Antimicrobial therapy of native valve endocarditis - UpToDate

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Antimicrobial therapy of native valve endocarditis - UpToDate

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Antimicrobial therapy of native valve endocarditis Authors: Daniel J Sexton, MD, Vivian H Chu, MD, MHS Section Editor: Stephen B Calderwood, MD Deputy Editor: Elinor L Baron, MD, DTMH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2019. | This topic last updated: Sep 03, 2019.

INTRODUCTION Issues related to the antimicrobial therapy of native valve infective endocarditis (IE) will be reviewed here; the content reflects American, British, and European guidelines [1-3]. An overview of the management of IE in adults is presented separately. (See "Overview of management of infective endocarditis in adults".) General issues related to echocardiography are discussed separately. (See "Role of echocardiography in infective endocarditis".) Issues related to complications of IE and indications for surgery are discussed separately. (See "Complications and outcome of infective endocarditis" and "Surgery for left-sided native valve infective endocarditis" and "Infective endocarditis in people who inject drugs", section on 'Surgery'.) Issues related to IE in people who inject drugs are discussed separately. (See "Infective endocarditis in people who inject drugs".) Issues related to management of prosthetic valve IE are discussed separately. (See "Antimicrobial therapy of prosthetic valve endocarditis" and "Surgery for prosthetic valve endocarditis".) Issues related to management of cardiac device infections are discussed separately. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Infections involving cardiac implantable electronic devices: Treatment and prevention".) Issues related to management of mycotic aneurysm and brain abscess are discussed separately. (See "Overview of infected (mycotic) arterial aneurysm" and "Treatment and prognosis of bacterial https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_resu…

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brain abscess".)

GENERAL CONSIDERATIONS Bactericidal agents are necessary for effective treatment of endocarditis. Therefore, antimicrobial therapy should be dosed to optimize sustained bactericidal serum concentrations throughout as much of the dosing interval as possible. In vitro determination of the minimum inhibitory concentration should be performed routinely. Empiric therapy — In general, therapy for infective endocarditis (IE) should be targeted to the organism isolated from blood cultures; cultures are positive in over 90 percent of patients with IE. For patients with suspected IE who present without acute symptoms, empiric therapy is not always necessary, and therapy can await blood culture results. Results of blood cultures are usually available within one to three days, and an accurate diagnosis is a critical first step in designing a management strategy. (See "Clinical manifestations and evaluation of adults with suspected native valve endocarditis".) In some cases, a clinician may choose to initiate antibiotic therapy prior to blood culture results; the decision to start or withhold antibiotic therapy prior to a microbiologic diagnosis must be individualized. For example, we initiate empiric antibiotic therapy for patients with hemodynamic instability and clinical presentation suggestive of acute endocarditis (eg, fever and new murmur, particularly in the setting of relevant cardiac risk factors [such as prior IE, history of valvular or congenital heart disease] or other predisposing conditions [intravenous drug use, indwelling intravenous lines, immunosuppression, or a recent dental or surgical procedure]). Empiric therapy should be administered after at least two (preferably three) sets of blood cultures have been obtained from separate venipunctures and ideally spaced over 30 to 60 minutes. (See "Clinical manifestations and evaluation of adults with suspected native valve endocarditis".) The choice of empiric therapy should take into consideration the most likely pathogens. In general, empiric therapy should cover staphylococci (methicillin susceptible and resistant), streptococci, and enterococci. Vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g per dose) is an appropriate choice for initial therapy in most patients. Additional issues related to the approach to empiric treatment of Staphylococcus aureus bacteremia are discussed further separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Empiric treatment'.) Early consultation with a cardiac surgeon should be obtained for cases in which complications are observed or expected (such as in infections complicated by moderate to severe heart failure). In addition, consultation by specialists in infectious diseases or cardiology may be useful. Clinical response to initial therapy — Most patients with IE become afebrile three to five days after initiation of appropriate antimicrobial therapy. Patients with S. aureus endocarditis may https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_resu…

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respond somewhat more slowly, remaining febrile for five to seven days after initiation of therapy. Patients with right-sided endocarditis and septic pulmonary emboli may remain febrile for an even longer duration of time. The initial microbiologic response to therapy should be assessed by obtaining repeat blood cultures 48 hours after antibiotics are begun; it is reasonable to obtain at least two sets of blood cultures every 24 to 48 hours until bloodstream infection has cleared [1]. Thereafter, careful serial physical examinations should be performed to evaluate for signs of heart failure, emboli, or other complications. Patients who develop new complications while on appropriate antimicrobial therapy (such as new emboli, heart failure, heart block, or other complications) should have a repeat echocardiogram to assess for worsening valve dysfunction, cardiac abscess, or fistula. Duration of therapy — The duration of therapy depends on the site of valvular infection and on the specific pathogen, as discussed in the sections below and as summarized in the tables (see 'Specific pathogens' below). The duration of therapy should be counted from the first day of negative blood cultures (for cases in which blood cultures were initially positive) [1]. In general, the suggested duration of therapy in patients with native valve endocarditis (NVE) ranges up to six weeks (with the exception of NVE due to highly resistant enterococcus, for which the duration is at least six weeks). Some data suggest that a shortened duration of intravenous therapy may be sufficient in some cases [4,5]; however, thus far, the weight of this evidence has been insufficient to change practice. A full course of therapy is particularly important for patients with virulent or relatively resistant pathogens, secondary cardiac or extracardiac complications, and in the setting of prolonged infection prior to diagnosis. This approach is based upon our understanding of the pathogenesis of vegetation formation and pathogen susceptibility, rather than on an evidence-based approach based on outcome data. Prolonged therapy is presumed to be necessary because bacterial concentrations within vegetations are as high as 109 to 1011 colony-forming units/gram of tissue; in addition, organisms within vegetations are not accessible to phagocytic cells and may be in a state of reduced metabolic activity [6]. (See "Pathogenesis of vegetation formation in infective endocarditis".) Shorter regimens may be reasonable in selected patients. These include: ●

Patients with right-sided endocarditis (see 'Uncomplicated right-sided endocarditis' below and "Infective endocarditis in people who inject drugs")

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Patients with endocarditis due to susceptible viridans streptococci [7] (see 'Viridans streptococci and S. bovis/S. equinus complex' below)

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Patients with endocarditis due to HACEK organisms (see 'HACEK organisms' below)

A shortened duration of parenteral therapy has been studied in select patients with left-sided endocarditis. In one study (Partial Oral Treatment of Endocarditis, or POET trial), including 400 https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_resu…

