin susceptibility is known is uncertain. Although the large majority of staphylococci are resis- tant to penicillin, occasional strains remain susceptible. Unfortunately, the current laboratory screening procedures for detecting penicillin susceptibility may not be reliable. Therefore, IE caused by these organisms should be treated with regimens outlined for MSSA that includes nafcillin (or equivalent antistaphylococcal penicillin) as an option rather than penicillin (Table 10). There are no evidence-based data that demonstrate the most appropriate duration of nafcillin therapy for treat- ment of left-sided NVE caused by MSSA. For patients with uncomplicated infection, 6 weeks of therapy is recommended. For patients with complications of IE such as perivalvular abscess ormation and septic metastatic complications, at least 6 weeks of nafcillin is recommended. Currently, defining the optimal therapy for NVE attribut- able to MRSA is challenging. Historically, vancomycin has been used and is recommended. As outlined in the Therapy of MSSA IE in Patients Allergic to or Intolerant of -Lactams section below, daptomycin may be a reasonable alternative to daptomycin for left-sided NVE caused by MRSA on the basis of limited data in a prospective, randomized trial; a multina- tional, prospective cohort investigation of the use of high-dose ( 9 mg/kg per dose) daptomycin; and a multicenter, retro- spective, observational study that included daptomycin at 8 mg/kg per dose.13,155 Selection of daptomycin dosing should be assisted by infectious diseases consultation. At this time, additional study of ceftaroline is needed to define its role, if any, in the treatment of left-sided NVE caused by MRSA. Recommendations 1. Gentamicin should not be used for treatment of NVE caused by MSSA or MRSA (Class III; Level of Evidence B). 2. In cases of brain abscess resulting from MSSA IE, nafcillin should be used instead of cefazolin; vanco- mycin should be given in cases of nafcillin intoler- ance (Class I; Level of Evidence C). 3. The usefulness of empirical combination ther- apy with vancomycin plus an antistaphylococcal -lactam antibiotic in patients with S aureus bac- teremia until oxacillin susceptibility is known is uncertain (Class IIb; Level of Evidence B). 4. IE caused by staphylococci that are penicillin sus- ceptible should be treated with antistaphylococcal -lactam antibiotics rather than aqueous crystalline penicillin G because clinical laboratories are not able to detect penicillin susceptibility (Class I; Level of Evidence B). 5. Six weeks of nafcillin (or equivalent antistaphylo- coccal penicillin) is recommended for uncompli- cated left-sided NVE caused by MSSA; at least 6 weeks of nafcillin (or equivalent antistaphylococcal penicillin) is recommended for complicated left- sided NVE caused by this organism (Class I; Level of Evidence C). 6. Daptomycin may be a reasonable alternative to vancomycin for treatment of left-sided IE resulting from MRSA (Class IIb; Level of Evidence B). 7. Selection of daptomycin dosing should be assisted by infectious diseases consultation (Class I; Level of Evidence C). Therapy of MSSA IE in Patients Allergic to or Intolerant of -Lactams Therapy for MSSA IE in patients truly unable to tolerate -lactams is problematic. One decision analysis study con- cluded that patients with a questionable history of immediate- type hypersensitivity to penicillins in the context of IE caused by MSSA should be skin tested before starting antibiotic However, the limited availability of standardized skin test reagents makes testing impractical. Instead, most experts endorse one of the published standard desensitization protocols. For patients with a well-defined history of nonana- phylactoid reactions to penicillins (eg, simple skin rash), a first-generation cephalosporin such as cefazolin is reasonable. Although cefazolin may be more susceptible to -lactamase mediated hydrolysis than nafcillin157 and less effective in the treatment of MSSA experimental IE, the clinical significance of these observations is unknown. Many experts regularly use cefazolin for S aureus IE instead of nafcillin because of drug Table 10. Therapy for NVE Caused by Staphylococci Regimen Dose* and Route Duration, wk Strength of Recommendation Comments Oxacillin-susceptible strains Nafcillin or oxacillin 12 g/24 h IV in 4 6 equally divided doses 6 Class I; Level of Evidence C For complicated right-sided IE and for left-sided IE; for uncomplicated right-sided IE, 2 wk (see text). For penicillin-allergic (nonanaphylactoid type) patients Consider skin testing for oxacillin-susceptible