Infective Endocarditis: Epidemiology, Diagnosis and Management Holger P. Salazar, MD, FACC Stern Cardiovascular Foundation No financial relation to disclose

Epidemiology of Infective Endocarditis

Epidemiology of Infective Endocarditis Annual incidence in USA 10,000-20,000 new cases, stable over past 30 years Prosthetic valve endocarditis accounts for 15% of cases Mortality is about 20%, due to CHF, valvular dysfunction, or uncontrolled infection 50% over the age of 50

Valvular Involvement in Infective Endocarditis Valve Percent of Cases Mitral 28-45% Aortic 5-36% Aortic + Mitral 0-35% Tricuspid 5% Combined right and left 0-4%

Most Common Underlying Cardiac Lesions In Infective Endocarditis Mitral valve prolapse Degenerative valvular lesions Calcified mitral annulus Valve nodules Bicuspid Aortic Valve Prosthetic Valve

Risk of Infective Endocarditis for Selected Groups Risk Factor Incidence* Injection Drug Use 150-2000 Rheumatic heart disease 440 Bioprosthesis 383 Prior endocarditis 340-740 Mechanical prosthesis 308 VSD (Medical therapy) 220 *Cases per 105 patient-years

Classification of Infective Endocarditis

Infective Endocarditis: Classification Native Valve (75-90% of cases) Acute -- ˃ 1 to 2 weeks Subacute-- >2 week Prosthetic Valve (10-25% of cases) Early Onset-- ˃ 12 months Late Onset-- > 12 months

Two Flavors of Infective Endocarditis: Native and Prosthetic Valves

Clinical Manifestations of Endocarditis

Infective Endocarditis: Symptoms (%) Fever 80 Chills 40 Weakness 40 Dyspnea 40 Sweats 25 Weight loss 25 Malaise 25 Stroke 20 Skin lesions 20 Headache 20 Achiness 20 Chest pain 15 Altered mental status 10-15 Back pain 10

Native Valve Endocarditis: Signs (%) Fever 90 Murmur 85 New 3-5 Changing 5-10 Emboli 50+ Splenomegaly 20-57 Metastatic 20 infection Retinal lesions 20 Skin manifestations 18-50 Petechiae 20-40 Splinters 15 Osler’s nodes 10-23 Janeway lesions <10

Cutaneous Findings of Endocarditis Janeway lesions are nontender macular lesions most commonly involving the palms and soles and are caused by septic emboli Osler’s nodes are small raised, swollen, painful erythematous lesions the size of a pea, on pads of fingers or toes Splinter hemorrhages

Roth’s Spots and Endocarditis Round or oval retinal hemorrhages with white spots seen in the retina early in the course of IE, caused by complex mediated vasculitis

Microbiology of Endocarditis

Microbiology of Native Valve Endocarditis Organism Percent of Cases Viridans streptococci 30-40% Other streptococci 15-25% Staphylococcus aureus 10-27% Enterococcus species 5-18% Gram negative bacilli 2-13%

Microbiology of Prosthetic-Valve Endocarditis Organism Percentage of Cases Early Onset Late Onset (> 12 m) Coagulase negative staph 30-35% 15% Staphylococcus aureus 17-23% 20% Gram negative bacilli 10% 5% Streptococci 5-10% 33% Fungi 10% 2%

Causes of Culture-Negative Endocarditis Coxiella burnetti (Q fever) Bartonella species (cat scratch disease) HACEK organisms* Legionella species Aspergillus species Lactobacillus species * Haemophilus species; Actinobacillus actinomycetemcomitans; Cardiobacteriumhominis; Eikenella corrodens; and Kingella kingae

Echocardiography and Diagnosis of Endocarditis

Transthoracic Echocardiography and Endocarditis No technological advance has had as much impact on approach to patients with IE Rapid, non-invasive and specific for vegetations (98%) May be inadequate in 20% of patients because of obesity, COPD, or chest-wall deformities TTE should be used in the evaluation of those with suspected native valve IE who are good candidates for imaging

