1. 1
Infective Bacterial Endocarditis
Amy Yeh, PharmD Candidate 2015
APPE Internal Medicine I
March 19, 2015
Objectives
 Define infective bacterial endocarditis (IBE)
 Describe the significance, etiology, pathophysiology, and clinical presentation of IBE
 Explain the diagnostic parameters and prognosis of IBE
 Recommend an appropriate pharmacologic regimen for patients presenting with IBE
 Describe how IBE medications are monitored for safety and efficacy
Abbreviations
IBE infective bacterial endocarditis
Abx antibiotic
Tx treatment/treating
DDIs drug-drug interactions
ADRs adverse drug reactions
HR heart rate
IV intravenous
IM intramuscular
HACEK Haemophilus aphrophilus
Actinobacillus actinomycetemcomitans
Cardiobacterium hominis
Eikenella corrodens
Kingella kingae
TTE transthoracic echocardiography
TEE transesophageal echocardiography
MIC minimum inhibitory concentration
Strep Streptococcus
Staph Staphylococcus
Vanco vancomycin
PCN penicillin
Rxns reactions
PVE prosthetic valve endocarditis
NVE native valve endocarditis
IBW ideal body weight
ABW actual body weight
What is infective bacterial endocarditis (IBE)? How common is it? What is the prognosis?
 IBE is a bacterial infection of the inner lining of the heart (endocardium)
 Incidence
o 10,000-20,000 infections per year
o More common in men than women
 3-9 times as many cases
 Prognosis
o Fatal if not treated promptly and correctly
o In-hospital mortality rate 18-23%

2. 2
o 6 month mortality rate of 22-27%
o S. aureus IBE + neurologic complications  74% mortality rate
Risk factors
o Age > 60
o Male sex
o IV drug use
o Poor dental hygiene/dental infection
o Comorbidities
 Structural heart disease
 Prosthetic heart valves
 Implanted medical devices
 Long-standing IV catheter
 History of IBE
 Chronic hemodialysis
 HIV infection
Etiology/Pathophysiology
 Typical causes of IBE
o Staphylococcus aureus (31%)
 Risk of IBE especially high
 Evaluate all patients with bacteremia for IBE
o Viridans streptococci (17%)
o Enterococci (11%)
o Streptococcus bovis (7%)
o HACEK group (2%)
 Haemophilus aphrophilus
 Actinobacillus actinomycetemcomitans
 Cardiobacterium hominis
 Eikenella corrodens
 Kingella kingae
 Bacteria enters bloodstream from cuts/abrasions  attaches to damaged areas of heart  proliferates inside
vegetations
o Preexisting clot on heart facilitates the binding
o Structural heart defect must be present in order for infection to occur
o Sources of bacteria
 Skin
 GI tract
 Lining of mouth
 What is a vegetation?
o An avascular aggregate of fibrin, platelets, leukocytes, RBC fragments, and bacteria
o Often develops in low-pressure areas (away from turbulent flow)
 Vegetation formation
o Endocardial injury  attachment of platelets and fibrin  secondary infection from pathogens  microbial
proliferation activates clotting pathway  more fibronectin is deposited
 Vegetations shield bacteria from immune system  difficult to eradicate infection
 Treatment may or may not eradicate vegetations
o May take years to clear the debris
o Detection of non-viable organisms is not indicative of tx failure

3. 3
Complications
o Cardiac (up to 50% of patients)
 Heart failure
 Vascular damage valvular insufficiency
 The most common cause of IBE-related death
 Warrants cardiac surgery
 Perivalvular abscess (30-40% of patients)
 Involvement of conduction system  heart block
 Mycocardial infarction
 Caused by embolized fragments of vegetations
o Metastatic infection
 Septic embolization (13-44% of patients)
 Occlusion/damage of vessels  complications
o Stroke
o Paralysis
o Blindness
o Pulmonary embolism
o Metastatic abscess
 Mycotic aneurysm
 High risk of rupture and hemorrhage  High mortality rate
o Neurologic
 Outcomes are variable for those with neurologic complications
 May be the presenting symptom in IBE
 Consider IBE for stroke, meningitis, brain abscess patients
 Acute encephalopathy
 Meningitis
 Cerebral hemorrhage
 Seizures
o Renal failure
o Musculoskeletal
 Osteomyelitis
 Septic arthritis
 Acute involvement of joints  suspect IBE
o Complications from tx
 Drug-induced
 Ototoxicity or nephrotoxicity
 C. difficile infection
 Allergic rxns
 IV-associated thrombosis or infection
Clinical Presentation
 Flu-like symptoms
o Fever
o Chills
o Fatigue
o Myalgia
o Night sweats
o Headache
 Dyspnea or persistent cough
 New heart murmur or changes in existing heart murmur
 Skin, fingernail, or eye changes