staphylococci and questionable history of immediate- type hypersensitivity to penicillin. Cefazolin* 6 g/24 h IV in 3 equally divided doses 6 Class I; Level of Evidence B Cephalosporins should be avoided in patients with anaphylactoid-type hypersensitivity to -lactams; vancomycin should be used in these cases. Oxacillin-resistant strains Vancomycin 30 mg/kg per 24 h IV in 2 equally divided doses 6 Class I; Level of Evidence C Adjust vancomycin dose to achieve trough concentration of 10 20 g/mL (see text for vancomycin alternatives). Daptomycin 8 mg/kg/dose 6 Class IIb; Level of Evidence B Await additional study data to define optimal dosing. IE indicates infective endocarditis; IV, intravenous; and NVE, native valve infective endocarditis. *Doses recommended are for patients with normal renal function. For specific dosing adjustment and issues concerning vancomycin, see Table 7 footnotes. Baddour et al Infective Endocarditis in Adults 1453 tolerability and cost, for MSSA IE in penicillin-intolerant patients, or to facilitate outpatient antibiotic administration. Vancomycin is often recommended as an alternative to -lactam therapy for MSSA IE. As outlined above, -lactam allergy evaluation should be conducted in every case in which vancomycin is considered for use because poorer outcomes related to vancomycin therapy for a variety of MSSA infec- tions are well recognized.140 Clindamycin has been associated with IE relapse and is For MSSA IE in patients with anaphy- lactoid-type -lactam allergy who exhibit either a suboptimal response to vancomycin or vancomycin allergy, -lactam desensitization should be considered as noted above.159 Daptomycin is a reasonable alternative to vancomycin for adults in the treatment of S aureus NVE. In the above-noted of S aureus bacteremia and right-sided IE, this agent (at 6 mg kg 1 ) was noninferior to standard ther- apy with vancomycin or an antistaphylococcal penicillin plus low-dose, short-course gentamicin. Importantly, the small number (n=18; 9 in each arm) of patients with left-sided IE enrolled in the trial prevented meaningful conclusions on the comparative efficacy of daptomycin in this infection. For this reason, the FDA indication for daptomycin explicitly omitted left-sided IE. However, in an observational study, high-dose daptomycin ( 9 mg/kg per dose) for treatment of left-sided IE was as effective as standard-of-care therapy and cleared MRSA bacteremia significantly faster than did standard-of- The emergence of organisms with decreased susceptibility to daptomycin was observed in 5% of daptomycin-treated patients. All of these patients needed but for a variety of rea- sons did not receive surgical intervention for debridement of deep-seated infections or left-sided IE. As indicated, the FDA-approved dose of daptomycin for S aureus bacteremia and right-sided IE is currently 6 mg/kg IV once daily. Some experts recommend higher doses of daptomycin at 8 to 10 mg/ kg for complicated infections, including left-sided IE (these doses are not approved by the FDA).109 This recommenda- tion is based in part on evidence suggesting that higher-dose daptomycin may reduce the likelihood of treatment-emergent resistance, is generally well tolerated, and is not associated with excess toxicities. Whether this higher dosing strategy prevents treatment-emergent resistance of daptomycin is still not answered. Daptomycin is inhibited by pulmonary surfactant160 and thus is contraindicated in the treatment of S aureus pneu- monia acquired via the aspiration route. In the registrational however, this agent performed as well as vancomycin or -lactams in treating septic pulmonary emboli caused by S aureus, reflecting the distinct pathogenesis of this syndrome as opposed to traditional pneumonia. Recommendations 1. Cefazolin is reasonable in patients with a well- defined history of nonanaphylactoid reactions to penicillins (Class IIa; Level of Evidence B). 2. Allergy evaluation for tolerance to -lactam therapy should be done in every case in which vancomycin is considered for treatment of MSSA IE (Class I; Level of Evidence B). 3. Clindamycin is not recommended as a result of an increased IE relapse rate (Class III; Level of Evidence B). 