Continuing Education Activity

Infective endocarditis is an uncommon infection with a high mortality rate. It requires prompt identification and carefully selected antibiotic therapy. This activity outlines the general antibiotic principles associated with treating infective endocarditis and highlights the importance of the interprofessional team in caring for patients with this condition.

Objectives:

• Identify treatment considerations for patients with infective endocarditis.
• Review the classic presentation of infective endocarditis.
• Describe the etiology of infective endocarditis.
• Outline important interprofessional management considerations for infective endocarditis treatment.

Introduction

Endocarditis is an uncommon infection occurring in every 3 to 7 per 100000 person-years, yet it is also the fourth most common life-threatening infection after sepsis, pneumonia and intraabdominal abscess with an estimated inpatient mortality rate between 15 to 30%. When endocarditis was first widely studied in the 1960s, streptococcus viridian was the most commonly identified pathogen. However, the epidemiology has shifted with Staphylococcus aureus being the most frequently identified pathogen. While this shift is partially attributable to an increased rate of intravenous drug abuse in North America, the healthcare-associated infection has become increasingly common representing about 30% of all endocarditis cases.

The management of endocarditis requires an interprofessional approach by infectious disease, cardiology, and cardiac surgery to manage antimicrobial therapy and assess for possible surgical intervention.[1] Early consultation with cardiothoracic surgery has been shown to improve mortality and is mandatory in patients presenting with complications. Approximately 50% of patients with endocarditis will require some form of surgical intervention.[2] As per the American Heart Association recommendation, a consult with an infectious disease expert should take place before initiating empiric antibiotic therapy due to the many nuances associated with treating endocarditis. Vegetations contain a densely packed bacteria interlocked within a biofilm composed of fibrin and platelets which creates a mechanical barrier limiting antibiotic penetration. Each antibiotic class has differing pharmacological properties which influence the rate of diffusion, distribution, and ability of the antibiotic to penetrate the vegetation which ultimately determines the bactericidal efficacy. The duration of therapy for the successful eradication of bacteria has its basis in the bactericidal action of the specific antibiotic, minimal inhibitory concentration, pathogen, vegetation burden and area of involvement. The duration of treatment can range from 2 to 6 weeks.

The American Heart Association 2015 Adult Infective Endocarditis guidelines and European Society of Cardiologist 2015 management of infective endocarditis guidelines serve as the basis for the following recommendation.[2][3] The treatment of endocarditis should be pathogen-directed and directed by blood cultures and antibiotic sensitivities. Therefore it is imperative to obtain at least two separate blood cultures (preferably three) from two different venous sites for targeted antibiotic therapy before the administration of antibiotics. Blood cultures ideally should be repeated every 24 to 48hrs until they are negative. Patients should undergo assessment for clinical response to antibiotics. Most patients become afebrile within 3 to 5 days of appropriate antibiotics.

In patients who present with an indolent, uncomplicated course antibiotic therapy can be delayed until cultures and sensitivities are available. However, in patients with a more acute presentation or features of complicated endocarditis, prompt empiric treatment is often required to reduce the risk of complications. The recommendation is for an Infectious disease consultation when selecting empiric antibiotic therapy as a variety of factors influence the choice of empiric antibiotics including patients characteristics and risk factors, epidemiological factors, recent administration of antibiotics, whether the infection was healthcare-associated and severity of presentation.

Issues of Concern

The presence of a bioprosthetic valve or implantable cardiac device plays a significant influence on antibiotic selection duration of treatment as it portends a more severe infection with higher rates of treatment failure then native valve endocarditis. They also have a higher mortality rate, increased complications rate, and a higher rate of treatment failure then patients with native valve endocarditis even if infection occurs with the same pathogen. Additionally, patients with a prosthetic valve or implantable cardiac device are at higher risk for developing endocarditis. Empiric antibiotic therapy for prosthetic valve and health-care associated endocarditis should be broader and cover MRSA, enterococci, and gram-negative pathogens. Empiric antibiotics should consist of combination bactericidal treatment with vancomycin, gentamicin and either cefepime or another antipseudomonal carbapenem (imipenem, meropenem or doripenem). If the patient is found to have Staphylococcus and a prosthetic valve combination antibiotic therapy with rifampin is the recommended therapy. Rifampin has been shown to sterilize and should be started three to five days after blood cultures become negative.