4. 4
o Nonspecific
 Petechiae: spots of broken blood vessels under the skin
 Splinter hemorrhages under the nail
o Specific
 Janeway lesions: nonpainful, erythematous lesions on palms and soles
 Osler’s nodes: painful pustular nodules on fingers and toes
 Roth spots: hemorrhagic lesions on retina
 Unexplained weight loss
Diagnosis
 Obtain 3 sets of blood cultures before initiating abx therapy
 From different venipuncture sites
 Minimum of 10 mL  higher detection rate of bacteremia
 Echocardiography
 Allows detection and visualization of vegetations/abnormalities
 TTE for patients with suspected IBE
 Positive if vegetation present
 Indications for TEE
 Further evaluation after positive TTE
 Determine if surgery is required
o Significant valvular regurgitation
 Risk factors for perivalvular abscess
 Prosthetic valves
 Valvular abnormality or history of IBE infection
 Obscured visibility
 obesity
 mechanical ventilation
 Modified Duke Criteria for diagnosis
 Positive blood cultures for suspicious organisms + evidence of endocardial infection
 Definite IBE
 2 major criteria
 1 major and 2 minor criteria
 5 minor criteria
 Major criteria
 Positive blood culture for typical IBE pathogens
 Positive echocardiogram
 New valvular regurgitation
 Minor criteria
 Predisposing heart condition or IV drug use
 Fever
 Vascular phenomena
 Immunologic phenomena
 Evidence of active infection with IBE pathogen
 Differential diagnosis
 Bacteremia without endocardial involvement
 Skin and soft tissue infection
 Cardiac device infection
 Prosthetic joint infection
 Intravascular catheter infection
 Osteomyelitis
 Meningitis

5. 5
 Pneumonia
 Cardiac vegetation without positive blood culture
 Culture-negative endocarditis
 Marantic endocarditis
 Lupus
 Antiphospholipid syndrome
Goals of therapy
 Eradicate infection
 Minimize morbidity and mortality
 Prevent future recurrence of IBE
General principles of treatment for native valve IBE (NVE)
 Empiric therapy
 For acutely ill patients with signs/symptoms of IBE
 Non-acute  wait for results
 Obtain at least 2 sets of blood cultures before abx therapy
 Cover Staph, Strep, and Enterococci
 Vanco 15-20 mg/kg IV every 8-12 hours (max 2 g/dose)
 Target pathogen found in blood culture
 Repeat blood culture 48-72 hours later to assess response
 Patient should become afebrile 3-5 days after initiation of appropriate abx
 Tx for 4-6 weeks, depending on location and complexity of infection
 Once hemodynamically stable, continue IV therapy in outpatient setting
*Dosing information provided in this handout*
 *IV administration, unless otherwise stated
 IV/IM are acceptable for ceftriaxone and gentamicin
 *Adult dosing with normal renal function
Native Valve IBE: Viridans streptococci and Streptococcus bovis
 Most are PCN-susceptible (MIC ≤ 0.12)
o High cure rate
 PCN-susceptible (MIC ≤ 0.12)
o 4 weeks (elderly, renal/otic impairment)
 Aqueous PCN G (continuously or 4-6 times daily)
 Ceftriaxone IV/IM daily
 Vanco bid
 Only if allergic to PCN and ceftriaxone
 Target trough 15-20
 Max 2 g/24 hrs
o 2 weeks (no complications + CrCl ≥ 20 + no otic disease)
 Aqueous PCN G (continuously or 4-6 times daily) + Gentamicin (daily, bid, or tid)
 Ceftriaxone daily + Gentamicin (daily, bid, or tid)
 Gentamicin monitoring (once weekly)
 Renal function
 Gentamicin serum concentrations
o 2-3 daily doses (hospitalized patients)
 Peak 3-4 mcg/mL (1 hr post-dose)

