Treatment of Infectious Endocarditis

US Pharm. 2007;32(5):HS-32-HS-43.

Infectious endocarditis (IE) is a relatively uncommon infection that was first described in 1885 by William Osler.¹ Although IE is somewhat rare, the condition continues to have a mortality rate of approximately 40%.^2,3 Depending on the severity and rapidity of onset of symptoms, IE can be classified as acute or subacute.⁴ The typical presentation of IE comprises fever, weight loss, and fatigue; almost all patients present with a heart murmur.

According to the Duke criteria, a diagnostic tool for IE, certain symptoms and laboratory and echocardiographic findings can be categorized as major or minor criteria. ^5-7 Major criteria include a positive result from two separate blood cultures as well as the presence of a vegetation, visualized via transesophageal echocardiogram or transthoracic echocardiogram. Minor criteria include a predisposing heart condition, fever, vascular and immunologic findings (e.g., Janeway's lesions or Osler's nodes and Roth spots, respectively), and a positive blood culture that does not meet the major criteria. Janeway's lesions are reddened lesions on the palms and soles of the feet, whereas Osler's nodes are nodules on the surface of the fingertips and toes.⁴ Roth spots are an ophthalmologic phenomenon involving retinal hemorrhages.⁸

The diagnosis of IE can be categorized as definite, possible, or rejected, depending on the presence of major or minor criteria. A diagnosis of definite IE requires either pathologic evidence of a vegetation or a combination of two major criteria, one major and three minor criteria, or five minor criteria. Possible IE requires either two criteria (one major and one minor) or three minor criteria. IE can be rejected for any of the following reasons: an alternative diagnosis is determined; there is no pathologic support for the findings of IE; the patient defervesces with antibiotic treatment in less than four days with resolution of the manifestations of IE; or the patient does not meet any Duke criteria.^5-7,9

The pathogenesis of IE involves clot formation, as a result of blood and "subendothelial" particles, on one of the heart valves followed by binding of pathogens from bacteremia to the clot. An immunologic response is then initiated involving cytokines and white blood cells that results in the formation of a vegetation.^10,11 Usually, patients who develop IE have underlying risk factors, such as the presence of a prosthetic heart valve, rheumatic heart disease, mitral valve prolapse, hemodialysis, diabetes, HIV, inadequate dental care, and intravenous drug abuse.^4,12-21

The most common bacterial pathogens implicated in IE are Streptococcus and Staphylococcus species, accounting for up to 80% to 90% of cases, while Enterococcus species are the third most common bacterial etiology. ^22-26 Other causative organisms are the HACEK organisms (Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, and Kingella denitrificans), Enterobacteriaceae, Pseudomonas species, Neisseria gonorrhoeae, and fungi.⁷ Although blood cultures are usually positive, culture-negative IE can occur in up to 20% of patients.²⁷

Pharmacologic Treatment of Common Organisms
Initiating the appropriate treatment in patients is critical because of the high mortality rate associated with IE. This article focuses on the treatment of IE according to the American Heart Association (AHA) guidelines for the most common organisms: viridans group streptococci, the Staphylococcus species, and the Enterococcus species.⁷ In addition, daptomycin, a new treatment option for staphylococcal IE, is reviewed.

The treatment of IE is highly dependent on whether the patient has a native or prosthetic valve. Not only is the treatment slightly different, but the duration of treatment is often longer for patients with a prosthetic valve.⁷

Viridans Group Streptococci: The viridans group streptococci are also known as alpha-hemolytic streptococci and are common causes of IE in patients with native valves.⁷ Common inhabitants of the oral cavity, these gram-positive organisms can become pathogenic causes of IE in patients who require dental and/or gingival treatment and have a history of IE or in those who have had cardiac valve surgery.^2,28 In the viridans group streptococci, bacteria frequently associated with IE include Streptococcus anguis, Streptococcus oralis (mitis), Streptococcus salivarius, Streptococcus mutans, and Gemella morbillorum (formerly Streptococcus morbillorum). In addition, Streptococcus bovis, a group D streptococcus, is another common pathogen of IE.

