9/28/2016 Megan Patch MS, PharmD, BCPS Antimicrobial Stewardship Pharmacist Don’t Go Veggin’ my Heart: Updates to the Infective Endocarditis Diagnosis and Treatment Guidelines

Objectives Describe updated diagnosis criteria for infective endocarditis (IE) Discuss changes to treatment recommendations within the updated guidelines Apply new treatment recommendations for IE from various microbial sources Evaluate the role of the pharmacist in management of IE

Infective Endocarditis Annual incidence: 3-7/100,000 person-years Remained stable 4th most common life-threatening infectious process High morbidity and mortality Staphylococcus aureus is the most common causative organism Contemporary surveys – sepsis, PNA, intra-abdom abscess Baddour LM et al. Circulation 2015

Infective Endocarditis Shift in causative organism to S. aureus dominance Also increase in mean age of patient Higher portion of prosthetic valve IE Increase in other cardiac devices Decrease in rheumatic heart disease as cause Outcomes have not improved despite advances in care Product of increase in Staphylococcal origin Viridans group step Streptococcus gallolyticus (bovis) HACEK organisms Enterococci --Original Duke criteria for major criteria Baddour LM et al. Circulation 2015

American Heart Association - IDSA 2015 Update Last guidelines in 2005 Baddour LM et al. Circulation 2015

Duke Criteria Have been modified over the years Used to aid in determining diagnosis Endocarditis is heterogenous and these criteria should be paired with a complete clinical workup for a diagnosis Major and minor criteria 1994 Durack and colleagues at Duke University Medical Center came up with these They have been verified with 12 major studies and over 1,700 patients to confirm specificity and sensitivity IE is a heterogenous disease with highly variable clinical presentations, and therefore the use of the Duke criteria alone will not suffice Baddour LM et al. Circulation 2015

Duke Criteria Baddour LM et al. Circulation 2015

Diagnosis Early identification is key Reliable history of patient High risk patients who can benefit from surgery Reliable history of patient Risk factor profile Valve replacement Intravenous drug use (IVDU) Clinical picture Duke Criteria Baddour LM et al. Circulation 2015

Diagnostic Testing At least 3 sets of cultures should be obtained 1st and last drawn at least 1 hour apart Different venipuncture sites Commonly, only 2 sets of cultures will be drawn Imaging Transthoracic echocardiogram (TTE) Transesophageal echocardiogram (TEE) More cultures drawn – increased chance of growing organism http://www.bd.com/ds/productCenter/442192.asp Baddour LM et al. Circulation 2015

Antibiotic Therapy - Goals Eradicate infection Sterilize vegetation Prevent sequelae Challenges of treatment High bacterial density Penetration into vegetation Slow rate of bacterial growth in biofilms Goal + Challenges = prolonged IV antibiotics Slow rate of growth – harder to target with agents that work on replicating bacteria Need bactericidal therapy Stationary growth phase – those that work on bacterial cell wall and are Baddour LM et al. Circulation 2015

Inoculum Effect High bacterial density at vegetation Higher minimum inhibitory concentration (MIC) at vegetation site Antimicrobials can be less effective with a high inoculum β-lactams (ceftriaxone) and glycopeptides (vancomycin) Require higher antimicrobial doses to overcome higher MIC More β-lactamase produced In large densities, some organisms can become resistant to bactericidal effects of some antibiotics Resistant subpopulations with higher inoculum Lesser extent lipopeptides such as daptomycin Penicillin vs streptococci – demonstrated this. Curative dose of PCN for strep in animal models increased with the number of organisms inoculated and the duration of the infection Stationary growth phase organisms have been associated with loss of penicillin binding protein that are active target sites of beta-lactam antibiotics. This may be responsible for the inoculum B-lactamase – enterococci, staph aureus, gram negative bacilli Baddour LM et al. Circulation 2015

Antimicrobial Therapy Drug penetration Mechanical barrier to drug target Bactericidal drugs May need combination to achieve bactericidal activity β-lactam + aminoglycoside Duration of therapy 2-6 weeks Right-sided vegetations tend to have lower bacterial densities Baddour LM et al. Circulation 2015

Antimicrobial Therapy Pharmacokinetic and pharmacodynamic properties Penicillins and cephalosporins require free drug to exceed the MIC for 60-70% of the dosing interval for bactericidal action Less than 60% only achieves bacteriostatic effects When administering antibiotics to achieve synergy, administration together or as close as possible can maximize synergistic effect We will revisit the antibiotics Baddour LM et al. Circulation 2015

Other Treatment Considerations Broad empiric therapy based on most likely organisms Complete and thorough history should be obtained Infectious Diseases consultation should be obtained when IE is suspected Duration of treatment should start with the first negative culture Keep in mind some organisms involved in IE are hard to culture Two sets of blood cultures should be drawn every 24-48 hours while still positive Native valve IE with prosthetic valve replacement, no consensus on how to treat If valve resection (with culture positive valve)– it is reasonable to start the course of antibiotics after the removal of the valve If negative, reasonable to include treatment duration from prior to surgery Gram staining of valve tissue can actually reveal killed organism and should not be a factor in the duration of treatment Baddour LM et al. Circulation 2015

Viridans Group Streptococcus Streptococcus gallolyticus Abiotrophia defectiva Granulicatella species Treatment Strep gallolyticus previously Strep bovis

NVE: Highly PCN-susceptible S. gallolyticus Red box: outpatient use Ampicillin is reasonable alternative to PCN (12g/day or 2g every 4 hours) Vancomycin in patients with severe PCN allergy TROUGH 10-15, dosing is not going to be the same as guidelines If giving gentamicin – give at the same time as beta-lactam. Baddour LM et al. Circulation 2015