6. 6
 Trough < 1 mcg/mL
o 1 daily dose (outpatients)
 Peak 10-12 mcg/mL
 Trough < 1 mcg/mL
 PCN-Intermediate susceptibility (MIC > 0.12 and ≤ 0.5)
o Higher dose of PCN G
 24 million units daily
o Same monitoring parameters for gentamicin and vanco
o Options
 Aqueous PCN G (4 weeks) + gentamicin (first 2 weeks)
 Ceftriaxone daily (4 weeks)+ gentamicin (first 2 weeks)
 Vanco bid (4 weeks)
 Max 2 g/24 hrs
 Only if allergic to PCN and ceftriaxone
 Target trough 15-20
 PCN-Resistant (MIC > 0.5)
o Follow enterococcal regimen
Native Valve IBE: Enterococci
 Resistant to low concentrations of PCN
o Give PCN, ampicillin, or vanco with gentamicin
 Most cases caused by E. faecalis
 Susceptible to PCN, gentamicin, and vanco
o Gentamicin tid for 4-6 weeks
 Monitoring (once weekly)
 Peak 3-4 mcg/mL
 Trough < 1 mcg/mL
 Renal function
o PLUS one of the following
 Aqueous PCN G (continuously or 6 times daily) for 4-6 weeks
 Ampicillin 6 times daily for 4-6 weeks
 Higher risk of allergic rxns than PCN
 Vanco bid for 6 weeks
 Max 2 g/dose
 For PCN and cephalosporin allergy
 Trough 15-20 mcg/mL
o Duration
 4 wks if symptoms present ≤ 3 months
 6 wks
 Symptoms present > 3 months
 Vanco tx option
o less activity against Enterococci than PCN
 Relapsed infection
 Prosthetic valve infection
 PCN-resistant (MIC > 16), susceptible to aminoglycosides and vanco
o Beta-lactamase producing
 Gentamicin tid for 6 wks
 Same monitoring as above
 PLUS one of the following
 Ampicillin-sulbactam 4 times daily for 6 wks
o If gentamicin resistance, more than 6 wks of tx will be required

7. 7
 Vanco bid for 6 wks
o If PCN resistance or allergy
o Trough 15-20 mcg/mL
o Intrinsic PCN resistance
 Consult with infectious disease specialist
 Vanco bid + gentamicin tid for 6 wks
 Resistant to PCN, aminoglycosides, and vanco
o Surgical resection may be required for refractory cases
 Cure rate < 50%
o E. faecium
 Widespread vanco resistance, but rare cause of IBE
 Tx recommendations based on case reports
 Linezolid IV/PO bid for at least 8 wks
 Monitor hematology
o After 2 wks of tx, severe thrombocytopenia may occur
 Quinupristin-dalfopristin tid for at least 8 wks
 Effective against E. faecium only
 Severe myalgia may warrant d/c of tx
o E. faecalis
 Imipenem-cilastatin qid + Ampicillin 6 times daily for at least 8 wks
 Ceftriaxone bid + Ampicillin 6 times daily for at least 8 wks
 Bid dosing of ceftriaxone is more effective than once daily dosing
Native valve IBE: Staphylococcus aureus
 Variable success rate
o Most strains are PCN-resistant
o Test to verify MIC and absence of beta-lactamase activity
 PCN-sensitive (MIC ≤ 0.1) + no beta-lactamase activity
 Aqueous PCN G (4-6 times daily) x 6 wks
 May add gentamicin IV/IM (2-3 times daily) for 3-5 days
 Clinical benefit is undetermined
 May result in more renal toxicity
 Oxacillin-sensitive [methicillin-susceptible]
o Nafcillin or oxacillin 4-6 times daily x 6 wks
 Flucloxacillin q4-6h is an alternative
 May add gentamicin IV/IM (2-3 times daily) for 3-5 days
 Clinical benefit is undetermined
 May result in more renal toxicity
o Cefazolin tid x 6 wks
 For moderately PCN allergic patients
 If severe allergy, use vanco bid x 6 wks
 May add gentamicin IV/IM (2-3 times daily) for 3-5 days
 Clinical benefit is undetermined
 May result in more renal toxicity
 Oxacillin-resistant or severe PCN allergy
o Vanco bid x 6 wks
 Max 2 g/24 hrs
 Target trough 15-20 mcg/mL