Transesophageal Echocardiography and Endocarditis More costly and invasive but increases the sensitivty (from 75% to 95%) while maintaining specificity (85-98%) More sensitive for defining perivalvular extension, perforation of valves, and myocardial abscess A negative TEE has a negative predictive value for IE of > 92%

TTE or TEE or Both? Recent guidelines suggest that among patients with suspected endocarditis appropriate use of echocardiography depends on prior probability of IE If this probability is < 4% , a negative TTE is cost effective and satisfactory in ruling out IE If this probability is 4 to 60%, initial use of TEE is more cost effective and efficient than initial TTE followed by TEE (if former negative) Mylonakis & Calderwood NEJM 2001;345:1318

Limitations of Echocardiography in the Diagnosis of Endocarditis Falsely negative early in disease False positive diagnosis with thickened valve leaflets, valve nodules or tumors Inability to distinguish healed from active vegetations Lower sensitivity in those with mechanical prostheses Blood cultures remain the test of choice for patients with suspected endocarditis

Duke Criteria for Diagnosis of Endocarditis

Duke Criteria for Diagnosis of Infective Endocarditis: Major Criteria Positive blood culture for typical organism (from 2 separate cultures or Staphylococcus aureus or enterococcal bacteremia without a primary focus) or Persistent bacteremia for any organism > 12 hrs apart or All of 3 or majority of 4 BC positive drawn > 1 hr apart Echocardiographic criteria - Oscillating mass, abscess or new dehiscence of prosthesis - New valvular regurgitation

Duke Criteria for Diagnosis of Infective Endocarditis: Minor Criteria Predisposing heart condition or injection drug use Fever greater than or equal to 38o C Immunologic phenomena: GN, Osler’s nodes, Roth Spots, RF Echo consistent, but not meeting major criteria Vascular phenomena: arterial embolism, septic PE, mycotic aneurysm, intracranial hemorrhage, Janeway lesions Microbiologic evidence: positive BC not meeting major criteria or serology indicating active infection with consistent organism

Duke Criteria for Diagnosis of Infective Endocarditis Definite endocarditis: Pathologic criteria Organisms by culture or histology in vegetation, embolus, or cardiac abscess or Pathologic lesion such as vegetation or cardiac abscess Clinical criteria 2 major, or 1 major plus 3 minor, or 5 minor criteria

Right Sided Endocarditis in Injection Drug Users

Right-sided Endocarditis in Injection Drug Users 46 y/o man injection drug user (heroin) with fevers, sweats and right sided pleuritic chest pain. Blood cultures grew penicillin- susceptible S. aureus and echocardiogram showed 1 mm Tricuspid valve vegetation. HIV negative and in hospital for 7 days with oxacillin and gentamicin followed by 21 days of outpatient ceftriaxone (2 gms/ day). Multiple peripheral septic emboli with cavitation

Right-Sided Endocarditis in Injection Drug Users Common complication with overall favorable prognosis Vegetations > 2 cm associated with higher mortality (33% vs 1.3%) S. aureus most common pathogen (>80%) than Viridans streptococci >50% with septic emboli on chest radiographs Hecht SR and Berger M Ann Int Med 1992;117:560

Right Sided Endocarditis in Injection Drug Users: Treatment Two week regimen (nafcillin or oxacillin + gentamicin) for susceptible isolates Oral therapies still controversial Exclusion to “short-course” protocol: Extracardiac complications of IE Fever for > 7 days HIV infection Vegetation > 1-2 cm Chambers HF Ann Intern Med 1988;109:619

AHA Guidelines for Treatment of Endocarditis

Aortic Versus Mitral Valve Endocarditis Overall incidence Surgical Patients Aortic ~55% ~75% Mitral ~85% ~40% Pulmonary ~1% Tricuspid ~20% Acute aortic regurgitation is poorly tolerated because the LV is less compliant than the LA resulting higher LV wall stress! Watch out for abrupt deterioration!