The treatment of IE caused by these organisms involves classifying the bacteria as highly penicillin-susceptible (minimum inhibitory concentration [MIC] £0.12 mcg/mL) or relatively/fully penicillin-resistant (MIC >0.12 mcg/mL). In both native- and prosthetic-valve IE, penicillin and ceftriaxone are considered the drugs of choice, and gentamicin may be added for synergy. The duration of treatment depends on whether the valve is native or prosthetic. If gentamicin is used, it is important to achieve peak and trough serum concentrations of 3 to 4 mcg/mL and less than 1 mcg/mL, respectively.⁷ Vancomycin can be considered in patients unable to take a beta-lactam antibiotic. It should be noted that target peak and trough concentrations for vancomycin are 30 to 45 mcg/mL and 10 to 15 mcg/mL, respectively.⁷ For IE patients with a native valve, the duration of treatment is two to four weeks depending on the drug regimen and MIC of the organism. However, six weeks of treatment is required for prosthetic valve disease. Table 1 describes the appropriate dosages and duration of therapy according to the type of valve involved.

Staphylococcus Species: Recently, staphylococcal infections in general have increased significantly in both the inpatient and the outpatient settings.^29-31 Common causative staphylococcal organisms of IE include Staphylococcus aureus (coagulase-positive) and Staphylococcus epidermidis (coagulase-negative), correlating most commonly to native-valve and prosthetic-valve IE, respectively.⁷ The treatment of staphylococcal IE involves determining whether the pathogen is oxacillin-susceptible or oxacillin-resistant. If susceptible, nafcillin or oxacillin are the preferred agents, with the addition of gentamicin or rifampin depending on the presence of a prosthetic valve. For native-valve patients who have a "nonanaphylactoid" penicillin allergy, cefazolin with or without gentamicin may be considered. For native-valve patients with oxacillin-resistant strains, vancomycin is considered first-line therapy; however, the addition of rifampin and gentamicin to the vancomycin regimen is recommended for patients with a prosthetic valve. A minimum of six weeks of therapy is required, although as with viridans streptococci, the exact duration of treatment is determined based on the type of valve involved. In addition, target vancomycin and gentamicin peak and trough concentrations are identical to viridans streptococci treatment.⁷ Further details of treatment are described in Table 2.

Daptomycin: Daptomycin (Cubicin), a cyclic lipopeptide with concentration-dependent bactericidal activity against S aureusand other gram-positive organisms, including vancomycin-resistant Enterococcus (VRE) and methicillin-resistant S aureus (MRSA), was recently approved by the FDA for the treatment of bacteremia and right-sided endocarditis caused by S aureus (both methicillin-susceptible S aureus [MSSA] and MRSA). ^32-35 Based on a randomized, controlled, multinational, open-label study, daptomycin was considered noninferior to standard therapy with comparable success rates. In this clinical study, daptomycin (6 mg/kg every 24 hours) was compared to standard treatment, which consisted of either an antistaphylococcal penicillin (nafcillin, oxacillin, or flucloxacillin 2 g every four hours) or vancomycin (1 g every 12 hours) (based on susceptibility testing) plus gentamicin (1 mg/kg every eight hours) in the treatment of S aureus bacteremia and endocarditis.³⁴ Of the 236 patients randomized, 181 were diagnosed as having definite or possible IE at baseline. Of these patients, only 53 were determined to have staphylococcal IE; 35 patients had right-sided IE, and 18 patients had left-sided IE. The overall incidence of MRSA was 38%. The primary outcome of the study was the clinical success rate six weeks after the last treatment dose. For patients with uncomplicated right-sided IE (n = 10), success occurred in 50% (three of six patients) versus 25% (one of four patients) of patients receiving daptomycin and standard therapy, respectively (absolute difference, 25%; 95% confidence interval [CI], –33.3 to 83.3). Patients with complicated right-sided IE (n = 25) had a 38.5% response in the daptomycin arm versus a 50% response in the standard therapy arm (absolute difference, –11.5%; 95% CI, –50.3 to 27.2). Success rates for patients with left-sided IE were 11.1% (one of nine patients) for daptomycin versus 22.2% (two of nine patients) in patients receiving standard therapy (absolute difference, –11.1%; 95% CI, –45.2 to 22.9) and was lower in comparison to right-sided IE patients. Treatment failure (combined data of patients with IE or bacteremia) due to relapsing or persisting S aureus infections was 15.8% and 9.6%, respectively for daptomycin and the standard therapy arm (P = .17). Six out of the 19 patients in the daptomycin failure group (32%) had isolates that developed resistance to the drug while on therapy (MIC ?2 mcg/mL). Overall survival rates were similar between the groups (10.8% mortality rate with daptomycin compared with 11.3% mortality rate for those receiving standard therapy). The incidence of adverse effects was also comparable between the groups, 35% (daptomycin) versus 42.2% (standard therapy) (P = .29), with the most common events in both groups being gastrointestinal complaints and anemia. Creatine kinase (CK) elevations were more common in the daptomycin group (6.7% vs. 0.9%; P = .04); however, only three patients had to discontinue therapy as a result. Therefore, based on the results of this study, daptomycin may be considered an option--although probably not first-line--for patients with right-sided IE caused by S aureus (MRSA or MSSA).³⁴