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Danish patients with (NVE) due to methicillin-susceptible S. aureus (23 percent), streptococci (54 percent), Enterococcus faecalis (25 percent), or coagulase-negative staphylococci (13 percent) who completed at least 10 days of intravenous therapy, patients in stable condition were randomly assigned to continue intravenous treatment or switch to oral treatment with a two-drug antibiotic regimen; the groups completed a similar duration of therapy (median 19 versus 17 days, respectively) [4]. Treatment completion with oral antibiotic therapy was noninferior to continued intravenous antibiotic therapy; the primary outcome (a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen [from the time of randomization until six months after completion of therapy]) occurred in 12 versus 9 percent of patients (between-group difference 3.1 percentage points, 95% CI 3.4-9.6). In a subsequent report of 3.5 year follow-up of patients in the above trial [5], the composite endpoint was reached in 38 percent of the patients who completed treatment with intravenous therapy and 26 percent of the patients who completed treatment with oral therapy (hazard ratio 0.64 favoring oral completion, 95% CI 0.45-0.91). However, the generalizability of these results is hampered by selection bias (only 20 percent of those assessed were randomly assigned) and referral bias (all patients received care in tertiary centers). Therefore, no alteration in the approach to treatment of IE is warranted based on these findings; further study of oral antibiotic therapy for completing treatment of IE is needed. Completing therapy — Patients may complete intravenous therapy as outpatients once hemodynamically stable. They must be capable of managing the technical aspects of intravenous therapy. Such patients require careful monitoring and must have ready access to full medical care should complications occur [1,8]. Patients should be counseled regarding the need for immediate evaluation in the setting of new fever, chills, or other signs of systemic toxicity, including a thorough clinical evaluation and repeat blood cultures [1]. While on antimicrobial therapy, patients should be monitored for antimicrobial toxicity. Weekly laboratory monitoring (complete blood count, chemistries, liver function tests, erythrocyte sedimentation rate, and C-reactive protein) should be performed. Serial audiograms may be appropriate for patients receiving long-term aminoglycosides [1]. Issues related to echocardiographic monitoring during therapy are discussed separately. (See "Overview of management of infective endocarditis in adults", section on 'Echo monitoring during therapy'.) Patients should be monitored for development of complications related to IE, including embolic complications and heart failure (see "Complications and outcome of infective endocarditis"). Development of complications should prompt evaluation for cardiac surgery. (See "Surgery for leftsided native valve infective endocarditis".)

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Follow up — Issues related to follow up after completion of antibiotic therapy for IE are discussed separately. (See "Overview of management of infective endocarditis in adults".) Relapse — Patients with relapse of NVE following completion of appropriate antimicrobial therapy should receive a repeat course of antibiotics as described in the following sections. Bacterial isolates should be retested carefully for complete antibiotic susceptibility profiles.

SPECIFIC PATHOGENS Staphylococci — The success of therapy for staphylococcal endocarditis depends on a number of factors, including involvement of right- versus left-sided valvular structures and the susceptibility of the staphylococcal isolate. Occasional strains of S. aureus are penicillin susceptible; however, laboratory screening procedures for detecting penicillin susceptibility may not be reliable [9]. Therefore, infective endocarditis (IE) caused by these organisms should be treated with regimens outlined for methicillin-susceptible S. aureus (MSSA) unless penicillin susceptibility can be confirmed (table 1) [1]. Methicillin susceptible General approach — Treatment for NVE due to MSSA consists of a semisynthetic penicillin, such as nafcillin or oxacillin (table 1). Cefazolin is an acceptable alternative agent; it may be used for patients with intracerebral septic emboli (in the absence of meningitis or brain abscess), since cefazolin is capable of reaching sites of endovascular infection. For patients with NVE in the setting of meningitis and/or brain abscess, treatment with nafcillin or oxacillin is preferred over cefazolin (good evidence to show that semisynthetic penicillins achieve therapeutic levels with abscesses is lacking) [1]; in such cases, cefazolin should not be used since it has limited blood-brain barrier penetrability [10]. Some experts caution against substituting cefazolin for nafcillin in the treatment of staphylococcal endocarditis because of concerns about the inoculum effect [11]; this issue is discussed further separately (see "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Methicillin-susceptible S. aureus (MSSA)'). However, to our knowledge, there are only two studies suggesting cefazolin was inferior to nafcillin for treatment of MSSA endocarditis; one was based on anecdotal observations of two patients with S. aureus endocarditis who relapsed after treatment or failed therapy [12], and another reported relapse in a patient with a retained cardiac device [13]. Low-dose aminoglycosides should NOT be combined routinely with antistaphylococcal penicillins or vancomycin for treatment of native valve S. aureus endocarditis. The evidence for clinically significant benefit relative to potential harm is minimal [14-16]. In a randomized trial including more https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_resu…

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than 230 patients with S. aureus bacteremia and endocarditis treated with either daptomycin monotherapy or gentamicin combined with a antistaphylococcal penicillin (or vancomycin), those who received gentamicin experienced significantly more renal impairment than those who did not (22 versus 8 percent, respectively) [15,16]. The duration of therapy for uncomplicated left-sided staphylococcal IE is six weeks; longer duration of therapy may be warranted in complicated IE [1]. Patients with penicillin allergy — Patients with NVE due to S. aureus who have a history of penicillin allergy can be treated with a first-generation cephalosporin such as cefazolin (2 g intravenously (IV) every eight hours), if there is no prior history of penicillin reaction that is typical of an immediate-type allergy [1]. Alternately, if penicillin desensitization is undertaken and successful, treatment with an antistaphylococcal penicillin may be used. (See "Rapid drug desensitization for immediate hypersensitivity reactions".) Cefazolin has limited blood-brain barrier penetrability so should not be used for treatment of patients with MSSA meningitis or brain abscess. If patients with MSSA IE and meningitis or brain abscess cannot tolerate nafcillin or oxacillin, vancomycin should be used. (See 'General approach' above.) The American Heart Association and the European Society for Cardiology (ESC) recommend cefazolin as an alternative in patients with penicillin allergy that is not anaphylactoid type [1,2]; however, the British Society for Antimicrobial Chemotherapy (BSAC) recommends vancomycin therapy for all patients with penicillin allergy regardless of type [3]. In addition, the BSAC recommends adding rifampin (300 to 600 mg orally every 12 hours) to vancomycin when treating methicillin-susceptible NVE in patients with penicillin allergy [3]. Vancomycin and daptomycin are acceptable alternative agents for treatment of NVE due to MSSA in patients with immediate-type penicillin allergy (documented by formal allergy evaluation) [1]. Vancomycin should not be used on the basis of convenience in patients without a true history of penicillin allergy, since clinical experience and in vitro studies have suggested that vancomycin is a less effective antistaphylococcal antibiotic than nafcillin or oxacillin. Issues related to use of vancomycin for treatment of MSSA infection are discussed further separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Methicillin-susceptible S. aureus (MSSA)'.) Clindamycin is not an acceptable alternative agent for treatment of staphylococcal endocarditis, because relapse is common [1]. Uncomplicated right-sided endocarditis — Select patients with native valve right-sided endocarditis due to MSSA may be treated with nafcillin, oxacillin, or flucloxacillin for two weeks; exclusion criteria include [1,17]:

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Renal failure

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Metastatic infection outside the lung (diagnosed by physical examination (eg, bone/joint involvement) and/or computed tomography imaging (eg, intra-abdominal abscesses)

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Simultaneous left-sided valvular infection

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Failure to defervesce within 48 to 72 hours of antibiotic therapy

Substitution of vancomycin (or teicoplanin) for nafcillin (eg, for penicillin-allergic patients) is not reliably effective if only two weeks of therapy are given [11]. If vancomycin is used, four weeks of therapy should be administered. Combination short-course (two weeks) beta-lactam plus aminoglycoside therapy has been a standard approach for treatment of right-sided staphylococcal IE [11,17]; however, a growing body of evidence suggests that the addition of adjunctive aminoglycoside therapy is not necessary and may cause harm [18]; the American Heart Association (AHA) guidelines discourage use of adjunctive gentamicin for this indication [1]. Issues related to right-sided IE are discussed further separately. (See "Infective endocarditis in people who inject drugs".) Methicillin resistant — Treatment of NVE due to methicillin-resistant S. aureus (MRSA) consists of vancomycin for six weeks (table 1) [1,2,19]. However, there have been a number of reports of vancomycin treatment failure in serious infections due to MRSA, even when isolates are proven to be susceptible using current microbiologic testing methods [20-22]. Furthermore, there is some concern that infections due to S. aureus isolates with high minimum inhibitory concentration (MIC) yet still within the susceptible range may be associated with poorer outcomes (see "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia"). In clinical cases where patients are responding poorly to therapy or there is concern about vancomycin susceptibility, an alternative approach may be needed. For patients with MRSA IE who are unable to tolerate vancomycin or for patients infected with an isolate with a vancomycin MIC ≥2 mcg/mL, daptomycin (8 mg/kg/day) is an acceptable alternative agent [1]. Daptomycin may be used for treatment of left- or right-sided IE, even if septic pulmonary emboli are present [23,24]. Daptomycin should not be used in the setting of concomitant MRSA pneumonia [1,19]. In one randomized trial including more than 240 patients with S. aureus bacteremia with or without endocarditis treated with daptomycin or standard therapy, the frequency of treatment success was comparable (44 versus 42 percent) [15]. In a subsequent prospective cohort study including more than 170 patients with gram-positive left-sided IE treated with daptomycin or conventional therapy, the median time to clearance of bacteremia among patients treated with daptomycin was shorter (1 versus 5 days) [25]. We are in agreement with the AHA which recommends against addition of rifampin to vancomycin for treatment of NVE due to MRSA [1]; in contrast, the BSAC favors this approach [3]. In addition, https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_resu…

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we do not favor adjunctive use of rifampin for patients with staphylococcal NVE who undergo surgical management with prosthetic valve placement [26]. The risk of rifampin-induced drug interactions and hepatic toxicity should be weighed carefully. Gentamicin should NOT be combined with vancomycin for treatment of MRSA native valve IE [19]. (See 'Methicillin susceptible' above.) Alternative agents for treatment of MRSA bacteremia are discussed separately (see "Methicillinresistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia"). Thus far, there is insufficient evidence for routine use of agents such as teicoplanin, ceftaroline, telavancin, dalbavancin, oritavancin, linezolid, or tedizolid for treatment of MRSA IE. Agents such as quinupristin-dalfopristin, tigecycline, linezolid, tedizolid, ceftaroline, or fluoroquinolones are generally not recommended for treatment of IE due to MRSA because of lack of sufficient evidence for treating IE and/or associated adverse effects. Coagulase-negative staphylococci — Treatment regimens for NVE due to coagulasenegative staphylococci are identical to those for coagulase-positive staphylococci. Most strains of coagulase-negative staphylococci are methicillin resistant. As a result, unless susceptibility to methicillin can be demonstrated conclusively, coagulase-negative staphylococci causing endocarditis should be assumed to be methicillin resistant and treated accordingly [1]. (See 'Methicillin resistant' above.) Streptococci Viridans streptococci and S. bovis/S. equinus complex — Members of the viridans group include S. mitis, S. mutans, S. oralis, S. sanguinis, S. sobrinus, and the S. milleri group (S. anginosus, S. constellatus, and S. intermedius). The nomenclature of the S. bovis/S. equinus complex is summarized in the table (table 2). (See "Infections due to group D streptococci (Streptococcus bovis/Streptococcus equinus complex)".) The MIC breakpoints differ between the guidelines published by the AHA, British Society for Antimicrobial Chemotherapy (BSAC), and ESC; the MIC breakpoints are summarized in the tables (table 3 and table 4). Penicillin-susceptible strains — MIC breakpoints and treatment regimens for endocarditis due to highly penicillin-susceptible streptococci are summarized in the table (table 3) [1-3]. For treatment of patients with NVE due to highly penicillin-susceptible streptococci (defined by the AHA as MIC ≤0.12 mcg/mL), we are in agreement with the AHA and ESC which favor aqueous crystalline penicillin G (12 to 18 million units daily for four weeks) or ceftriaxone (2 g per day) for four weeks [1,2].