AHA Guidelines for Antibiotic Therapy in Native Valve Endocarditis Organism Regimen Weeks PCN-sensitive PCN G 12-18 MI qd or 4 Ceftriaxone 2 g qd or 4 Ceftriaxone 2 g qd + 2 Gentamicin 3 mg/kg qd or Vancomycin 1 g bid 4 PCN-insensitive PCN G 18 MI qd + 4 Gentamicin 1 mg/kg tid 2 or Vancomycin 1 g bid 4 Doses assume normal renal function

AHA Guidelines for Antibiotic Therapy in Native Valve Endocarditis Organism Regimen Weeks MSSA Oxacillin or Nafcillin 2 g q4h 4-6 or Cefazolin 2 g tid 4-6 both +/- Gentamicin 1 mg/kg tid 3-5d or Vancomycin 1 g bid +/- Gent MRSA Vancomycin 1 g bid 4-6 +/- Gentamicin 1 mg/kg tid 4-6 Doses assume normal renal function

AHA Guidelines for Antibiotic Therapy in Native Valve Endocarditis Organism Regimen Weeks Enterococci (VSE) PCN + Gentamicin or 6 Vancomycin + Gentamicin 6 as above HACEK Ceftriaxone 2 g qd or 4 Ampicillin 2 g q4h + 4 Gentamicin 1 mg/kg tid 4 Doses assume normal renal function

AHA Guidelines for Antibiotic Therapy in Prosthetic Valve Endocarditis Organism Regimen Weeks MSSA or MSSE Oxacillin or Nafcillin 2 g q4h 6+ + Gentamicin 1 mg/kg tid 2 + Rifampin 300 mg tid 6+ MRSA or MRSE Vancomycin 1 g bid 6+ + Gentamicin 1 mg/kg tid 2 + Rifampin 300 mg tid 6+ Doses assume normal renal function

Steel: Often the Best Antimicrobial Agent In Treating Infective Endocarditis

Medical versus Surgical therapy Surgery is always in addition to medical therapy The vast majority of the operated patients would die if not operated Some medically treated patients are “inoperable”

Surgical Indications in Endocarditis Refractory CHF > 1 serious embolic event Uncontrolled infection Physiologically significant valve dysfunction by echo Fungal endocarditis Ineffective antimicrobial therapy Mycotic aneurysm Most cases of PVE due to antibiotic resistant pathogens Local cardiac suppurative complications

Echocardiographic Features Predicting Need for Surgery in Endocarditis Persistent vegetations after a major embolus Large (> 1 cm) mitral valve vegetation Increasing vegetation size after 4 weeks of antimicrobial therapy Acute mitral insufficiency Valve perforation or rupture Periannular extension of infection AHA Committee on Endocarditis

Homograft or Prosthetic Valve Replacement for Aortic Valve IE There are no and probably will be no randomized studies! Good results are possible to obtain with either However, an increasing number of publications favor homografts Technically easier and safer Lower risk of heart block Lower infection and re-infection rate Homograft does not require anticoagulation Limited supply of homografts Limited durability of homograft

Timing of Surgery 30% require surgery in the acute phase another 20-40% will require surgery later Main principle: Don’t postpone an indicated operation, however: Pts with strokes: Postpone surgery, if possible 1-3 weeks, particularly if evidence of hemorrhage If valve repair is planned: 1 week of preop antibiotic treatment Re-infection rate is lower after surgery for healed endocarditis

Early Surgery Versus Conventional Treatment for IE Kaplan–Meier Curves for Cumulative Probabilities of Death and Composite End Point at 6 Months Figure 2. Kaplan–Meier Curves for the Cumulative Probabilities of Death and of the Composite End Point at 6 Months, According to Treatment Group. There was no significant between-group difference in all-cause mortality at 6 months (Panel A). The rate of the composite end point of death from any cause, embolic events, recurrence of infective endocarditis, or repeat hospitalization due to the development of congestive heart failure was 3% in the early-surgery group versus 28% in the conventional-treatment group (hazard ratio, 0.08; 95% CI, 0.01 to 0.65; P=0.02) (Panel B). Kang DH, et al: NEJM 2012; 366:2466