4. Daptomycin is a reasonable alternative to vancomy- cin for NVE caused by MSSA (Class IIa; Level of Evidence B). Additional or Adjunctive Therapies As discussed above, combination therapy with gentamicin therapy in S aureus NVE is discouraged because of the rela- tively high rates of intrinsic gentamicin resistance, a lack of clear-cut efficacy, and documented toxicity issues.149,153,161 Although most staphylococci are highly susceptible to rifampin, resistance develops rapidly when this agent is used alone. The in vivo efficacy of rifampin in combination with nafcillin, oxacillin, vancomycin, trimethoprim/sulfamethoxa- zole, or aminoglycosides is highly variable. Moreover, use of rifampin as adjunct therapy for S aureus NVE has been associ- ated with higher rates of adverse events (primarily hepatotox- icity) and a significantly lower survival rate.162 Thus, routine use of rifampin is not recommended for treatment of staphy- lococcal NVE. Of note, a prospective trial in patients with IE caused by MRSA failed to demonstrate that the addition of rifampin to vancomycin either enhanced survival or reduced the duration of bacteremia compared with treatment with Rifampin is often used in native valve S aureus IE when this infection is complicated by involvement of selected anatomic sites where rifampin penetrates effec- tively (eg, bone, joint, cerebrospinal fluid).164 No standard therapies exist for the treatment of S aureus IE caused by isolates that are not susceptible to vancomy- cin. Classification of these isolates has become complex and includes designations of reduced susceptibility (hVISA), intermediate resistance (VISA), and high-level resistance (VRSA). To date, the limited number of patients reported to have IE caused by these isolates precludes specific treatment recommendations. Thus, these infections should be managed in conjunction with an infectious diseases consultant. Although Markowitz et al165 showed that trimethoprim- sulfamethoxazole was inferior to vancomycin in the treat- ment of invasive S aureus infections, it is sometimes used in salvage situations. Interestingly, all treatment failures with trimethoprim-sulfamethoxazole occurred in patients infected with MSSA in that report,165 whereas patients with MRSA infection were uniformly cured. The efficacy of trimethoprim- sulfamethoxazole and other folate antagonists may be attenu- ated by thymidine release from damaged host cells (eg, at sites of tissue damage such as abscesses).166 In an in vitro study,167 the addition of trimethoprim-sulfamethoxazole to daptomy- cin was rapidly bactericidal for a daptomycin-nonsusceptible strain compared with daptomycin monotherapy. The com- bination of daptomycin and a -lactam antibiotic has been reported to be effective in treating a limited number of patients with persistent MRSA bacteremia.168 The potential effective- ness of this combination may be due in part to the capacity of the -lactam agent to alter the surface charge of the organism in a nonbactericidal mechanism, allowing enhanced surface binding of daptomycin.169 171 Linezolid was reported to be effective in the treatment of persistent MRSA bacteremia,172 but this study had important study design weaknesses.173 Patient outcomes with linezolid therapy for S aureus left-sided IE have generally been poor.174 176 have been used successfully as salvage ther- apy in selected patients with MRSA IE who clinically failed vancomycin therapy. Ceftaroline received FDA registrational indications for acute bacterial skin and soft tissue infections caused by both MRSA and MSSA, as well as community-acquired pneu- monia caused by MSSA. Several case series suggest that it may have utility in complicated S aureus infections, including These promising observations should be verified with appropriately designed clinical studies before ceftaroline can be recommended for widespread use in such off-label settings. Recommendations 1. Routine use of rifampin is not recommended for treatment of staphylococcal NVE (Class III; Level of Evidence B). 2. IE caused by vancomycin-resistant staphylococci (hVISA, VISA, or VRSA) should be managed in conjunction with an infectious diseases consultant (Class I; Level of Evidence C). IE Caused by Staphylococci in the Presence of Prosthetic Valves or Other Prosthetic Material Coagulase-Negative Staphylococci CoNS that cause PVE usually are methicillin resistant, particu- larly when IE develops within 1 year after surgery.182 Unless susceptibility to methicillin can be demonstrated conclusively, it should be assumed that the organism is methicillin resistant, and treatment should be planned accordingly. Experimental IE models caused by methicillin-resistant staphylococci demon- strated that vancomycin combined with rifampin and gentami- cin is the optimal regimen, and limited clinical reports support The dosing of rifampin is done by convention and is not based on PK data. Vancomycin and rifampin are rec- ommended for a minimum of 6 weeks, with the use