2015 AHA Guidelines For the Management of Infective Endocarditis: An Update Albina Ongari, PharmD PGY-1 Pharmacy Resident Kennedy University Hospitals April 26th, 2016

Disclosure Statement I have no conflicts of interest to disclose Anthony Fryckberg, PharmD, BCPS, BCCCP(Mentor)

Objectives Pharmacist Technicians Describe recent changes to the guidelines for the treatment of infective endocarditis Identify patients who require antimicrobial prophylaxis for infective endocarditis and recommend an appropriate antibiotic regimen Technicians Identify the signs and symptoms of infective endocarditis Recognize the treatment regimens involved in the treatment of infective endocarditis

Infective Endocarditis (IE) Infection of the endocardial surface of the heart (endocardium) Includes one or more heart valves, mural endocardium, or septal defects Associated with underlying cardiac defects Valvular abnormalities Heart failure and myocardial abscesses Fatal if left untreated Baddour LM, et al. Circulation 2015; 32:1-40. Cahill TJ. Lancet 2016; 387:882-93.

Pathophysiology

Pathophysiology 1 2 3 4 Endothelial surface of heart is damaged Turbulent blood flow associated with valvular damage 2 Platelet and fibrin adhere to damaged epithelial surface 3 Bacteria most commonly introduced hematogenously (bacteremia) Attach to platelet and fibrin 4 A “vegetation” of platelets, fibrin, and bacteria forms; platelets and fibrin protect bacteria from antibiotics and immune system and allow for unimpeded growth On prosthetic valves, gram-positive organisms (specifically Staphylococccus species) create biofilm; further protects bacteria Cahill TJ. Lancet 2016; 387:882-93.

Epidemiology Incidence is rare High mortality and morbidity 3 to 7 per 100,000 people per year High mortality and morbidity 20% mortality rate 3rd most common life threatening infection More commonly in males 25-30 % of IE cases are caused by health care-acquired organisms Baddour LM, et al. Circulation 2015; 32:1-40. Cahill TJ. Lancet 2016; 387:882-93.

Risk Factors Degenerative valve disease (volvulopathy) Rheumatic heart disease (low income countries) Intravenous drug use Congenital heart disease Prosthetic heart valves Dental procedures and poor dentation Ages >60 Presence of intravascular device Diabetes Long term hemodialysis Cahill TJ. Lancet 2016; 387:882-93.

Complications Heart failure Septic emboli Abscess formation Stroke Conduction complications Heart block Circulating immune complexes Brain, kidneys, spleen, skin lesions Cahill TJ. Lancet 2016; 387:882-93.

Microbiology Microorganism Prevalence (%) Staphylococcus Staphylococcus aureus: 26.6% Coagulase-negative staphylococci: 9.7% Streptococci and enterococci Oral streptococci: 18.7% Non-oral streptococci: 17.5% Enterococci: 10.5% Other: 1.6% HACEK (haemophilus, aggregatibacter, cardiobacterium, Eikenella corrodens, kingella) species 1to 2% Candida species Other 6% Polymicrobial (≥2 microorganisms) 1.8% No microorganism identified 5.2% Baddour LM, et al. Circulation 2015; 32:1-40. Cahill TJ. Lancet 2016; 387:882-93.

Microbiology Staphylococcal IE Coagulase-negative staphylococci Both prosthetic and native valves Coagulase-negative staphylococci Indwelling lines and devices Prosthetic valves High rates of abscess formation and antimicrobial resistance Streptococcal IE Viridans group- oral, gastrointestinal, urogenital tract Enterococcal IE Elderly and chronic condition Both native and prosthetic valves Fungal endocarditis Candida and Aspergillus- rare but fatal Cahill TJ. Lancet 2016; 387:882-93.

Clinical Manifestations Signs Symptoms Heart murmur (85% cases) Tricuspid, mitral or aortic regurgitation Skin lesions (rare) Osler nodes Janeway lesions Roth spots Splinter hemorrhages Petechiae Splenomegaly WBC normal or slightly elevated Persistent bacteremia (98%) Vegetation on valve on echocardiography Anemia, thrombocytopenia Fever (90% cases) Chills Weakness Dyspnea Night sweats Weight loss Malaise Baddour LM, et al. Circulation 2015; 32:1-40. Cahill TJ. Lancet 2016; 387:882-93.