Dosing recommendations for daptomycin for the treatment of IE/bacteremia is 6 mg/kg every 24 hours, with dosing adjustments necessary in patients with a creatinine clearance of less than 30 mL/minute (estimated by the Cockcroft-Gault equation) and those who are dependent on dialysis (6 mg/kg every 48 hours).^34,35 Clinicians should be aware of the need to monitor patients for the development of muscle pain or weakness, especially in patients who have renal insufficiency or who are taking concomitant statin therapy. Temporarily discontinuing statin therapy should be considered if deemed necessary in some patients. Additionally, creatine phosphokinase should be monitored weekly while on therapy and possibly more often in patient populations at an increased risk for rhabdomyolysis.^32,35 Furthermore, patients who do not seem to respond to daptomycin should have their treatment evaluated due to the potential emergence of resistance to the antimicrobial. At this time, there are limited data for the use of daptomycin in patients with prosthetic-valve endocarditis (not included in the study) and left-sided IE (small number of patients in the study). Further investigation is needed in those patient populations before routine use of daptomycin can be recommended.^34,35

Enterococcus Species : Enterococcus, a gram-positive organism, is considered to be part of the normal flora of the gastrointestinal tract and sometimes the anterior urethra.²⁴ IE associated with the Enterococcus species often occurs in patients with a history of genitourinary or obstetrical procedures.²⁶ There are over 15 different species of Enterococcus, of which Enterococcus faeciumand Enterococcus faecalis are most commonly associated with IE.^2,7,24,26 Of the two species, E faecium is often more resistant in comparison to E faecalis, but it causes IE less frequently. ²⁴ Enterococcal IE is associated with high relapse rates, and, therefore, susceptibility testing (MIC determination) to ampicillin/penicillin, vancomycin, and aminoglycosides (specifically, gentamicin or streptomycin) should be performed.^7,26,36

In contrast to the Staphylococcus and Streptococcus species, the drug therapy for enterococcal IE is the same regardless of the presence or absence of a prosthetic valve. Treatment often involves the use of a cell-wall active drug such as a beta-lactam (ampicillin or penicillin) or vancomycin in combination with an aminoglycoside (gentamicin or streptomycin) for synergy. Synergy is needed with an aminoglycoside in order to achieve a bactericidal effect because most cell-wall active drugs are only considered bacteriostatic against enterococci.^2,7,26,37 Of the two aminoglycosides used to treat enterococcal endocarditis, gentamicin is primarily used unless resistance is present.⁷ Other aminoglycosides such as tobramycin and amikacin are not used in enterococcal infections due to the presence of intrinsic resistance.⁷ Aminoglycoside dosing should be based on the patient's renal function. Gentamicin levels should target peaks of 3 to 4 mcg/mL and troughs of less than 1 mcg/mL. Streptomycin dosing should target peaks of 20 to 35 mcg/mL and trough concentrations of 10 mcg/mL.⁷ Currently, once-daily or consolidated aminoglycoside dosing is not recommended in the treatment of enterococcal IE due to the lack of clinical evidence. ^7,26 In terms of duration of treatment, patients with a prosthetic valve who are receiving vancomycin-aminoglycoside combination therapy (less active in comparison to ampicillin/penicillin combinations with aminoglycoside) and those who have had symptoms for longer than three months should be treated for a minimum of six weeks. Similarly, patients with VRE not susceptible to ampicillin should be treated for at least eight weeks.⁷