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In the setting of uncomplicated infection in the absence of pre-existing renal disease, patients who have a prompt response to therapy may be treated with a shortened (two week) duration of combination therapy with gentamicin. In such cases, gentamicin may be given as a single daily dose (3 mg/kg per day; preferred in outpatients) or in two to three equally divided doses (adjusted to achieve a peak serum level of 3 to 4 mcg/mL; preferred in hospitalized patients when serum concentrations can be followed). In one randomized study including 61 patients with IE due to penicillin-susceptible streptococci treated with a four-week ceftriaxone regimen or a two-week combination of ceftriaxone plus gentamicin, cure rates were similar [27]. In choosing between these regimens, one must weigh the risk of longer therapy with the potential risk of renal toxicity with gentamicin. Patients with penicillin allergy (in the absence of immediate-type hypersensitivity) may be treated with ceftriaxone. Patients with immediate-type hypersensitivity reaction to beta-lactams may be treated with vancomycin for four weeks, or may be desensitized to penicillin and treated with a standard regimen. In general, treatment with penicillin is preferred over vancomycin; therefore, when feasible, we favor desensitization to penicillin over treatment with vancomycin. (See "Rapid drug desensitization for immediate hypersensitivity reactions".) Relatively penicillin-resistant strains — MIC breakpoints and treatment regimens for endocarditis due to relatively penicillin-resistant streptococci are summarized in the table (table 4). For treatment of patients with NVE due to relatively penicillin-resistant streptococci (defined by the AHA as MIC >0.12 mcg/mL and 0.1-1.0 mcg/mL), and penicillin-resistant S. pneumoniae (MIC ≥2.0 mcg/mL). Presence of meningitis — In the setting of concomitant meningitis, in vitro susceptibility to cefotaxime or ceftriaxone should be obtained. For patients with isolates susceptible to cefotaxime or ceftriaxone, treatment of pneumococcal NVE consists of cefotaxime (2 g IV every 4 to 6 hours) or ceftriaxone (2 g IV every 12 hours) for 4 weeks [1]. For patients with isolates resistant to cefotaxime (MIC >2.0 mcg/mL) or ceftriaxone (MIC ≥2.0 mcg/mL), addition of vancomycin (30 mg/kg IV every 24 hours in two divided doses) and rifampin (900 mg every 24 hours IV or by mouth in three divided doses) may be warranted. Issues related to extrameningeal infection with pneumococcal strains resistant to beta-lactam antibiotics are discussed further separately. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia".) Pneumococcal endocarditis is usually fulminant and causes severe valve damage and embolic complications; valve replacement may be necessary [29]. (See "Surgery for left-sided native valve infective endocarditis".) Streptococcal groups A, B, C, F, and G — Streptococcal groups A, B, C, F, and G are occasional causes of endocarditis [28,30]. Regimens used to treat endocarditis due to viridans group streptococci are typically effective since most of these organisms are highly sensitive to penicillin.

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For treatment of IE due to Streptococcus pyogenes, we are in agreement with the AHA which recommends treatment with penicillin G (24 million units IV continuously or in 4 to 6 divided doses) for four to six weeks; ceftriaxone (eg, IV every 12 hours) is a reasonable alternative and is easier to administer as an outpatient or in an intermediate care facility [1]. Vancomycin may be used for patients intolerant of beta-lactam therapy. Some strains of groups B, C, F, and G streptococci are more resistant to penicillin than S. pyogenes. For this reason, depending on sensitivity results, we are in agreement with some experts who favor adding gentamicin to a penicillin or cephalosporin for the first two weeks of a four- to six-week course of therapy [1]. Enterococci — Most cases of enterococcal endocarditis are caused by E. faecalis strains [31]. Vancomycin resistance is observed most commonly among Enterococcus faecium strains, which are a less frequent cause of endocarditis. Enterococci have a narrower spectrum of susceptibility than streptococcal species. In particular, members of the genus Enterococcus are all resistant to low concentrations of penicillin. They are also relatively resistant to expanded-spectrum penicillins, resistant to cephalosporins, and typically resistant to aminoglycosides at concentrations achieved with standard dosing regimens. However, many strains of enterococci are killed both in vitro and in vivo if penicillin, ampicillin, or vancomycin is given in synergistic combination with an aminoglycoside such as gentamicin. Issues related to enterococcal resistance are discussed further separately. (See "Mechanisms of antibiotic resistance in enterococci".) Enterococci should be tested routinely for in vitro susceptibility to penicillin and vancomycin and for high-level resistance to gentamicin (>500 mcg/mL) to predict synergistic interactions [1]. For strains that are resistant to beta-lactams or vancomycin, in vitro susceptibility to daptomycin and linezolid should be obtained. General principles related to treatment of enterococcal infections are discussed separately. (See "Treatment of enterococcal infections".) Susceptible strains General approach — Treatment regimens for NVE due to enterococcal strains susceptible to penicillin and gentamicin are summarized in the table (table 5) [1-3]. Regimens include a betalactam combination regimen (ceftriaxone plus ampicillin for six weeks, for IE due to E. faecalis) or an aminoglycoside combination regimen (penicillin or ampicillin plus gentamicin for four to six weeks; the duration of gentamicin may be shortened to two weeks in the setting of nephrotoxicity, as discussed below). Most strains of E. faecium are not susceptible to ampicillin; in the setting of IE due to E. faecium, the combination beta-lactam regimen should not be used.

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For patients with NVE due to enterococcal strains susceptible to penicillin and gentamicin, we favor treatment with a beta-lactam combination regimen. This approach may be better tolerated and associated with fewer side effects than regimens containing an aminoglycoside, particularly in older patients and/or in patients with renal insufficiency [32-35]. In an observational study including more than 240 patients with E. faecalis IE treated with ampicillin and ceftriaxone or ampicillin and gentamicin (AG), rates of mortality, treatment failure and relapse were comparable between the groups; renal failure occurred more frequently among those treated with AG [35]. For patients treated with an aminoglycoside combination regimen, some experts prefer penicillin over ampicillin because of the possibility of increased allergic reaction to ampicillin. Patients with duration of symptoms 3 months and patients with relapsed infection. Longer duration of gentamicin treatment has been associated with increased likelihood for decline in renal function. In one nonrandomized study including more than 80 patients with enterococcal IE with absence of high-level aminoglycoside resistance and duration of symptoms 6 days) may be required to detect growth if traditional (nonautomated) blood culture systems are used. (See "Culture-negative endocarditis: Epidemiology, microbiology, and diagnosis".) HACEK organisms are considered ampicillin resistant. Unless growth in vitro is adequate to obtain susceptibility testing results, penicillin and ampicillin should not be used for treatment of IE due to these organisms [1]. Virtually all HACEK organisms are highly susceptible to third-generation cephalosporins such as ceftriaxone, even strains that produce beta-lactamase. Treatment regimens for NVE due to HACEK organisms are summarized in the table (table 9) [1,2]. We are in agreement with the AHA which recommends treatment with ceftriaxone, ampicillin (if in vitro testing is feasible and the organism is susceptible), or ciprofloxacin for four weeks [1]. Gentamicin is generally not recommended because of risk for nephrotoxicity. Other gram-negative organisms — NVE due to other gram-negative bacilli (such as Escherichia coli, Pseudomonas, Klebsiella, or Serratia) is extremely rare. The most common predisposing factor is an implanted endovascular device, and most cases occur in the setting of recent health care contact [39]. The choice of antimicrobial therapy depends on the antimicrobial susceptibility of the causative organism. Combination antimicrobial therapy with a beta-lactam (penicillins, cephalosporins, or carbapenems) and either an aminoglycoside or fluoroquinolone for six weeks is reasonable [1]. Such patients may also warrant cardiac surgery, particularly in the setting of left-sided infection due to Pseudomonas. (See "Surgery for left-sided native valve infective endocarditis".) Fungi — Treatment of fungal endocarditis consists of antifungal therapy and valve replacement. Issues related to Candida endocarditis are discussed separately. (See "Candida endocarditis and suppurative thrombophlebitis".) Issues related to endocarditis caused by Aspergillus are discussed separately. (See "Treatment and prevention of invasive aspergillosis", section on 'Antifungal therapy' and "Treatment and prevention of invasive aspergillosis", section on 'Duration' and "Treatment and prevention of invasive aspergillosis", section on 'Role of surgery'.) https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_res…