Assessment Question #1 Which of the following are risk factors for infective endocarditis? Mitral valve regurgitation Intravenous drug user Poor dentation Diabetes All of the above For technician??? Answer E. all of the above

Assessment Question #1 Which of the following are risk factors for infective endocarditis? Mitral valve regurgitation Intravenous drug user Poor dentation Diabetes All of the above

Diagnosis Modified Duke Criteria Tool utilized for diagnosis of IE Major and Minor criteria Now lets talk about diagnosis, Has anyone here heard about duke criteria? So this is a tool that we utilize to dx IE but before we talk in detail about that lest first review the major and minor components of duke criteria

Major Clinical Criteria Blood cultures positive for IE Typical microorganisms consistent with IE from two separate blood cultures Single positive blood culture for Coxiella burnetii, or phase 1 IgG antibody titre >1:800 Evidence of endocardial involvement with echocardiography positive for IE Presence of a vegetation, abscess, or new partial dehiscence of prosthetic valve New valvular regurgitation Baddour LM, et al. Circulation 2015; 32:1-40. San Roman AJ, et al. Rev Esp Cardiol 2016; 69(1):7-10.

Minor Clinical Criteria 1. Predisposition Predisposing heart condition, intravenous drug use 2. Fever Temperature >38°C 3. Vascular phenomena Major arterial emboli, septic, pulmonary infarcts, mycotic aneurysm, intracranial, janeway lesions 4. Immunological phenomena Osler’s nodes, Roth spots, rheumatoid factor 5. Microbiological evidence not meeting major criteria Baddour LM, et al. Circulation 2015; 32:1-40. San Roman AJ, et al. Rev Esp Cardiol 2016; 69(1):7-10.

Diagnosis Modified Duke Criteria Diagnosis of IE is definite in the presence of One pathological criterion OR Two major criteria OR One major criteria and three minor criteria OR Five minor criteria Baddour LM, et al. Circulation 2015; 32:1-40.

Imaging Studies Transthoracic echocardiogram (TTE) Easier to perform Less sensitive Transesophageal echocardiogram (TEE) More sensitive Invasive procedure TTE is recommended for all patient TEE is recommended for high risk patients Prosthetic valve, congenital heart disease, previous IE, new murmur Negative echo does not rule out IE Baddour LM, et al. Circulation 2015; 32:1-40. San Roman AJ, et al. Rev Esp Cardiol 2016; 69(1):7-10.

Echocardiography Baddour LM, et al. Circulation 2015; 32:1-40.

Echocardiography -for high risk patient such initial TTE, followed by TEE. Again everyone intially gets TTE bc non-invasive Baddour LM, et al. Circulation 2015; 32:1-40.

Blood Cultures Positive blood culture is the cornerstone of microbiological diagnosis Cultures should be drawn before administration of antibiotics Is this always achievable? At least 2 sets of blood cultures obtained from different sites Every 24 to 48 hours until blood stream infection is cleared First and last drawn at least 1 hour apart Just read this Baddour LM, et al. Circulation 2015; 32:1-40.

Treatment of Infective Endocarditis

Background Last AHA guidelines for diagnosis and management of IE were published 2005 August 2015, European Society of Cardiology (ESC) published guidelines for management of IE October 2015, AHA released the new guidelines for diagnosis and management of IE Lets focus on the updates!

Antimicrobial Therapy Goals of therapy Eradicate infection (bacteremia), including sterilization of the vegetation Prolonged, parenteral, bactericidal therapy is required for treatment and cure of IE Antimicrobial properties Bactericidal drugs Penetrate the cardiac vegetation Break down the layers of fibrin of the biofilm Addition of aminoglycosides and B-lactams Combination of two bacteriostatic drugs for synergy Baddour LM, et al. Circulation 2015; 32:1-40. Thanavaro KL. Heart & Lung 2014; 43:334-337.

Approach to Regimen Selection Organism and susceptibility (MIC) Type of Valve (Prosthetic vs. native ) Allergies Here are some of the elements we want to consider before choosing therapy… 1. Organisms and suceptibility Baddour LM, et al. Circulation 2015; 32:1-40. Thanavaro KL. Heart & Lung 2014; 43:334-337.

Approach to Regimen Selection Additional consideration Patient specific characteristics Previous antimicrobial therapy Microbiological findings Local antimicrobial resistance rates Baddour LM, et al. Circulation 2015; 32:1-40. Thanavaro KL. Heart & Lung 2014; 43:334-337.

