TREATMENT Infective Endocarditis ANTIMICROBIAL THERAPY
To cure endocarditis, all bacteria in the vegetation must be killed. However, it is difficult to eradicate these bacteria because local host defenses are deficient and because the bacteria are largely nongrowing and metabolically inactive and thus are less easily killed by antibiotics. Accordingly, therapy must be bactericidal and prolonged. Antibiotics are generally given parenterally to achieve serum concentrations that, through passive diffusion, result in effective concentrations in the depths of the vegetation. To select effective therapy requires knowledge of the susceptibility of the causative microorganisms. The decision to initiate treatment empirically must balance the need to establish a microbiologic diagnosis against the potential progression of disease or the need for urgent surgery (see “Blood Cultures,” earlier). Simultaneous infection at other sites (such as the meninges), allergies, end-organ dysfunction, interactions with concomitantly administered medications, and risks of adverse events must be considered in the selection of therapy.
Although given for several weeks longer, the regimens recommended for the treatment of PVE (except that caused by staphylococci) are similar to those used to treat NVE (Table 155-4). Recommended doses and durations of therapy should be followed unless alterations are required by end-organ dysfunction or adverse events. Organism-Specific Therapies STREPTOCOCCI
Optimal therapy for streptococcal endocarditis is based on the minimal inhibitory concentration (MIC) of penicillin for the causative isolate (Table 155-4). The 2-week penicillin/gentamicin or ceftriaxone/gentamicin regimens should not be used to treat PVE or complicated NVE. Caution should be exercised in considering aminoglycoside-containing regimens for the treatment of patients at increased risk for aminoglycoside toxicity. The regimens recommended for relatively penicillin-resistant streptococci are advocated for treatment of group B, C, or G streptococcal endocarditis. Nutritionally variant organisms (Granulicatella or Abiotrophia species) and Gemella species are treated with the regimens for moderately penicillin-resistant streptococci, as is PVE caused by these organisms or by streptococci with a penicillin MIC of >0.1 μg/mL (Table 155-4). ENTEROCOCCI
Enterococci are resistant to oxacillin, nafcillin, and the cephalosporins and are only inhibited—not killed—by penicillin, ampicillin, teicoplanin (not available in the United States), and vancomycin. To kill enterococci requires the synergistic interaction of a cell wall–active antibiotic that is effective at achievable serum concentrations (penicillin, ampicillin, vancomycin, or teicoplanin) and an aminoglycoside (gentamicin or streptomycin) to which the isolate does not exhibit high-level resistance. An isolate’s resistance to cell wall–active agents or its ability to replicate in the presence of gentamicin at ≥500 μg/mL or streptomycin at 1000–2000 μg/mL—a phenomenon called high-level aminoglycoside resistance—indicates that the ineffective antimicrobial agent cannot participate in the interaction to produce killing. High-level resistance to gentamicin predicts that tobramycin, netilmicin, amikacin, and kanamycin also will be ineffective. In fact, even when enterococci are not highly resistant to gentamicin, it is difficult to predict the ability of these other aminoglycosides to participate in synergistic killing; consequently, they should not, in general, be used to treat enterococcal endocarditis. High concentrations of ampicillin plus ceftriaxone or cefotaxime, by expanded binding of penicillin-binding proteins, also kill E. faecalis in vitro and in animal models of endocarditis.