Early Surgery Versus Conventional Treatment for IE Clinical End Points Early Surgery Versus Conventional Treatment for Infective Endocarditis Kang D et al. N Engl J Med 2012;366:2466-2473. Kang DH, et al: NEJM 2012; 366:2466

Special Surgical Considerations Related to Location Aortic valve IE: Be aggressive! Acute aortic regurgitation is poorly tolerated Mitral valve IE: Repair whenever possible, consider risk of embolism Right-sided IE: Be conservative! Repair, excision, (replacement) Pulmonary valve IE is very uncommon

Aortic Root Endocarditis With Vegetation and Fistula to Right Atrium

The infection penetrates through to the floor of the Right atrium just about to destroy the A-V node

Ventricular Assist Device Associated Endocarditis

LVAD and Endocarditis

Endocarditis and Ventricular Assist Devices Patients with VADs are at high risk for nosocomial bloodstream infections Incidence of VAD associated IE may be as high as 13% (relapsing bacteremia/fungemia common) At least 24 cases in literature (33% Candida 20% Enterococcus) with 50% associated mortality Difficult to visualize inflow and outflow conduits by echocardiography Treatment: tranplantation! Device exchange high rate of failure/death Gordon and McCarthy in Advanced Therapy Cardiac Surgery 2002

Pacemaker Associated Endocarditis

Pacemaker-Associated Endocarditis >2 million people (including 1 million Americans) use pacemakers Infections uncommon but difficult to eradicate without device removal (generator + leads via laser extraction if possible) Pacemaker endocarditis can be difficult diagnosis to make on clinical grounds TEE sensitive in finding suspicious lesions on pacemaker Chua J et al Ann Int Med 2000;133:644

Pacemaker-Associated Endocarditis

Prophylaxis to Prevent Endocarditis

Endocarditis Prophylaxis Class I: No class I indications. Class IIa: Reasonable for pts at highest risk for adverse outcomes from IE having dental procedures that involve manipulation of either gingival tissue or the periapical region of the teeth or perforation of the oral mucosa - Pts with prosthetic cardiac valves or prosthetic material used for valve repair - Pts with previous IE - Pts with CHD: unrepaired cianotic CHD including paliative shunts and conduits ACC/AHA 2008 Guideline Update on Valvular Heart Disease: JACC 2008; 676

Endocarditis Prophylaxis Class IIa (cont): - Complete repaired CHD fixed with prosthetic material or device, whether placed surgically or by catheter intervention, during first 6 months after procedure - Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or device - Cardiac transplant pts with valve regurgitation due to structurally abnormal valve Class III: Prophylaxis not recommended against nondental procedures: TEE, EGD or colonoscopy ACC/AHA 2008 Guideline Update on Valvular Heart Disease: JACC 2008; 676

Endocarditis Prophylaxis Prophylaxis accepted in high risk pts: - Incision of the respiratory tract mucosa, such as tonsillectomy and adenoidectomy - Infections of the GI or GU tract - Pts undergoing elective cistoscopy or other urinary tract manipulation who have enterococcal UTI ACC/AHA 2008 Guideline Update on Valvular Heart Disease: JACC 2008; 676

Procedures Not Requiring Prophylaxis in At Risk Patients Dental restoration Adjustment of braces Flexible bronchoscopy GI endoscopy C-section deliveries Cardiac catheterization Urethral catheterization (sterile urine)

ACC/AHA Guidelines for Prevention of Bacterial Endocarditis Oral: Amoxicillin 2g 30-60 min before oral procedure Unable to take PO: Ampicillin 2g IM or IV, or cefazolin or ceftriaxome IV 1g IM or IV 30-60 min before procedure Allergic to PCN – oral: clindamycin 600mg, azithromycin or clarithromycin 500mg 30-60 min before procedure Allergic to PCN and unable to take PO: clindamycin 600mg IM or IV or cefazolin or ceftriaxone 1g IM or IV (do not use if anaphylaxis, angioedema, urticaria with PCN ACC/AHA 2008 Guideline Update on Valvular Heart Disease: JACC 2008; 676