The treatment of enterococcal IE depends on susceptibilities to ampicillin (or penicillin), gentamicin (or streptomycin), and vancomycin (see Table 3). For patients with enterococcal IE that is susceptible to ampicillin/penicillin, gentamicin, and vancomycin, recommended treatment is with ampicillin or penicillin G plus gentamicin for four to six weeks. Vancomycin (goal peak 30 to 45 mcg/mL and trough 10 to 15 mcg/mL) should be used only in patients with allergies to beta-lactam therapy or in those patients with enterococcal infection that is penicillin-resistant (MIC >16 mcg/mL); however, treatment must be for six weeks in these cases. If the Enterococcus species is resistant to gentamicin but susceptible to streptomycin, then streptomycin can be used in place of gentamicin. Beta-lactamase–producing strains of the Enterococcus species can be treated with ampicillin-sulbactam (or vancomycin) plus gentamicin for six weeks. Conversely, strains resistant to gentamicin will require more than six weeks of therapy.⁷

For patients with enterococcal strains that are multidrug resistant, including reduced susceptibility to penicillins, aminoglycosides, and vancomycin therapy, drug options should be guided based on the specific species of Enterococcus; in addition, the treatment duration is usually eight to 12 weeks.⁷ These types of organisms are often challenging to treat due to their resistance against multiple antibiotics. VRE can be occasionally sensitive to ampicillin, and in these cases it is recommended to use ampicillin/penicillin (in combination with an aminoglycoside if sensitive). Newer antienterococcal agents such as quinupristin-dalfopristin, which is effective only against E faecium, and linezolid, which is effective against both E faecium and E faecalis, can be used to treat VRE that is not susceptible to ampicillin/penicillin. However, neither agent is likely to be curative in nature due to bacteriostatic effects.⁷ Although daptomycin may have a role in VRE endocarditis, further investigation for this use is needed. ^32,38 For VRE strains that are E faecium and not susceptible to ampicillin, linezolid or quinupristin-dalfopristin may be considered for treatment. VRE strains that are E faecalis and not susceptible to ampicillin can be treated with double-beta lactam combinations of imipenem-cilastin plus ampicillin or ceftriaxone plus ampicillin due to the presence of synergistic bactericidal activity between these agents. ^7,26,39,40

Role of the Pharmacist

The treatment of IE involves prompt and appropriate pharmacologic therapy, although surgery may be required. Pharmacists have a vital role in preventing certain adverse effects of medications, as well as in ensuring optimal therapeutic efficacy. When using penicillin, the time-dependent killing nature of the antibiotic can be maximized by continuous infusions or by ensuring that the doses are given every four to six hours. In addition, monitoring of vancomycin and aminoglycoside concentrations can help avoid the side effects of nephrotoxicity and ototoxicity and ensure the efficacy of these drugs. With daptomycin, careful monitoring of CK serum concentrations and screening for concurrent statin use are also required to prevent cases of rhabdomyolysis. Regarding the use of rifampin, pharmacists should counsel patients on potential drug interactions.

Summary

IE continues to be a life-threatening infection that often requires a prolonged duration of antibiotic therapy and sometimes surgery in order to be treated appropriately. The most common organisms causing IE are Streptococcus, Staphylococcus, and Enterococcus species. The infecting organism, susceptibility patterns, and AHA guideline recommendations should be considered to guide antibiotic therapy as well as the duration of treatment. Newer treatment options for drug-resistant organisms such as MRSA and VRE need to be added to the repertoire of drugs that are currently available for the treatment of IE. However, further research on these agents is needed to establish their safety and efficacy for use in this setting.

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