Enterococci must be tested for high-level resistance to streptomycin and gentamicin, β-lactamase production, and susceptibility to penicillin and ampicillin (MIC, <8 μg/mL) and to vancomycin (MIC, ≤4 μg/mL) and teicoplanin (MIC ≤2 μg/ml). If the isolate produces β-lactamase, ampicillin/sulbactam or vancomycin can be used as the cell wall–active component; if the penicillin/ampicillin MIC is ≥8 μg/mL, vancomycin can be considered; and if the vancomycin MIC is ≥8 μg/mL, penicillin or ampicillin can be considered. In the absence of high-level resistance, gentamicin or streptomycin should be used as the aminoglycoside (Table 155-4). Although the dose of gentamicin used to achieve bactericidal synergy in treating enterococcal endocarditis is smaller than that used in standard therapy, nephrotoxicity (or vestibular toxicity with streptomycin) is not uncommon during treatment lasting 4–6 weeks. Regimens in which the aminoglycoside component is given for only 2–3 weeks have been curative and associated with less nephrotoxicity than those using longer courses of gentamicin. Thus regimens wherein gentamicin is administered for only 2–3 weeks are preferred by some.
If there is high-level resistance to both gentamicin and streptomycin, a synergistic bactericidal effect cannot be achieved by the addition of an aminoglycoside; thus no aminoglycoside should be given. Instead, an 8- to 12-week course of a single cell wall–active agent can be considered; for E. faecalis endocarditis, high doses of ampicillin combined with ceftriaxone or cefotaxime are suggested (Table 155-4). Nonrandomized comparative studies suggest that ampicillin-ceftriaxone may be as effective as (and less nephrotoxic than) penicillin or ampicillin plus an aminoglycoside in the treatment of E. faecalis endocarditis. Given the reduced risk of nephrotoxicity with ampicillin-ceftriaxone therapy, this regimen may also be preferred in patients who are at increased risk for aminoglycoside nephrotoxicity.
If the enterococcal isolate is resistant to all of the commonly used agents, suppression of bacteremia followed by surgical treatment should be considered. The role of newer agents potentially active against multidrug-resistant enterococci (quinupristin/dalfopristin [E. faecium only], linezolid, and daptomycin) in the treatment of endocarditis has not been established. STAPHYLOCOCCI
The regimens used to treat staphylococcal endocarditis (Table 155-4) are based not on coagulase production but rather on the presence or absence of a prosthetic valve or foreign device, the native valve(s) involved, and the susceptibility of the isolate to penicillin, methicillin, and vancomycin. All staphylococci are considered penicillin-resistant until shown not to produce penicillinase. Similarly, methicillin resistance has become so prevalent among staphylococci that empirical therapy should be initiated with a regimen that covers methicillin-resistant organisms and should later be revised if the isolate proves to be susceptible to methicillin. The addition of 3–5 days of gentamicin to a β-lactam antibiotic or vancomycin to enhance therapy for native mitral or aortic valve endocarditis has not improved survival rates and may be associated with nephrotoxicity. Neither this addition nor the addition of fusidic acid or rifampin is recommended.
For treatment of endocarditis caused by methicillin-resistant S. aureus (MRSA), vancomycin, dosed to achieve trough concentrations of 15–20 μg/mL, is recommended, with the caveat that this regimen may be associated with nephrotoxicity. Although resistance to vancomycin among staphylococci is rare, reduced vancomycin susceptibility among MRSA strains is increasingly encountered. Isolates with a vancomycin MIC of 4–16 μg/mL have intermediate susceptibility and are referred to as vancomycin-intermediate S. aureus (VISA). Isolates with an MIC of 2 μg/mL may harbor subpopulations with higher MICs. These heteroresistant VISA (hVISA) isolates are not detectable by routine susceptibility testing. Because of the pharmacokinetics/pharmacodynamics of vancomycin, killing of MRSA with a vancomycin MIC of >1.0 μg/mL is unpredictable, even with aggressive vancomycin dosing. Although not approved by the U.S. Food and Drug Administration for this indication, daptomycin (6 mg/kg [or, as some experts prefer, 8–10 mg/kg] IV once daily) has been recommended as an alternative to vancomycin, particularly for left-sided endocarditis caused by VISA, hVISA, or isolates with a vancomycin MIC of >1.0 μg/mL. These isolates should be tested to document daptomycin susceptibility. Daptomycin activity against MRSA—even against some isolates with reduced daptomycin susceptibility—is enhanced by the addition of nafcillin or ceftaroline. Case reports suggest that either the latter combinations or ceftaroline alone (600 mg IV q8h) may be effective in recalcitrant MRSA endocarditis. Nevertheless, a discussion of treatment of endocarditis in which MRSA bacteremia persists despite therapy is beyond the scope of this chapter and requires consultation with an infectious disease specialist. The efficacy of linezolid for left-sided MRSA endocarditis has not been established. Although not widely adopted by other groups, the recommendation of the British Society for Antimicrobial Chemotherapy is that a second drug be added to vancomycin (rifampin) or to daptomycin (rifampin, gentamicin, or linezolid) for the treatment of NVE due to MRSA.