Native valve, penicillin (PNC) susceptible strep bovis and viridans Streptococcus IE Native valve, penicillin (PNC) susceptible strep bovis and viridans MIC ≤0.12mg/ml Duration of therapy Penicillin G 12-18 million units/day (in 4 or 6 divided doses) OR Ceftriaxone 2 g/day IV 4 weeks PCN G or ceftriaxone PLUS Gentamicin 3 mg/kg IV q24h or 1 mg/kg IV q8h 2 weeks Vancomycin Beta-lactam allergic patients (IgE- mediated) NO CHANGES !!! Vancomycin 30 mg/kg per 24 hr in 2 equally divided doses or vancomycin 15-20 mg/kg IV q8-12h (per renal function) Baddour LM, et al. Circulation 2015; 32:1-40.

Streptococcus IE NO CHANGES !!! Native valve, Strep viridans/bovis PCN MIC >0.25; <0.5 (Relatively PCN resistant) Duration of therapy PCN G 24 million units/day (in 4 or 6 divided doses) IV (PCN G 4 million units IV q4h) OR Ceftriaxone 2 g IV/IM q24h (PCN rash) PLUS Gentamicin 3 mg/kg q 24 hrs 4 weeks 2 weeks Vancomycin for Beta-lactam allergic patients (IgE-mediated) NO CHANGES !!! Baddour LM, et al. Circulation 2015; 32:1-40.

Streptococcus IE NO CHANGES !!! Prosthetic valve, penicillin (PNC) susceptible strep bovis and viridans MIC ≤0.12mg/ml Duration of Therapy PCN G 24 million units/day (in 4 or 6 divided doses) IV PCN G 4 million units IV q4h OR Ceftriaxone 2 g IV/IM q24h With or without Gentamicin 3 mg/kg IV q24h or 1 mg/kg IV q8h 6 weeks 2 weeks Vancomycin Beta-lactam allergic patients (IgE-mediated) NO CHANGES !!! Baddour LM, et al. Circulation 2015; 32:1-40.

Prosthetic valve, penicillin (PNC) reristant strep bovis and viridans Streptococcus IE Prosthetic valve, penicillin (PNC) reristant strep bovis and viridans MIC > 0.12mg/ml Duration of Therapy PCN G 24 million units/day (in 4 or 6 divided doses) IV PCN G 4 million units IV q4h OR Ceftriaxone 2 g IV/IM q24h PLUS Gentamicin 3 mg/kg IV q24h or 1 mg/kg IV q8h 6 weeks Vancomycin (Beta-lactam allergic patients (IgE-mediated)) NO CHANGES !!! Baddour LM, et al. Circulation 2015; 32:1-40.

Staphylococcus IE UPDATE Native valve, S. aureus (MSSA) Duration of Therapy Nafcillin 2 g IV q4h (if no PCN allergy) 12g/24hrs OR Cefazolin 2 g IV q8h (if PCN-allergic, non-IgE mediated) 6g/24 6 weeks Vancomycin 15-20 mg/kg IV q8-12h (per renal function) Beta-lactam allergic patients (IgE-mediated) Gentamicin is no longer recommended UPDATE Baddour LM, et al. Circulation 2015; 32:1-40.

Staphylococcus IE UPDATE UPDATE Native valve, S. aureus (MRSA) Duration of therapy Vancomycin 15-20 mg/kg IV q8-12h (per renal function) Round to nearest 250 mg increment Generally capped at 2 g/dose ≥ 6 weeks Daptomycin ≥ 8mg/kg/dose No gentamicin or rifampin recommended UPDATE UPDATE Baddour LM, et al. Circulation 2015; 32:1-40.

Staphylococcus IE NO CHANGES !!! Prosthetic valve, S. aureus (MSSA) Duration of Therapy Nafcillin 2 g IV q4h (if no PCN allergy) /Oxacillin OR Cefazolin 2 g IV q8h (if PCN-allergic, non-IgE mediated) PLUS Rifampin 300 mg IV/PO q8h Gentamicin 1 mg/kg IV q8h ≥ 6 weeks 2 weeks Vancomycin 15-20 mg/kg IV q8-12h (per renal function) Beta-lactam allergic patients (IgE-mediated) Gentamicin 1mg/kg q 8 hr NO CHANGES !!! Baddour LM, et al. Circulation 2015; 32:1-40.

Staphylococcus IE NO CHANGES !!! Prosthetic valve, S. aureus (MRSA) Duration of Therapy Vancomycin 15-20 mg/kg IV q8-12h (per renal function) PLUS Rifampin 300 mg IV/PO q8h Gentamicin 1 mg/kg IV q8h ≥ 6 weeks 2 weeks NO CHANGES !!! Baddour LM, et al. Circulation 2015; 32:1-40.