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CULTURE-NEGATIVE ENDOCARDITIS Culture-negative infective endocarditis (IE) is defined as endocarditis without etiology following inoculation of three blood samples in a standard blood culture system (eg, negative cultures after seven days) [1]. Cultures are negative in IE for three major reasons: ●

Administration of antimicrobial agents prior to blood culture incubation

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Inadequate microbiologic techniques

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Infection with fastidious bacteria or nonbacterial pathogens

The most common causes of culture-negative IE are fastidious organisms (eg, zoonotic agents and fungi) and Streptococcus spp in patients who have received previous antibiotic treatment. (See "Culture-negative endocarditis: Epidemiology, microbiology, and diagnosis".) Coxiella burnetii and Bartonella spp are relatively common agents of culture-negative endocarditis; the frequency varies in different geographic locations. Treatment of these cases is discussed separately. (See "Q fever endocarditis" and "Endocarditis caused by Bartonella".) Empiric treatment of patients with culture-negative NVE should cover both gram-positive and gram-negative organisms and should be selected in consultation with an infectious disease specialist. The American Heart Association suggests the following approach [1]: ●

For patients with acute clinical presentation (ie, symptomatic for days), antimicrobial therapy for coverage of infection due to S. aureus, beta-hemolytic streptococci, and aerobic gramnegative bacilli is reasonable. Empiric coverage could include vancomycin and cefepime as an initial regimen [1].

●

For patients with a subacute clinical presentation (ie, symptomatic for weeks), antimicrobial therapy for coverage of infection due to S. aureus, viridans group streptococci, HACEK organisms, and enterococci is reasonable. Empiric coverage could include vancomycin and ampicillin-sulbactam as an initial regimen [1].

The above approach to empiric treatment can be modified depending on individual patient circumstances, including whether the patient received antimicrobial therapy prior to blood cultures, the type and duration of prior antimicrobial therapy, epidemiologic risk factors, the suspected site of primary infection, risk of toxicity, and allergy history. As examples: ●

In patients for whom gram-positive cocci or HACEK organisms are the most likely cause of endocarditis, we sometimes use a combination of vancomycin plus ceftriaxone or vancomycin plus ampicillin-sulbactam.

●

In patients receiving dialysis, a regimen consisting of vancomycin alone may be reasonable.

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In patients for whom there is a reasonable possibility of infection with an organism such as C. burnetii or Brucella, empiric therapy active against these pathogens is reasonable, pending test results. (See "Q fever endocarditis", section on 'Treatment'.)

Subsequent therapy should be directed to the specific microorganism if diagnostic tests such as polymerase chain reaction or serology identify the etiologic agent. For patients with IE and negative blood cultures who undergo valve replacement, the approach to antibiotic therapy may be guided by valve culture data. (See "Surgery for left-sided native valve infective endocarditis".)

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of infective endocarditis" and "Society guideline links: Outpatient parenteral antimicrobial therapy".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-toread materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Endocarditis (The Basics)")

SUMMARY AND RECOMMENDATIONS ●

Treatment of endocarditis requires bactericidal antimicrobial therapy, which should be dosed to optimize sustained bactericidal serum concentrations throughout as much of the dosing interval as possible. In vitro determination of the minimum inhibitory concentration should be performed routinely. (See 'General considerations' above.)

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Therapy for native valve endocarditis (NVE) should be targeted to the organism isolated from blood cultures. For patients with suspected infective endocarditis who present without acute symptoms, empiric therapy is not always necessary, and therapy can await blood culture results. (See 'Empiric therapy' above.)

●

The decision to start or withhold antibiotic therapy prior to a microbiologic diagnosis must be individualized. For patients with hemodynamic instability and clinical presentation suggestive of acute endocarditis (fever and new murmur, particularly in the setting of relevant cardiac risk factors or other predisposing conditions), we suggest administration of empiric antibiotic therapy (Grade 2C). Empiric therapy may be administered after at least two (preferably three) sets of blood cultures have been obtained from separate venipunctures and ideally spaced over 30 to 60 minutes. (See 'Empiric therapy' above.)

●

In general, empiric therapy should cover staphylococci (methicillin susceptible and resistant), streptococci, and enterococci. Vancomycin is an appropriate choice for initial therapy in most patients. (See 'Empiric therapy' above.)

●

The optimal antibiotic regimen depends upon the causative organism and in vitro susceptibility results. The approach is summarized in the tables and is discussed in the sections above:

• Staphylococci (table 1) (see 'Staphylococci' above) • Streptococci:

-

Viridans streptococci and S. bovis/S. equinus complex (table 2 and table 3 and table 4) (see 'Viridans streptococci and S. bovis/S. equinus complex' above)

-

S. pneumoniae (see 'Streptococcus pneumoniae' above)

-

Streptococcal groups A, B, C, F, and G (see 'Streptococcal groups A, B, C, F, and G' above)

• Enterococci (table 5 and table 6 and table 7 and table 8) (see 'Enterococci' above) • HACEK organisms (table 9) (see 'HACEK organisms' above) • Other gram-negative organisms (see 'Other gram-negative organisms' above) • Culture-negative endocarditis (see 'Culture-negative endocarditis' above) ●

The suggested duration of therapy in patients with NVE depends on the pathogen and site of valvular infection. In general, the suggested duration of therapy in patients with NVE ranges up to six weeks (with the exception of NVE due to highly resistant enterococcus, for which the duration is at least six weeks). Some data suggest that a shortened duration of intravenous therapy may be sufficient in some cases; however, thus far, the weight of this evidence has

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been insufficient to change practice. A full course of therapy is particularly important for patients with virulent or relatively resistant pathogens, secondary cardiac or extracardiac complications, and in the setting of prolonged infection prior to diagnosis. This approach is based upon our understanding of the pathogenesis of vegetation formation and pathogen susceptibility, rather than on an evidence-based approach based on outcome data. (See 'Duration of therapy' above.) ●

Early consultation with a cardiac surgeon should be obtained for cases in which complications are observed or expected (such as in the presence of moderate to severe heart failure, heart block, or systemic emboli). In addition, consultation with specialists in infectious diseases and/or cardiology may be important. Patients with endocarditis require careful regular clinical follow-up that includes serial physical examinations and obtaining follow-up blood cultures to document clearance of bacteremia. (See 'Empiric therapy' above and 'Clinical response to initial therapy' above.)