Methicillin-susceptible S. aureus endocarditis that is uncomplicated and limited to the tricuspid or pulmonic valve can often be treated with a 2-week course that combines oxacillin or nafcillin (but not vancomycin) with gentamicin. However, patients with prolonged fever (≥5 days) during therapy or multiple septic pulmonary emboli should receive standard-duration therapy. Vancomycin plus gentamicin for 2 weeks as treatment for right-sided endocarditis caused by MRSA yields suboptimal results; thus this entity is treated for 4 weeks with vancomycin or daptomycin (6 mg/kg as a single daily dose).
Staphylococcal PVE is treated for 6–8 weeks with a multidrug regimen. Rifampin is an essential component because it kills staphylococci that are adherent to foreign material in a biofilm. Two other agents (selected on the basis of susceptibility testing) are combined with rifampin to prevent in vivo emergence of resistance. Because many staphylococci (particularly MRSA and Staphylococcus epidermidis) are resistant to gentamicin, the isolate’s susceptibility to gentamicin or an alternative agent should be established before rifampin treatment is begun. If the isolate is resistant to gentamicin, then another aminoglycoside, a fluoroquinolone (chosen on the basis of susceptibility), or another active agent should be substituted for gentamicin. OTHER ORGANISMS
In the absence of meningitis, endocarditis caused by Streptococcus pneumoniae isolates with a penicillin MIC of ≤1 μg/mL can be treated with IV penicillin (4 million units every 4 h), ceftriaxone (2 g/d as a single dose), or cefotaxime (at a comparable dosage). Infection caused by pneumococcal strains with a penicillin MIC of ≥2 μg/mL should be treated with vancomycin. If meningitis is suspected or present, treatment with vancomycin plus ceftriaxone—at the doses advised for meningitis—should be initiated until susceptibility results are known. Definitive therapy should then be selected on the basis of meningitis breakpoints (penicillin MIC, 0.06 μg/mL; or ceftriaxone MIC, 0.5 μg/mL). P. aeruginosa endocarditis is treated with an antipseudomonal penicillin (ticarcillin or piperacillin) and high doses of tobramycin (8 mg/kg per day in three divided doses). Endocarditis caused by Enterobacteriaceae is treated with a potent β-lactam antibiotic plus an aminoglycoside. Corynebacterial endocarditis is treated with a penicillin plus an aminoglycoside (if the organism is susceptible to the aminoglycoside) or with vancomycin, which is highly bactericidal for most strains. Therapy for Candida endocarditis consists of amphotericin B plus flucytosine and early surgery; long-term (if not indefinite) suppression with an oral azole is advised. Echinocandin treatment of Candida endocarditis has been effective in sporadic cases; nevertheless, the role of echinocandins in this setting has not been established. Empirical Therapy
In designing therapy (largely with antimicrobials and doses from Table 155-4 to target putative microorganisms) to be administered before culture results are known or when cultures are negative, clinical clues (e.g., acute vs. subacute presentation, site of infection, patient’s predispositions) as well as epidemiologic clues to etiology must be considered. Thus empirical therapy for acute endocarditis in an injection drug user should cover MRSA and gram-negative bacilli. Treatment with vancomycin plus gentamicin, initiated immediately after blood samples are obtained for culture, covers these organisms as well as many other potential causes. Similarly, treatment of health