of gen- tamicin limited to the first 2 weeks of therapy (Table 11). If the organism is resistant to gentamicin, then an aminoglycoside to which it is susceptible should be substituted for gentamicin. Some authorities recommend delaying the initiation of rifampin therapy for several days to allow adequate penetration of van- comycin into the cardiac vegetations in an attempt to prevent treatment-emergent resistance to rifampin. If the organism is resistant to all available aminoglycosides, such adjunctive treatment should be omitted. In this situation, if the organism is susceptible to a fluoroquinolone, animal studies of therapy for foreign-body infection suggest that a fluoroquinolone can be used instead of gentamicin.184 Thus, although clinical data are not available to support the practice, selection for fluoroquino- lone resistance during treatment can occur, and prevalent fluo- roquinolone resistance among CoNS will limit its use, it may reasonable to use a fluoroquinolone in this setting. PVE, particularly when onset is within 12 months of cardiac valve implantation and an aortic valve prosthesis is involved, is frequently complicated by perivalvular or myo- cardial abscesses or valvular dysfunction.136 Surgery is often required in these patients and may be lifesaving. As noted above, CoNS may become resistant to rifampin during therapy for PVE. Because of the potential for changes in the patterns of antibiotic susceptibility during therapy, organisms recov- ered from surgical specimens or blood from patients who have had a bacteriological relapse should be carefully retested for complete antibiotic susceptibility profiles. Although published data on combinations of antimicrobial therapy are limited, we suggest that PVE caused by oxacillin- susceptible CoNS should be treated with nafcillin or oxacillin plus rifampin in combination with gentamicin for the first 2 weeks of therapy. A first-generation cephalosporin or vanco- mycin may be substituted for nafcillin/oxacillin for patients who are truly allergic to penicillin. Recommendations 1. Vancomycin and rifampin are recommended for a minimum of 6 weeks, with the use of gentamicin lim- ited to the first 2 weeks of therapy (Class I; Level of Evidence B). 2. If CoNS are resistant to gentamicin, then an amino- glycoside to which they are susceptible may be con- sidered (Class IIb; Level of Evidence C). 3. If CoNS are resistant to all aminoglycosides, then substitution with a fluoroquinolone may be consid- ered if the isolate is susceptible to a fluoroquinolone (Class IIb; Level of Evidence C). from patients who have had a bacteriological relapse should be carefully retested for complete antibiotic susceptibility profiles (Class I; Level of Evidence C). S aureus Because of the high mortality rate associated with S aureus combination antimicrobial therapy is recommended (Table 11). The use of combination therapy is based not on studies of in vitro synergy but rather on the efficacy of this therapy for treatment of CoNS PVE, as well as the results of treatment of experimental IE and infected devices. In animal studies, rifampin appears to be key in the complete steriliza- tion of foreign bodies infected by MRSA.184,185 For infection caused by MSSA, nafcillin or oxacillin together with rifampin is suggested; with MRSA, vancomycin and rifampin should be used. Gentamicin should be adminis- tered for the initial 2 weeks of therapy with either -lactam or vancomycin-containing regimens. If a strain is resistant to gentamicin, then a fluoroquinolone may be used if the strain is susceptible. Early cardiac surgical interventions play an important role in maximizing outcomes in S aureus PVE,186 especially in the presence of heart failure.11 Recommendations 1. Combination antimicrobial therapy is recom- mended (Class I; Level of Evidence C). Baddour et al Infective Endocarditis in Adults 1455 2. Gentamicin should be administered for the initial 2 weeks of therapy with either -lactam or vancomycin- containing regimens (Class I; Level of Evidence C). Enterococci Although there are >15 species within the Enterococcus genus, E faecalis and E faecium are the major species isolated from clinical sources in IE patients. Enterococci are the third leading cause of IE and account for 10% of cases in non- IDUs. E faecalis causes 97% of cases of IE; E faecium, 1% to 2%; and other species, 1%. Regimens recommended for enterococcal IE are shown in Tables 12 through 15. Enterococci should be routinely tested in vitro for susceptibility to penicillin or ampicillin and van- comycin (MIC determination) and for high-level resistance