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REFERENCES 1. Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation 2015; 132:1435. 2. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for CardioThoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36:3075. 3. Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67:269. 4. Iversen K, Ihlemann N, Gill SU, et al. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. N Engl J Med 2019; 380:415. 5. Bundgaard H, Ihlemann N, Gill SU, et al. Long-Term Outcomes of Partial Oral Treatment of Endocarditis. N Engl J Med 2019; 380:1373. 6. Durack DT, Beeson PB. Experimental bacterial endocarditis. II. Survival of a bacteria in endocardial vegetations. Br J Exp Pathol 1972; 53:50. https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_res…

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7. Karchmer AW, Moellering RC Jr, Maki DG, Swartz MN. Single-antibiotic therapy for streptococcal endocarditis. JAMA 1979; 241:1801. 8. Tice AD, Rehm SJ, Dalovisio JR, et al. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis 2004; 38:1651. 9. El Feghaly RE, Stamm JE, Fritz SA, Burnham CA. Presence of the bla(Z) beta-lactamase gene in isolates of Staphylococcus aureus that appear penicillin susceptible by conventional phenotypic methods. Diagn Microbiol Infect Dis 2012; 74:388. 10. Weis S, Kesselmeier M, Davis JS, et al. Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcus aureus bacteraemia. Clin Microbiol Infect 2019; 25:818. 11. DiNubile MJ. Short-course antibiotic therapy for right-sided endocarditis caused by Staphylococcus aureus in injection drug users. Ann Intern Med 1994; 121:873. 12. Bryant RE, Alford RH. Unsuccessful treatment of staphylococcal endocarditis with cefazolin. JAMA 1977; 237:569. 13. Nannini EC, Singh KV, Murray BE. Relapse of type A beta-lactamase-producing Staphylococcus aureus native valve endocarditis during cefazolin therapy: revisiting the issue. Clin Infect Dis 2003; 37:1194. 14. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: A prospective study. Ann Intern Med 1982; 97:496. 15. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653. 16. Cosgrove SE, Vigliani GA, Fowler VG Jr, et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis 2009; 48:713. 17. Chambers HF, Miller RT, Newman MD. Right-sided Staphylococcus aureus endocarditis in intravenous drug abusers: two-week combination therapy. Ann Intern Med 1988; 109:619. 18. Ribera E, Gómez-Jimenez J, Cortes E, et al. Effectiveness of cloxacillin with and without gentamicin in short-term therapy for right-sided Staphylococcus aureus endocarditis. A randomized, controlled trial. Ann Intern Med 1996; 125:969.

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19. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18. 20. Sander A, Beiderlinden M, Schmid EN, Peters J. Clinical experience with quinupristindalfopristin as rescue treatment of critically ill patients infected with methicillin-resistant staphylococci. Intensive Care Med 2002; 28:1157. 21. Moise PA, Schentag JJ. Vancomycin treatment failures in Staphylococcus aureus lower respiratory tract infections. Int J Antimicrob Agents 2000; 16 Suppl 1:S31. 22. Moise-Broder PA, Sakoulas G, Eliopoulos GM, et al. Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin Infect Dis 2004; 38:1700. 23. Dohmen PM, Guleri A, Capone A, et al. Daptomycin for the treatment of infective endocarditis: results from a European registry. J Antimicrob Chemother 2013; 68:936. 24. Rehm SJ, Boucher H, Levine D, et al. Daptomycin versus vancomycin plus gentamicin for treatment of bacteraemia and endocarditis due to Staphylococcus aureus: subset analysis of patients infected with methicillin-resistant isolates. J Antimicrob Chemother 2008; 62:1413. 25. Carugati M, Bayer AS, Miró JM, et al. High-dose daptomycin therapy for left-sided infective endocarditis: a prospective study from the international collaboration on endocarditis. Antimicrob Agents Chemother 2013; 57:6213. 26. Shrestha NK, Shah SY, Wang H, et al. Rifampin for Surgically Treated Staphylococcal Infective Endocarditis: A Propensity Score-Adjusted Cohort Study. Ann Thorac Surg 2016; 101:2243. 27. Sexton DJ, Tenenbaum MJ, Wilson WR, et al. Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Endocarditis Treatment Consortium Group. Clin Infect Dis 1998; 27:1470. 28. Aronin SI, Mukherjee SK, West JC, Cooney EL. Review of pneumococcal endocarditis in adults in the penicillin era. Clin Infect Dis 1998; 26:165. 29. Lefort A, Mainardi JL, Selton-Suty C, et al. Streptococcus pneumoniae endocarditis in adults. A multicenter study in France in the era of penicillin resistance (1991-1998). The Pneumococcal Endocarditis Study Group. Medicine (Baltimore) 2000; 79:327. 30. Baddour LM. Infective endocarditis caused by beta-hemolytic streptococci. The Infectious Diseases Society of America's Emerging Infections Network. Clin Infect Dis 1998; 26:66. https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_res…

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31. Anderson DJ, Murdoch DR, Sexton DJ, et al. Risk factors for infective endocarditis in patients with enterococcal bacteremia: a case-control study. Infection 2004; 32:72. 32. Pericas JM, Cervera C, del Rio A, et al. Changes in the treatment of Enterococcus faecalis infective endocarditis in Spain in the last 15 years: from ampicillin plus gentamicin to ampicillin plus ceftriaxone. Clin Microbiol Infect 2014; 20:O1075. 33. Beganovic M, Luther MK, Rice LB, et al. A Review of Combination Antimicrobial Therapy for Enterococcus faecalis Bloodstream Infections and Infective Endocarditis. Clin Infect Dis 2018; 67:303. 34. El Rafei A, DeSimone DC, Narichania AD, et al. Comparison of Dual β-Lactam therapy to penicillin-aminoglycoside combination in treatment of Enterococcus faecalis infective endocarditis. J Infect 2018; 77:398. 35. Fernández-Hidalgo N, Almirante B, Gavaldà J, et al. Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating enterococcus faecalis infective endocarditis. Clin Infect Dis 2013; 56:1261. 36. Wilson WR, Wilkowske CJ, Wright AJ, et al. Treatment of streptomycin-susceptible and streptomycin-resistant enterococcal endocarditis. Ann Intern Med 1984; 100:816. 37. Dahl A, Rasmussen RV, Bundgaard H, et al. Enterococcus faecalis infective endocarditis: a pilot study of the relationship between duration of gentamicin treatment and outcome. Circulation 2013; 127:1810. 38. Britt NS, Potter EM, Patel N, Steed ME. Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream Infection: A National Cohort Study of Veterans Affairs Patients. Clin Infect Dis 2015; 61:871. 39. Morpeth S, Murdoch D, Cabell CH, et al. Non-HACEK gram-negative bacillus endocarditis. Ann Intern Med 2007; 147:829.