Staphylococcus IE UPDATE In concurrent brain abscess and MSSA IE, nafcillin should be used over cefazolin (Level of Evidence C) Vancomycin should be used in patients with nafcillin intolerance Baddour LM, et al. Circulation 2015; 32:1-40.

Assessment Question #2 Which of the following is an appropriate therapy option for patients with prosthetic valves and S. aureus (MSSA)IE? Patient does not have any drug allergies. Cefazolin Nafcillin plus rifampin plus gentamicin Vancomycin Daptomycin Lets do another question… B. Both nafcillin and Cefazolin needs to be given with rifampin and gent

Assessment Question #2 Which of the following is an appropriate therapy option for patients with prosthetic valves and S. aureus (MSSA)IE? Patient does not have any drug allergies. Cefazolin Nafcillin plus rifampin plus gentamicin Vancomycin Daptomycin HINT: its prosthetic valve therefore we need to do triple coverage, dapto is not first line and we need to give it with gent; gent needs to be given with gen

Enterococcus IE UPDATE Enterococcus susceptible to amp/gent/vanco, prosthetic or native valve Duration of Therapy Ampicillin 2 g IV q4h OR PNC G 18-30 U/24 hrs in dived PLUS Gentamicin 1 mg/kg (IBW) IV q8h Both total of 4 to 6 weeks Native valve: 4 weeks for with symptoms ≤ 3 months; 6 weeks for symptoms > 3 months Prosthetic valve: At least 6 weeks Double B-lactam Ampicillin 2g IV q4 hr Ceftriaxone 2g IV q12 hr 6 weeks For CrCl< 50 ml/min UPDATE Baddour LM, et al. Circulation 2015; 32:1-40.

Enterococcus IE UPDATE UPDATE Enterococcus susceptible to PNC and resistant to aminoglycosides or streptomycin susceptible and gent resistant, native or prosthetic valve Duration of Therapy Double B-lactam Ampicillin 2g IV q4 hr PLUS Ceftriaxone 2g IV q12 hr Both for 6 weeks Option for impaired renal function Ampicillin 2 g IV q4 hr or PNC G Streptomycin sulfate 15mg/kg (IBW) per 24 hrs divided into 2 doses Both for 4 to 6 weeks  Avoid streptomycin in crcl< 50 ml/min UPDATE UPDATE Baddour LM, et al. Circulation 2015; 32:1-40.

Enterococcus IE NO CHANGES !!! Enterococcus susceptible to gent/vanco and resistant to PCN, prosthetic or native valve Duration of Therapy No B-lactam allergy: Ampicillin-sulbactam 3 g IV q6h PLUS Gentamicin 1 mg/kg IV q8h Both for 6 weeks  B-lactam producing strains B-lactam allergy: Vancomycin 15-20 mg/kg IV q8-12h (per renal function) Note: Duration of gentamicin is for the entire duration NO CHANGES !!! Baddour LM, et al. Circulation 2015; 32:1-40.

Enterococcus IE ID consult UPDATE Enterococcus susceptible to amp/gent/vanco, either native valve or prosthetic valve Duration of Therapy Linezolid 600 mg IV/PO 12h OR Daptomycin 10-12 mg/kg IV per dose Quinupristin/dalfropristin 7.5 mg IV q8h (off label) >6 weeks Alternative therapy: Daptomycin + ampicillin Daptomycin + ceftaroline Considered for patients with persistent bacteremia and high MIC (3μg/ml) ID consult UPDATE Baddour LM, et al. Circulation 2015; 32:1-40.

HACEK IE Therapy Duration of therapy 4 weeks for native valve Considered ampicillin resistant Avoid ampicillin and penicillin for empiric therapy Ceftriaxone 2 g IV daily Ampicillin 2 g IV q 4h ( if susceptibilities are known) Ciprofloxacin 500 mg IV q12h ( if patient has true PNC allergy or can’t tolerate b-lactams) Duration of therapy 4 weeks for native valve 6 weeks for prosthetic valve Baddour LM, et al. Circulation 2015; 32:1-40.

Fungal IE Candida > aspergillus Associated with high mortality rates Survival rate <20% Valve surgery is recommended in most cases of fungal IE (Level of Evidence B) Fungicidal agent- drug of choice Amphotericin B, Echinocandins Duration of therapy >6 weeks Life-long suppressive therapy is indicated Oral azoles Flucanozole Baddour LM, et al. Circulation 2015; 32:1-40.