care–associated endocarditis must cover MRSA. In the treatment of culture-negative episodes, marantic endocarditis must be excluded and fastidious organisms sought by serologic testing. In the absence of prior antibiotic therapy, it is unlikely that S. aureus, CoNS, or enterococcal infection will present with negative blood cultures; thus, in this situation, recommended empirical therapy targets not these organisms but rather nutritionally variant organisms, the HACEK group, and Bartonella species. Pending the availability of diagnostic data, blood culture–negative subacute NVE is treated with gentamicin plus ampicillin-sulbactam (12 g every 24 h) or ceftriaxone; doxycycline (100 mg twice daily) is added for enhanced Bartonella coverage. For culture-negative PVE, vancomycin, gentamicin, cefepime, and rifampin should be used if the prosthetic valve has been in place for ≤1 year. Empirical therapy for infected prosthetic valves in place for >1 year is similar to that for culture-negative NVE. If cultures may be negative because of confounding by prior antibiotic administration, broader empirical therapy may be indicated, with particular attention to pathogens that are likely to be inhibited by the specific prior therapy. CIED Endocarditis
Antimicrobial therapy for CIED endocarditis is adjunctive to complete device removal. The antimicrobial selected is based on the causative organism and should be used as recommended for NVE (Table 155-4). Bacteremic CIED infection may be complicated by coincident NVE or remote-site infection (e.g., osteomyelitis). A 4- to 6-week course of endocarditis-targeted therapy is recommended for patients with CIED endocarditis and for those with bacteremia that continues during ongoing antimicrobial therapy after device removal. Although S. aureus bacteremia (and persistent CoNS bacteremia) in patients who have a CIED in place is likely—in the absence of another source—to reflect endocarditis and should be managed accordingly, not all bloodstream infections in these patients indicate endocarditis. If evidence suggesting endocarditis is lacking, bloodstream infection due to gram-negative bacilli, streptococci, enterococci, and Candida species may not indicate device infection. However, in the absence of another source, relapse after antimicrobial therapy increases the likelihood of CIED endocarditis and warrants treatment as such. Outpatient Antimicrobial Therapy
Fully compliant, clinically stable patients who are no longer bacteremic, are not febrile, and have no clinical or echocardiographic findings that suggest an impending complication may complete therapy as outpatients. Careful follow-up and a stable home setting are necessary, as are predictable IV access and use of antimicrobial agents that are stable in solution. Recommended regimens should not be compromised to accommodate outpatient therapy. Monitoring Antimicrobial Therapy
Measurement of the serum bactericidal titer—the highest dilution of the patient’s serum during therapy that kills 99.9% of the standard inoculum of the infecting organism—is not recommended for assessment of standard regimens but may be useful for assessment of the treatment of endocarditis caused by unusual organisms. Serum concentrations of aminoglycosides and vancomycin should be monitored and doses adjusted to avoid or address toxicity.
Antibiotic toxicities, including allergic reactions, occur in 25–40% of patients and commonly arise after several weeks of therapy. Blood tests to detect renal, hepatic, and hematologic toxicity should be performed periodically.