Prosthetic valve endocarditis is more challenging to treat with higher rates of antibiotic failure and increased risk of complications. These patients should receive an early evaluation with a cardiothoracic surgeon as surgery has been shown to improve mortality.[4] Prosthetic valve endocarditis can be subdivided based on the time interval since valve replacement.

• Early prosthetic valve endocarditis (PVE) occurs within 60 days of valves replacement. It is typically iatrogenic and caused by S. aureus or coagulase-negative Staph
• Intermediate PVE occurs between 60 to 365 days of valve replacement and most commonly is the result of Streptococcus or staph infection
• Late endocarditis occurs one year or longer after valve replacement. It typically results from organisms similar to those found in native valve endocarditis

Clinical Significance

The diagnosis of infective endocarditis is contingent upon positive blood cultures. Persistent bacteremia is typical of this infection. However, 5 to 10% of infections are found to be culture negative. Several factors can influence this including prior administration of antibiotics before culture, fastidious or hard to cultures infectious organisms such as HACEK organisms or fungal infection, or poor microbiologic technique upon collection and cultures. Administration of antibiotics before culture reduces the ability to accurately culture bacteria by 35 to 40%. Selection of antibiotic therapy in culture-negative patients is very challenging. Withdrawal of antibiotics and repeating blood cultures until an organism is isolated can be a consideration. Serology for a fastidious organism such as Coxiella, Bartonella, Brucella, Mycoplasma or Aspergillus can also be an option.

Prognosis of endocarditis depends upon infecting organism, the presence of complications, echo findings, and patient characteristics such as age or comorbidities. Acute heart failure, staph aureus infection and periannular complications convey the highest risk of death, and early urgent surgical consultation is strongly recommended.

Other Issues

Empiric antimicrobial therapy in native valve endocarditis targets the three most common pathogens: staphylococcus, streptococcus or enterococci.[5] Critically ill patients may require more intensive antibiotic therapy such as ampicillin with gentamicin and flucloxacillin or oxacillin can be used empirically in severely ill patients with native valve endocarditis or late PVE.[6] Antibiotic therapy should undergo adjustment as gram stain, culture and susceptibilities become available. Native valve endocarditis treatment typically requires 2 to 6 weeks of antibiotics.

• Initial antibiotic therapy for critically ill patients before cultures and sensitivities[3]:
  • Ampicillin + gentamicin + flucloxacillin or oxacillin
  • Vancomycin + gentamicin (if PCN allergic)
  • Vancomycin + gentamicin + rifampin if early prosthetic valve endocarditis (under one year) or healthcare-associated endocarditis

For patients with gram-positive cocci in clusters found on gram stain, monotherapy with empiric vancomycin every 8 to 12 hours dosed to maintain a concentration of 15 to 20 mg/kg is appropriate. When cultures and sensitivities are available antibiotics coverage should be narrowed. If the patient is found to have methicillin sensitive endocarditis, then nafcillin or oxacillin dosed up to 12g per day divided dosed every four to six hours. Vancomycin has less effective bactericidal action than penicillin or beta-lactamase based therapies. As such it should be limited to patients with severe reactions to PCN or beta-lactamase or patients with MRSA. In patients who have methicillin-resistant staph aureus, monotherapy with vancomycin 30mg/kg or daptomycin 6 to 10mg/kg is the treatment of choice. Historically, combination therapy using a beta-lactam with an aminoglycoside was formerly the treatment of choice. However, aminoglycosides in combination with vancomycin have increased the risk of nephrotoxicity and ototoxicity while providing minimal to no survival benefit. As such the American Heart Association now discourage concomitant aminoglycoside use with vancomycin for use in MRSA.