Culture Negative IE Decision for treatment is based on patient’s past medical history and risk factors Risk factors Prior infections (cardiovascular infections) Prior exposures to antimicrobials (duration of abx, severity of infections) Infection of the extra-cardiac sites Expert involvement (ID consult) Baddour LM, et al. Circulation 2015; 32:1-40.

Culture Negative IE Empiric therapy Native Valve Prosthetic Valve Coverage of S. aureus, B-hemolytic Streptococci and gram negative bacilli Coverage for S. aureus, Viridans group streptococci, HACEK, and enterococci Baddour LM, et al. Circulation 2015; 32:1-40.

Assessment Question #3 True/False Gentamicin is one of the therapy options available to treat MSSA IE in patients with native valve?

Assessment Question #3 Gentamicin is one of the therapy options available to treat MSSA IE in patients with native valve? False

Additional Updates

Surgical Management Valve surgery for left-sided IE Early surgery is indicated in patients with valve dysfunction and symptoms of heart failure Valve surgery for right-sided IE Early surgery is indicated especially in patients with complications Valve repair is recommended over replacement if feasible Baddour LM, et al. Circulation 2015; 32:1-40.

Surgical Management Patient with stroke or cerebral emboli Surgery may be considered in IE patients with stroke or cerebral emboli or residual vegetation once intracranial hemorrhage is excluded by imaging In presence of ischemic stroke or intracranial hemorrhage surgery can be delayed for at least 4 weeks Baddour LM, et al. Circulation 2015; 32:1-40.

Dental Management Current recommendations Broad recommendations and very nonspecific Oral hygiene and gingival disease (periodontal disease) is responsible for the majority of IE cases Dental visits (minor) Inpatients with IE should be evaluated by a dentist to identify and eliminate possible oral diseases Baddour LM, et al. Circulation 2015; 32:1-40.

Who needs prophylaxis? Prosthetic heart valves History of IE Congenital heart disease (CHD) Unrepaired cyanotic CHD Completely repaired congenital heart defect Cardiac transplant recipients who develop valvular disease Thanavaro KL. Heart & Lung 2014; 43:334-337.

Who needs prophylaxis? Recommended for all dental procedures involving manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa Procedures not requiring prophylaxis include Routine anesthetic injections through non-infected tissue Dental x-rays Placement and adjustment of orthodontic appliances Shedding of primary teeth Bleeding from trauma to the lips or oral mucosa Thanavaro KL. Heart & Lung 2014; 43:334-337.

Prophylaxis: Therapy Options Amoxicillin 2 g po X 1 dose, Azithromycin 500 mg po X1 dose, Cephalexin 1 g po X1 dose Clindamycin 600mg po X1 dose Give the dose 30 to 60 mins prior to procedure Thanavaro KL. Heart & Lung 2014; 43:334-337.

Assessment Question #4 AH is a 59 yo female with PMH of HTN, DM, and prosthetic heart valve surgery (2012) who is going to see her dentist for a root canal procedure. Does AH need to receive IE prophylaxis for her scheduled dental procedure. Yes/no? 2. If yes, why does AH qualify for prophylaxis?

Summary of Updates Gentamicin is no longer recommended for treatment of native valve staphylococcal IE Daptomycin has been added as an alternative agent for treating IE caused by MSSA or MRSA Use of double b-lactam therapy for treatment of enterococcal IE Ampicillin+ high dose ceftriaxone Use of high dose daptomycin alone or combination with a b-lactam for treatment of resistant enterococcal IE We covered a lot of changes… lets summarize and recap on the main points… Gent, for staph ( both MSSA/MRSA); yet is still reccomanded for MSSA/MRSA prosthetic valve Dapto has been added as na alternative for staph IE both MSSA and MRSA 6 mg/kg dose Dapro can also be used alone or combo in enteroccocal IE high dose here 10-12 mg/kg

Summary of Updates Cont. Recommendations to treat gram negative IE based on patients risk factors Consult infectious diseases The new guidelines have recommendations of treatment of staphylococcal IE in patients with concurrent brain abscess A broader set of recommendations for prevention of IE (prophylaxis) Treat high risk patients

Questions

References Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications. Circulation 2015; 32:1-40. Cahill TJ, Prendergast BD. Infective endocarditis. Lancet 2016; 387:882-93. Thanavaro KL, Nixon JV. Endocarditis 2014: An update. Heart & Lung 2014; 43:334-337. San Roman AJ, Vilacosta I, Castillo JC, et al. Comments on the 2015 guidelines for the management of infective endocarditis. Rev Esp Cardiol 2016; 69(1):7-10.