Topic 2152 Version 64.0

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GRAPHICS Treatment regimens for native valve endocarditis due to Staphylococcus American Heart Association (AHA)

European Society of Cardiology* (ESC)

British Society for Antimicrobial Chemotherapy (BSAC) Methicillin sensitive

Adult

Pediatric

Methicillin-susceptible strains ¶

Methicillin-susceptible strains

Methicillin-susceptible strains Δ

Nafcillin or oxacillin 200 mg/kg per 24 hours IV (maximum dose: 12 g per 24 hours) in four or six divided doses for 4 to 6 weeks

Oxacillin or cloxacillin or flucloxacillin 12 g per 24 hours IV in four or six divided doses for 4 to 6 weeks or

or

Cefazolin ◊ 6 g per 24 hours IV in three divided doses for 6 weeks

Nafcillin or oxacillin 12 g per 24 hours IV in four or six divided doses for 6 weeks or Cefazolin ◊ 6 g per 24 hours IV in three divided doses for 6 weeks

Methicillin-resistant strains

Vancomycin ¥ 30 mg/kg per 24 hours IV in two divided doses for 6 weeks or Daptomycin ≥8 mg/kg ‡ per 24 hours IV once daily for 6 weeks

Cefazolin ◊ 100 mg/kg per 24 hours IV (maximum dose: 6 g per 24 hours) in three divided doses for 4 to 6 weeks

Methicillin-resistant strains §

Vancomycin ¥ 40 mg/kg per 24 hours IV (maximum dose: 2 g per 24 hours unless levels are inappropriately low) in two or three divided doses for 6 weeks

Flucloxacillin 2 g IV every 4 to 6 hours for 4 weeks

or Cefotaxime ◊ 6 g per 24 hours in three divided doses Methicillin-resistant strains Δ

Vancomycin ¥ 30 to 60 mg/kg per 24 hours IV in two or three divided doses for 4 to 6 weeks or Daptomycin † 10 mg/kg per 24 hours IV once daily for 4 to 6 weeks

Methicillin resistant

Vancomycin ¥ 1 g IV every 12 hours for 4 weeks plus Rifampicin 300 to 600 mg orally every 12 hours for 4 weeks OR Daptomycin 6 mg/kg IV every 24 hours for 4 weeks plus Rifampicin 300 to 600 mg orally every 24 hours for 4 weeks or Gentamicin 1 mg/kg IV every 12 hours for 4 weeks

The doses in this table are intended for patients with normal renal function. The doses of many of these agents must be adjusted in the setting of renal insufficiency; refer to the Lexicomp drug-specific monographs for renal dose adjustments. IV: intravenously; IM: intramuscularly. * Pediatric doses (should not exceed adult doses): oxacillin, cloxacillin, or flucloxacillin: 200 to 300 mg/kg per 24 hours IV in four or six divided doses; trimethoprim-sulfamethoxazole (cotrimoxazole) 12 mg/kg trimethoprim component per 24 hours IV in two divided doses; clindamycin 40 mg/kg per 24 hours IV in three divided doses; vancomycin 40 mg/kg per 24 hours IV in two or three divided doses; daptomycin 10 mg/kg per 24 hours IV once daily. ¶ Regimens for complicated right-sided and all left-sided infective endocarditis. Δ Another alternative regimen for S. aureus consists of trimethoprim-sulfamethoxazole (cotrimoxazole) 960 mg trimethoprim/4800 mg sulfamethoxazole per 24 hours IV in four or six divided doses for 1 week followed by 5 weeks of oral trimethoprim-sulfamethoxazole plus clindamycin 1800 mg per 24 hours IV in three divided doses for 1 week. ◊ For use in patients with nonsevere penicillin allergy. Avoid cefazolin in complicating brain abscess; nafcillin is preferred. https://www.uptodate.com/contents/antimicrobial-therapy-of-native-valve-endocarditis/print?search=endocardite infecciosa&source=search_res…

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§ Consultation with a pediatric infectious disease specialist is recommended in cases of infection due to methicillinresistant strains. ¥ Vancomycin dose adjusted for trough concentration of 10 to 20 mcg/mL; some favor trough concentrations 15 to 20 mcg/mL. ‡ Daptomycin selection and dosing should be assisted by infectious diseases consultation. † Daptomycin is superior to vancomycin for S. aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L. Some experts recommend adding cloxacillin 12 g per 24 hours IV in six divided doses or fosfomycin 8 g per 24 hours IV in four divided doses to daptomycin in order to increase activity and avoid development of daptomycin resistance. Data from: 1. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: Diagnosis, antimicrobial therapy, and management of complications: A scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132:1435. 2. Baltimore RS, Gewitz M, Baddour LM, et al. Infective Endocarditis in Childhood: 2015 Update: A Scientific Statement From the American Heart Association. Circulation 2015; 132:1487. 3. Authors/Task Force Members, Habib G, Lancellotti P, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC)Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36:3075. 4. Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67:269. Graphic 81429 Version 15.0

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Streptococcus bovis/Streptococcus equinus complex: Phenotypic and genotypic species names [1-4] Phenotypic name