• MSSA
  • Native 
    • Four to six weeks of oxacillin 
    • Four to six weeks of cefazolin or cefotaxime is the recommendation for patients with non-anaphylactic PCN allergies
  • PVE
    • Six weeks of oxacillin + 6 weeks of rifampin + 2 weeks gentamicin
    • Six weeks of cefazolin or cefotaxime + 6 weeks of rifampin + 2 weeks gentamicin if PCN anaphylaxis
    • Six weeks of vancomycin + 6 weeks of rifampin + 2 weeks gentamicin if PCN anaphylaxis
• MRSA or PCN/beta-lactam anaphylaxis
  • Four to six weeks of vancomycin or daptomycin

For patients found to have streptococcus, determination of penicillin susceptibility is an important consideration. PCN susceptibility in Streptococcus is defined as (MIC less than or equal to 0.125 mg/L) and is associated with cure rates exceeding 95%. Patients with uncomplicated NVE and normal renal function can have a two-week course of Gentamicin and penicillin G or ceftriaxone. Ceftriaxone and gentamicin are both dosed once daily, so this therapy is ideal for outpatient antibiotic therapy. Intermediate PCN susceptibility defined as (MIC  0.25 – 2 mg/L) requires at least a four-week course of antibiotics with at least two weeks of gentamicin.

• PCN sensitive Streptococcus (MIC less than or equal to 0.125 mg/L)
  • Native Valve Endocarditis
    • Two weeks of penicillin G or ceftriaxone and gentamicin (only for non-complicated NVE and normal renal function)
    • Four weeks of penicillin G or ceftriaxone or amoxicillin (ESC only)
    • Four weeks of vancomycin if PCN allergic and unable to sensitize
  • Prosthetic Valve Endocarditis
    • Six weeks of penicillin G or ceftriaxone or amoxicillin for PVE
    • Six weeks of vancomycin (if PCN allergic and unable to sensitize)
• PCN resistant Streptococcus (MIC  0.25 – 2 mg/L) 
  • Native Valve Endocarditis
    • Four weeks of penicillin G or ceftriaxone + 2 weeks of gentamicin
    • Four weeks of vancomycin +/- gentamicin (ESC) if PCN allergic
  • PVE
    • Six weeks of penicillin G or ceftriaxone + 2 weeks of Gentamicin
    • Six weeks of vancomycin + 2 weeks of gentamicin (ESC) if PCN allergic

Enterococcus infective endocarditis typically results from Enterococcus faecalis (95%) or Enterococcus faecium (3%). Enterococci is difficult to treat as they have several defense mechanisms which allow the development of resistance to a wide range of antibiotics such as aminoglycosides, beta-lactams, and vancomycin. One important factor to consider when treating enterococci is aminoglycoside resistance. High-level aminoglycoside resistance (HLAR) has a MIC greater than 500 mg/L, and aminoglycoside therapy is inappropriate. Successful eradication requires combination synergistic bacteriocidal therapy for at least 4 to 6 weeks. Combination therapy frequently consists of either two cell wall inhibitors or an aminoglycoside with a cell wall inhibitor. The treatment of choice for susceptible enterococcus infection is ceftriaxone and ampicillin for both HLAR and non-HLAR enterococci.

• Enterococcus
  • Six weeks of ampicillin + ceftriaxone (for both HLAR and nonHLAR)
  • Four to six weeks of amoxicillin + gentamicin (not for HLAR)
  • Six weeks of vancomycin + gentamicin (if PCN allergic)

Enhancing Healthcare Team Outcomes

Selection of appropriate antibiotic regiments requires an interprofessional team approach involving physicians and nurses (in particular those with specialized infectious disease backgrounds), pharmacists, and primary care physicians. Further, consultation and coordination with an infectious disease specialist are usually necessary. [Level 5] Empirical antibiotic therapy is recommended if the suspicion of endocarditis is high; once culture results are obtained, the antibiotic selection can target the sensitivity of the organism.

In general, the nurse practitioner or physicians assistant will manage the empirical antibiotic selection and should coordinate with the physician in regards to antibiotic prophylaxis coverage. The pharmacist will review the selection, allergies, and indications to determine appropriate coverage. If there is a concern, the pharmacist should report back to the clinical team a need for an alternative selection. The medical team will need to monitor the patient for signs of endocarditis development and report back to the team leader as issues develop.

Management of antibiotic regimens for infective endocarditis is best achieved with an interprofessional team involving physicians, infectious disease experts, specialty-trained nursing staff, and pharmacists all collaborating to manage the cases to an optimal patient outcome. [7], [8] [Level 5]