to gentamicin to predict synergistic interactions (see below). Because of the striking increase in resistance of enterococci to vancomycin, aminoglycosides, and penicillin, additional susceptibility tests may be necessary to identify alternative antimicrobial regimens. For strains of enterococci resistant to -lactams, vancomycin, or aminoglycosides, it is reason- able to test for susceptibility in vitro to daptomycin and line- zolid. Linezolid is bacteriostatic in vitro against enterococci, whereas daptomycin is bactericidal in vitro in susceptible strains. Although rarely identified, -lactamase producing enterococci may account for relapse of infection. Routine screening for -lactamase production is not sensitive enough, and specialized testing will be needed for detection. Compared with VGS and -hemolytic streptococci, enterococci are relatively resistant to penicillin, ampicillin, and vancomycin. These streptococci usually are killed by monotherapy with these antimicrobials, whereas enterococci are inhibited but not killed. Killing of susceptible strains of enterococci requires the synergistic action of penicillin, ampi- cillin, or vancomycin in combination with either gentamicin or streptomycin. Enterococci are relatively impermeable to aminogly- cosides. High concentrations of aminoglycosides in the extracellular environment are required to achieve sufficient concentrations of the drug at the site of the ribosomal target within the bacterial cell for bactericidal activity. These con- centrations are higher than can be achieved safely in patients; however, cell wall active agents such as penicillin, ampicillin, and vancomycin raise the permeability of the enterococcal cell so that a bactericidal effect can be achieved by relatively low concentrations of an aminoglycoside. If an enterococcal strain is resistant to the cell wall active agent or high concentrations of an aminoglycoside (500 g/mL gentamicin or 1000 g/mL streptomycin), then the combination of an aminoglycoside and the cell wall active agent will not result in bactericidal activity in vitro or in vivo (ie, in experimental IE models), nor will it predictably produce a microbiological cure in human enterococcal IE. Recommendations 1. Enterococci should be tested routinely in vitro for susceptibility to penicillin and vancomycin (MIC determination) and for high-level resistance to gen- tamicin to predict synergistic interactions (Class I; Level of Evidence A). 2. In vitro susceptibility to daptomycin and linezolid should be obtained for strains that are resistant to -lactams, vancomycin, or aminoglycosides (Class I; Level of Evidence C). Table 11. Therapy for Endocarditis Involving a Prosthetic Valve or Other Prosthetic Material Caused by Staphylococci Regimen Dose* and Route Duration, wk Strength of Recommendation Comments Oxacillin-susceptible strains Nafcillin or oxacillin 12 g/24 h IV in 6 equally divided doses 6 Class I; Level of Evidence B Vancomycin should be used in patients with immediate-type hypersensitivity reactions to -lactam antibiotics (see Table 5 for dosing guidelines); cefazolin may be substituted for nafcillin or oxacillin in patients with non immediate-type hypersensitivity reactions to penicillins. Plus Rifampin 900 mg per 24 h IV or orally in 3 equally divided doses Plus Gentamicin 3 mg/kg per 24 h IV or IM in 2 or 3 equally divided doses Oxacillin-resistant strains Vancomycin 30 mg/kg 24 h in 2 equally divided doses 6 Class I; Level of Evidence B Adjust vancomycin to a trough concentration of 10 20 g/mL. (see text for gentamicin alternatives) Plus Rifampin 900 mg/24 h IV/PO in 3 equally divided doses Plus Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 equally divided doses IM indicates intramuscular; and IV, intravenous. *Doses recommended are for patients with normal renal function. Gentamicin should be administered in close proximity to vancomycin, nafcillin, or oxacillin dosing. See Table 7 for appropriate dose of gentamicin. Role of Aminoglycosides in the Treatment of Patients With Enterococcal IE: Special Considerations Aminoglycoside-containing regimens have been a cornerstone of antimicrobial therapy for enterococcal IE187 and have been recommended as standard therapy in previous (1995) AHA Since the publication of the latest (2005) AHA statement on antimicrobial therapy of patients with IE,12 the frequency of aminoglycoside-resistant strains of enterococci has increased significantly. In addition, a number of studies have been published on the dosing of aminoglycosides, the duration of aminoglycoside therapy, and the possible role of non