Genotypic name

Synonym

S. bovis biotype I

S. gallolyticus

S. gallolyticus subsp gallolyticus

S. bovis biotype II.1

S. lutetiensis

S. infantarius subsp coli

S. infantarius

S. infantarius subsp infantarius

S. pasteurianus

S. gallolyticus subsp pasteurianus

S. bovis biotype II.2

References: 1. Poyart C, Quesne G, Trieu-Cuot P. Taxonomic dissection of the Streptococcus bovis group by analysis of manganese-dependent superoxide dismutase gene (sodA) sequences: reclassification of 'Streptococcus infantarius subsp. coli' as Streptococcus lutetiensis sp. nov. and of Streptococcus bovis biotype 11.2 as Streptococcus pasteurianus sp. nov. Int J Syst Evol Microbiol 2002; 52:1247. 2. Schlegel L, Grimont F, Ageron E, et al. Reappraisal of the taxonomy of the Streptococcus bovis/Streptococcus equinus complex and related species: description of Streptococcus gallolyticus subsp. gallolyticus subsp. nov., S. gallolyticus subsp. macedonicus subsp. nov. and S. gallolyticus subsp. pasteurianus subsp. nov. Int J Syst Evol Microbiol 2003; 53:631. 3. Boleij A, van Gelder MM, Swinkels DW, Tjalsma H. Clinical importance of Streptococcus gallolyticus infection among colorectal cancer patients: systematic review and meta-analysis. Clin Infect Dis 2011; 53:870. 4. Chirouze C, Patry I, Duval X, et al. Streptococcus bovis/Streptococcus equinus complex fecal carriage, colorectal carcinoma, and infective endocarditis: a new appraisal of a complex connection. Eur J Clin Microbiol Infect Dis 2013; 32:1171. Graphic 89670 Version 16.0

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Treatment regimens for native valve endocarditis due to penicillin-susceptible viridans streptococci and Streptococcus gallolyticus (bovis)* American Heart Association (AHA)

Adult

Pediatric

(MIC ≤0.12 mcg/mL)

(MIC ≤0.1 mcg/mL)

4-week regimens ¶: Aqueous penicillin G 12 to 18 million units per 24 hours IV either continuously or in 4 or 6 divided doses or (if penicillin is unavailable) Ampicillin 2 g IV every 4 hours or Ceftriaxone 2 g per 24 hours IV or IM in 1 dose Beta-lactam-intolerant patients: Vancomycin ◊ 30 mg/kg per 24 hours IV in 2 divided doses

4-week regimens:

European Society of Cardiology (ESC) (MIC ≤0.125 mcg/mL)

4-week regimens Δ:

Aqueous penicillin G 200,000 to 300,000 units/kg per 24 hours IV in 6 divided doses (maximum dose: 24 million units per 24 hours)

Aqueous penicillin G ¶ 12

or (if penicillin is unavailable)

Amoxicillin 100 to 200 mg/kg per 24 hours IV in 4 to 6 divided doses

Ampicillin 200 to 300 mg/kg per 24 hours IV divided in 4 or 6 divided doses (maximum dose: 12 g per 24 hours) or Ceftriaxone 100 mg/kg per 24 hours IV § in 2 divided doses or 80 mg/kg in 1 daily dose (maximum dose: 4 g per 24 hours; if dose is >2 g per 24 hours, use divided dosing every 12 hours)

to 18 million units per 24 hours IV in 4 or 6 divided doses or continuous infusion or

British Society for Antimicrobial Chemotherapy (BSAC) (MIC ≤0.125 mcg/mL) 4- to 6-week regimens: Benzylpenicillin ‡ 1.2 g every 4 hours IV or Ceftriaxone 2 g per 24 hours IV/IM

or Ampicillin 12 g per 24 hours (or 100 to 200 mg/kg per 24 hours) IV in 6 divided doses or Ceftriaxone ¶¥ 2 g per 24 hours IV or IM in 1 dose or Vancomycin ◊ 30 mg/kg per 24 hours IV in 2 divided doses

Beta-lactam-intolerant patients: Vancomycin ◊ 40 mg/kg per 24 hours IV in 2 or 3 divided doses (maximum dose: 2 g per 24 hours) 2-week regimens †:

2-week regimens †:

2-week regimens Δ†:

2-week regimens †:

Either

Not recommended for children due to lack of data

Either

Either

Aqueous penicillin G 12 to 18 million units per 24 hours IV in 4 to 6 divided doses or continuous infusion

Benzylpenicillin ‡ 1.2 g every 4 hours IV

Aqueous penicillin G 12 to 18 million units per 24 hours IV either continuously or in 6 divided doses or

or

Ceftriaxone 2 g per 24 hours IV or IM in 1 dose

Amoxicillin 100 to 200 mg/kg per 24 hours IV in 4 to 6 divided doses

plus Gentamicin **,¶¶ 3 mg/kg per 24 hours IV or IM in 1 dose (preferred) or in 3 divided doses

or Ceftriaxone 2 g per 24 hours IV or IM plus Gentamicin ** 1 mg/kg every 12 hours IV

or Ampicillin 12 g (or 100 to 200 mg/kg) per 24 hours IV in 6 divided doses or

¶¥

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Ceftriaxone ¶¥ 2 g per 24 hours IV or IM in 1 dose plus Gentamicin **,ΔΔ 3 mg/kg per 24 hours IV or IM in 1 dose

The doses above are intended for patients with normal renal function. The doses of many of these agents must be adjusted in the setting of renal insufficiency; refer to the individual Lexicomp drug monographs for renal dose adjustments. Wherever intramuscular administration is provided as an alternative, intravenous route is preferred, particularly in infants and children. MIC: minimum inhibitory concentration; IV: intravenously; IM: intramuscularly. * MIC thresholds differ between guidelines. AHA adult guidelines use MIC ≤0.12 mcg/mL; AHA pediatric guidelines use MIC ≤0.1 mcg/mL. ESC and BSAC guidelines use MIC ≤0.125 mcg/mL. ¶ Preferred in most patients >65 years or with impairment of 8th nerve or renal function. Δ Pediatric doses (should not exceed adult doses): Penicillin G 200,000 units/kg per 24 hours IV in 4 to 6 divided doses; amoxicillin 300 mg/kg per 24 hours IV in 4 to 6 divided doses; ceftriaxone 100mg/kg per dose IV or IM daily; vancomycin 40 mg/kg per 24 hours IV in 2 or 3 divided doses; gentamicin 3 mg/kg per 24 hours IV or IM in a single daily dose or in 3 divided doses. ◊ Vancomycin therapy only recommended for patients allergic to penicillin and cephalosporins; vancomycin dose adjusted for trough concentration of 10 to 15 mcg/mL. Penicillin desensitization can be attempted in stable patients. § In infants and children, intravenous antibiotics are recommended rather than intramuscular agents. ¥ Preferred for outpatient therapy. ‡ Amoxicillin 2 g every 4 to 6 hours IV may be used in place of benzylpenicillin 1.2 to 2.4 g every 4 hours. † For noncomplicated infective endocarditis. Not intended for patients with known cardiac or extracardiac abscess or for creatinine clearance