Blood cultures should be repeated daily until sterile in patients with endocarditis due to S. aureus or difficult-to-treat organisms, rechecked if there is recrudescent fever, and performed again 4–6 weeks after therapy to document cure. Blood cultures become sterile within 2 days after the start of appropriate therapy when infection is caused by viridans streptococci, enterococci, or HACEK organisms. In S. aureus endocarditis, β-lactam therapy results in sterile cultures in 3–5 days, whereas in MRSA endocarditis, positive cultures may persist for 7–9 days with vancomycin or daptomycin treatment. MRSA bacteremia persisting despite an adequate dosage of vancomycin may indicate infection due to a strain with reduced vancomycin susceptibility and therefore may point to a need for alternative therapy. When fever persists for 7 days despite appropriate antibiotic therapy, patients should be evaluated for paravalvular abscess, extracardiac abscesses (spleen, kidney), or complications (embolic events). Recrudescent fever raises the possibility of these complications but also of drug reactions or complications of hospitalization. Vegetations become smaller with effective therapy; however, 3 months after cure, 50% are unchanged and 25% are slightly larger. SURGICAL TREATMENT
Intracardiac and central nervous system complications are important causes of morbidity and death due to infective endocarditis. In some cases, effective treatment for these complications requires surgery. The indications for cardiac surgical treatment of endocarditis (Table 155-5) have been derived from observational studies and expert opinion. The strength of individual indications varies; thus the risks and benefits as well as the timing of surgery must be individualized (Table 155-6). From 25% to 40% of patients with left-sided endocarditis undergo cardiac surgery during active infection, with slightly higher surgery rates for PVE than NVE. Intracardiac complications (which are most reliably detected by TEE) and CHF are the most commonly cited indications for surgery. The benefit of surgery has been assessed primarily in studies comparing populations of medically and surgically treated patients matched for the necessity of surgery (indications assessed in studies as propensity), with adjustments for predictors of death (comorbidities) and timing of the surgical intervention. Although study results vary, surgery for currently advised indications appears to convey a significant survival benefit (27–55%) that becomes apparent only with follow-up for ≥6 months. During the initial weeks after surgery, mortality risk may appear increased (disease + surgery–related mortality). Indications CONGESTIVE HEART FAILURE
Moderate to severe refractory CHF caused by new or worsening valve dysfunction is the major indication for cardiac surgery. At 6 months of follow-up, patients with left-sided endocarditis and moderate to severe heart failure due to valve dysfunction who are treated medically have a 50% mortality rate, while among matched patients who undergo surgery the mortality rate is 15%. The survival benefit with surgery, which is most predictable among patients with the most weighty indications (propensity), is seen in both NVE and PVE. Surgery can relieve functional stenosis due to large vegetations or restore competence to damaged regurgitant valves by repair or replacement. PERIVALVULAR INFECTION
This complication, which is most common with aortic valve infection, occurs in 10–15% of native valve and 45–60% of prosthetic valve infections. It is suggested by persistent unexplained fever during appropriate therapy, new electrocardiographic conduction disturbances, or pericarditis. TEE with color Doppler is the test of choice to detect perivalvular abscesses (sensitivity, ≥85%). For optimal outcome, surgery is required, especially when fever persists, fistulae develop, prostheses are dehisced and unstable, or infection relapses after appropriate treatment. Cardiac rhythm must be monitored since high-grade heart block may require insertion of a pacemaker. UNCONTROLLED INFECTION
Continued positive blood cultures or otherwise-unexplained persistent fevers (in patients with either blood culture–positive or –negative endocarditis) despite optimal antibiotic therapy may reflect uncontrolled infection and may warrant surgery. Surgical treatment is also advised for endocarditis caused by organisms against which effective antimicrobial therapy is lacking (e.g., yeasts, fungi, P. aeruginosa, other highly resistant gram-negative bacilli, Brucella species). S. AUREUS ENDOCARDITIS
The mortality rate for S. aureus PVE exceeds 50% with medical treatment but is reduced to 25% with surgical treatment. In patients with intracardiac complications associated with S. aureus PVE, surgical treatment reduces the mortality rate twentyfold. Surgical treatment should be considered for patients with S. aureus native aortic or mitral valve infection who have TTE-demonstrable vegetations and remain septic during the initial week of therapy. Isolated tricuspid valve endocarditis, even with persistent fever, rarely requires surgery. PREVENTION OF SYSTEMIC EMBOLI