8. 8
Native Valve IBE: HACEK organisms
 A group of gram-negative bacilli
o Fastidious delayed growth  7 days to incubate in traditional blood culture (5 days in automated culture
systems)
o Ampicillin-resistant due to beta-lactamase production
 Highly sensitive to third and fourth generation cephalosporins
 Ceftriaxone 2 g IV/IM daily x 4 wks
o Cefotaxime, ceftazidime, ceftizoxome, cefepime may be substituted
 Ampicillin-sulbactam 3 g qid x 4 wks
o Beta-lactamase inhibitor required for efficacy
 For PCN allergy/intolerance
o Ciprofloxacin 1000 mg PO daily x 4 wks
o Ciprofloxacin 400 mg IV bid x 4 wks
General principles of tx for prosthetic valve endocarditis (PVE)
 Tx of PVE is more difficult than that of native valve endocarditis
o Many cases refractory to abx monotherapy
o Invasive infections/complications are common
o Surgery may be required
 Obtain 3 sets of blood cultures before initiating abx tx
o Hemodynamic instability or critically ill  empiric tx
 Vanco + gentamicin + (cefepime or carbapenem)
 Adjust tx depending on culture results
o Not acute  wait for results to return
 Minimum tx duration of 6 wks
o Begin tx in hospital that offers cardiac surgery
o Hospitalize patients until afebrile and need for surgery is ruled out
o Complete tx as outpatient
 Use native valve IBE abx regimens for PVE
o Exception for Staphylococcus-induced PVE
Tx of Staphylococcus-induced PVE
 Immediate surgery often required
 Triple drug regimen
o 6 times more effective than monotherapy
o In NVE, one drug is sufficient
 Clinical benefit of gentamicin is undetermined
o Still recommended for optimal efficacy
o If resistance to gentamicin
 Use an alternative aminoglycoside for 2 wks
o If resistance to aminoglycosides
 Use a fluoroquinolone for 6 wks
o If resistance to aminoglycosides and fluoroquinolones
 Linezolid x 2 wks
 Ceftaroline x 2 wks
 Trimethoprim-sulfamethoxazole x 2 wks
 Gentamicin monitoring
o Dose using IBW
o Monitor renal function weekly
o Monitor serum level weekly
 Trough < 1 mcg/mL

9. 9
 Peak 3-4 mcg/mL
 Rifampin is effective against Staph growing on foreign material
o Essential for PVE tx
o Must use with other drugs to minimize resistance
 High mutation rate
 Assess susceptibility to rifampin if tx failure occurs
o CYP3A4 inducer
 DDIs: increases clearance of warfarin and other drugs
 If refractory to vanco
o Test isolate for vanco and daptomycin resistance
o Alternatives to vanco
 High dose daptomycin
 Telavancin
 Ceftaroline
 Linezolid
 Oxacillin-sensitive
o (Nafcillin or oxacillin 6 times daily + rifampin tid for 6 wks) + gentamicin IV/IM 2-3 times daily (2 wks)
 If PCN-sensitive (MIC ≤ 0.1) and no beta-lactamase
 PCN G (2-6 times daily) may be used instead of nafcillin or oxacillin
o (Cefazolin tid + rifampin IV/PO tid for 6 wks) + gentamicin IV/IM 2-3 times daily (2 wks)
 Cefazolin for moderate PCN allergy
o (Vanco bid + rifampin IV/PO tid for 6 wks) + gentamicin IV/IM 2-3 times daily (2 wks)
 Vanco for severe PCN allergy
 Dosing based on ABW
 May need to be given tid
 Target trough 15-20 mcg/mL
 Oxacillin-resistant
o (Vanco bid + rifampin IV/PO tid for 6 wks) + gentamicin IV/IM 2-3 times daily (2 wks)
Follow-Up/Patient Education
o At completion of tx
 Perform TTE to establish new baseline
 Refer drug users to rehab facility
 Patient Education
 Signs/symptoms of IBE relapse
 Proper dental hygiene
 Avoidance of IV drug use, body piercing, and tattoos
o Short-term/long-term follow-up
 If relapse, get 3 sets of blood cultures before initiation of tx
 Perform Echo to evaluate cardiac function
 Evaluate for toxicity from abx therapy
 Ototoxicity
 Renotoxicity
 Colitis due to C. difficile
 Maintain oral hygiene and professional dental cleanings

10. 10
References
 UpToDate website. Accessed March 16, 2015 at http://www.uptodate.com.proxy.pba.edu/contents/search.
 Lexi-Comp website. Accessed March 16, 2015 at http://online.lexi.com.proxy.pba.edu/.
 Cabell CH, Abrutyn E, Karchmer AW. Bacterial endocarditis: The disease, treatment, and prevention.
Circulation. 2003;107:e185-187.
 Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and
management of complications: a statement for healthcare professionals from the Committee on Rheumatic
Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils
on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association.
Circulation. 2005;111:e394-433.