aminoglycoside-containing regimens for the treatment of E faecalis IE.189 191 Approximately 97% of cases of enterococcal IE are caused by E faecalis, and the majority of these remain susceptible to -lactams and vancomycin, but aminoglycoside resistance is increasing in frequency. In the study by Gavald et al,190 approximately half of the patients had IE caused by high- level aminoglycoside-resistant strains of E faecalis. In the study by Fern ndez-Hidalgo et al,191 26% of the 272 patients had high-level aminoglycoside-resistant strains of E faecalis. Therefore, aminoglycoside-containing regimens would not be effective therapy for these patients. A number of factors should be considered in the selec- tion of aminoglycoside-containing regimens. Compared with other patients with IE, in general, patients with enterococcal IE are older; are often debilitated; may have complicated, underlying urological conditions, including pre-existing renal failure; may have healthcare-associated infections; and have significant other underlying comorbidities common in older In these patients, gentamicin-associated neph- rotoxicity may significantly complicate a standard 4- to 6-week course of therapy and could result in serious, possibly life-threatening, complications such as renal failure requiring hemodialysis. In these situations, the potential risk of attempt- ing to complete a 4- to 6-week course of gentamicin therapy may exceed the benefit.193 In patients with VGS IE treated with multiple divided doses of gentamicin, single daily-dose therapy with genta- micin resulted in similar response rates and was well tol- erated (see treatment of VGS IE above). Studies of single daily dosing of gentamicin compared with divided doses in enterococcal experimental IE and in humans have yielded conflicting results. These results may reflect different PK of aminoglycosides in animals compared with humans. Studies in humans of the dosing interval of gentamicin were not controlled or standardized. Dosing of gentamicin ranged from once daily to 3 times daily; therefore, the data were insufficient to compare the efficacy of once-daily doses with divided doses. Until more convincing data demonstrate that once-daily dosing of gentamicin is as effective as multiple dosing, in patients with normal renal function, gentami- cin should be administered in daily multiple divided doses ) rather than a daily single dose to patients with enterococcal IE. In patients with normal renal function, it is reasonable to administer gentamicin every 8 hours with the dose adjusted to achieve a 1-hour serum con- centration of 3 g/mL and a trough concentration of <1 g/ mL. Increasing the dose of gentamicin in these patients did not result in enhanced efficacy but did increase the risk of Many patients with enterococcal IE are managed in a nontertiary care facility, and the laboratory may not have the capability for rapid determination of serum gentamicin concentrations or may not have a clinical pharmacist avail- able to assist in optimal dosing adjustments. These and other factors have prompted studies to evaluate the efficacy of non gentamicin-containing regimens for the treatment of Table 12. Therapy for Endocarditis Involving a Native or Prosthetic Valve or Other Prosthetic Material Resulting From Enterococcus Species Caused by Strains Susceptible to Penicillin and Gentamicin in Patients Who Can Tolerate -Lactam Therapy* Regimen Dose and Route Duration, wk Strength of Recommendation Comments Either Class IIa; Level of Evidence B Native valve: 4-wk therapy recommended for patients with symptoms of illness <3 mo; 6-wk therapy recommended for native valve symptoms >3 mo and for patients with prosthetic valve or prosthetic material. Recommended for patients with creatinine clearance >50 mL/min. Ampicillin sodium 2 g IV every 4 h 4 6 4 6 Class IIa; Level of Evidence B Or Aqueous penicillin G sodium 18 30 million U/24 h IV either continuously or in 6 equally divided doses Plus Gentamicin sulfate 3 mg/kg ideal body weight in 2 3 equally divided doses Or Double -lactam Ampicillin 2 g IV every 4 h 6 Class IIa; Level of Evidence B Recommended for patients with initial creatinine clearance <50 mL/min or who develop creatinine clearance <50 mL/min during therapy with gentamicin-containing regimen. Plus Ceftriaxone 2 g IV every 12 h 6 IV indicates intravenous. *For patients unable to tolerate a -lactam, see Table 14. Doses recommended are for patients with normal renal and hepatic function. Dose of gentamicin should be adjusted to achieve a peak serum concentration of 3 to 4 g/mL and a trough concentration of <1 g/mL. 