Death and persisting morbidity may result from cerebral or coronary artery emboli. Predicting a high risk of systemic embolization by echocardiographic determination of vegetation size and anatomy does not by itself identify those patients in whom surgery to prevent emboli will result in increased chances of survival. Net benefits from surgery to prevent emboli are most likely when other surgical benefits can be achieved simultaneously—e.g., repair of a moderately dysfunctional valve or debridement of a paravalvular abscess. Only 3.5% of patients undergo surgery solely to prevent systemic emboli. Valve repair, with the consequent avoidance of prosthesis insertion, improves the benefit-to-risk ratio of surgery performed to address vegetations. CIED ENDOCARDITIS
Removal of all hardware is recommended for patients with established CIED infection (pocket or intracardiac lead) or erosion of the device through the skin. Percutaneous lead extraction is preferred. With lead vegetations of >3 cm and the resulting risk of a pulmonary embolus or with retained hardware after attempted percutaneous extraction, surgical removal should be considered. Removal of the infected CIED during the initial hospitalization is associated with increased 30-day and 1-year survival rates over those attained with antibiotic therapy and device retention. If necessary, the CIED can be reimplanted percutaneously or surgically (epicardial leads) at a new site after at least 10–14 days of effective antimicrobial therapy. CIEDs should be removed and replaced subsequently when patients undergo valve surgery for endocarditis. Timing of Cardiac Surgery
With the more life-threatening indications for surgery (valve dysfunction and severe CHF, paravalvular abscess, major prosthesis dehiscence), early surgery—i.e., during the initial week of therapy—is associated with a greater chance of survival than later surgery. With less compelling indications, surgery may reasonably be delayed to allow further treatment as well as improvement in overall health (Table 155-6). After 14 days of recommended antibiotic therapy, excised valves are culture-negative in 99% and 50% of patients with streptococcal and S. aureus endocarditis, respectively. Recrudescent endocarditis on a new implanted prosthetic valve follows surgery for active NVE and PVE in 2% and 6–15% of patients, respectively. These frequencies do not justify the risk of an adverse outcome due to a delay in surgery, particularly in patients with severe heart failure, valve dysfunction, and uncontrolled staphylococcal infections. Delay is justified when infection is controlled and CHF is resolved with medical therapy.
Neurologic complications of endocarditis may be exacerbated as a consequence of cardiac surgery. The risk of neurologic deterioration is related to the type of neurologic complication and the interval between the complication and surgery. Whenever feasible, cardiac surgery should be delayed for 2–3 weeks after a nonhemorrhagic embolic infarction and for 4 weeks after a cerebral hemorrhage. A ruptured mycotic aneurysm should be treated before cardiac surgery. Antibiotic Therapy after Cardiac Surgery
Organisms have been detected on Gram’s stain—or their DNA has been detected by polymerase chain reaction—in excised valves from 45% of patients who have successfully completed the recommended therapy for endocarditis. In only 7% of these patients are the organisms, most of which are unusual and antibiotic resistant, cultured from the valve. Detection of organisms or their DNA does not necessarily indicate antibiotic failure; in fact, relapse of endocarditis after surgery is uncommon. Thus, when valve cultures are negative in uncomplicated NVE caused by susceptible organisms, the duration of preoperative plus postoperative treatment should equal the total duration of recommended therapy, with ~2 weeks of treatment administered after surgery. For endocarditis complicated by paravalvular abscess, partially treated PVE, or cases with culture-positive valves, a full course of therapy should be given postoperatively. Extracardiac Complications
Splenic abscess develops in 3–5% of patients with endocarditis. Effective therapy requires either image-guided percutaneous drainage or splenectomy. Mycotic aneurysms occur in 2–15% of endocarditis patients; one-half of these cases involve the cerebral arteries and present as headaches, focal neurologic symptoms, or hemorrhage. Cerebral aneurysms should be monitored by angiography. Some will resolve with effective antimicrobial therapy, but those that persist, enlarge, or leak should be treated surgically if possible. Extracerebral aneurysms present as local pain, a mass, local ischemia, or bleeding; these aneurysms are treated surgically.