NVE: Relatively PCN-resistant S. gallolyticus and VGS Daily dosing of gentamicin for the first two weeks Baddour LM et al. Circulation 2015

NVE: Highly PCN-resistant S. gallolyticus and VGS Ampicillin 12g/day (2g every 4 hours) -OR- Penicillin 18-30 million units/day divided or continuous infusion -PLUS- Gentamicin 3 mg/kg/day in 2-3 divided doses Treatment is the same for Abiotrophia defectiva and Granulicatella spp Baddour LM et al. Circulation 2015

PVE: Penicillin-susceptible S. gallolyticus and VGS Difference in treatment duration of gentamicin, longer synergy Any time you see prosthetic valve, treatment is going to be 6 weeks Baddour LM et al. Circulation 2015

PVE: Penicillin-resistant S. gallolyticus and VGS Difference in treatment duration of gentamicin, longer synergy Any time you see prosthetic valve, treatment is going to be 6 weeks Baddour LM et al. Circulation 2015

Streptococcus pneumoniae, Streptococcus pyogenes, and Groups B, C, F, and G β-Hemolytic Streptococci Treatment

Highly PCN-susceptible Streptococcus pneumoniae Penicillin MIC < 0.1 µg/mL NVE 4 weeks of antibiotic therapy Penicillin, cefazolin, or ceftriaxone Vancomycin therapy recommended with β-lactam allergy PVE 6 weeks of antibiotic therapy Difference is 4-6 weeks Baddour LM et al. Circulation 2015

PCN-resistant Streptococcus pneumoniae Penicillin MIC > 0.1 µg/mL If no meningitis present High-dose penicillin or 3rd generation cephalosporin If meningitis present High-dose cefotaxime or ceftriaxone Uncommonly isolated All treated the same Did not have a worse prognosis Baddour LM et al. Circulation 2015

Other Streptococci Streptococcus pyogenes (group A Streptococci) Penicillin for 4-6 weeks Groups B, C, F, and G Streptococci Slightly more PCN resistance Penicillin -OR- Ceftriaxone for 4-6 weeks -PLUS- Gentamicin for at least 2 weeks Early cardiac surgical intervention Early surgery has improved overall survival rates in patients with beta-hemolytic strep IE compared with patients treated decades ago… Baddour LM et al. Circulation 2015

Patient Case #1 QR is a 46 year old male with a past history of gout, depression, and hypertension. He presented to the ER with weakness and fatigue. He was hospitalized 2 months prior with pneumonia. Blood cultures were positive 2/2 for Streptococcus pneumoniae. Vancomycin was initiated until sensitivity results are known. A TTE and TEE were performed and showed a large vegetation on his mitral valve. He has no history of endocarditis or valve replacement. Culture results show highly susceptible penicillin sensitivity. What therapy should be used for QR? PCN, cefazolin, or ceftriaxone. 4 weeks Possible surgical intervention. Mitral valve -

Patient Case #1 continued What is the appropriate treatment duration for QR? 2 weeks 4 weeks 6 weeks 8 weeks B. 4 weeks

Patient Case #1 continued What is the appropriate treatment duration for QR? 2 weeks 4 weeks 6 weeks 8 weeks B. 4 weeks

Staphylococci Treatment

History and Current State Staphylococcal species (specifically S. aureus) are the most common cause of IE Previously, S. aureus was traditionally associated with NVE and coagulase-negative Staphylococci (CoNS) was associated with PVE S. aureus becoming a larger cause of PVE Prevalence of CoNS NVE is increasing Increase in the incidence of S. aureus IE due to healthcare contact Treatment is complicated with increasing resistance This is no longer the case and there is considerable overlap Healthcare contact: intravascular catheters, surgical wounds, indwelling prosthetic devices, hemodialysis Baddour LM et al. Circulation 2015

Staphylococcus aureus IE Intravenous drug users (IVDU) Mainly right-sided (tricuspid) Non-intravenous drug users (non-IDUs) Mainly left-sided (mitral/bicuspid valve) http://www.heart.org/idc/groups/heart-public/@wcm/@hcm/documents/image/~extract/UCM_451092~2~staticrendition/large.jpg

Coagulase-Negative Staphylococci (CoNS) Similar risk factors and outcomes as S. aureus IE High methicillin resistance rate These organisms are also resistant to cephalosporins and carbapenems Staphylococcus lugdunensis More virulent form of IE Clinically resistant. May not be reflected in in vitro testing S lugdenensis: High rate of perivalvular extension (extra-cardiac spread) and metastatic manifestations Baddour LM et al. Circulation 2015

Staphylococcal IE in IDUs Gentamicin has previously been standard treatment for right-sided IE in patients with NVE β-lactam + gentamicin for 2 weeks for uncomplicated IE Increasing risk of nephrotoxicity without added benefit Vancomycin + gentamicin (short-course) less effective Difficult to penetrate vegetation Slowly bactericidal Increased drug clearance in this patient population Longer duration of therapy with vancomycin treatment in MRSA IE is warranted Uncomplicated: no evidence of renal failure, extrapulmonary metastatic infections, aortic or mitral valve involvement, meningitis, or infection by MRSA Baddour LM et al. Circulation 2015

Staphylococcal IE in non-IDUs MSSA Treatment with nafcillin + gentamicin shortened duration of bacteremia by roughly one day No effect on clinical outcomes Increase in nephrotoxicity with dual therapy MRSA Increased risk of nephrotoxicity when vancomycin + gentamicin are given concomitantly Baddour LM et al. Circulation 2015

NVE: Staphylococci Baddour LM et al. Circulation 2015 Uncomplicated right sided IE can be treated for 2-4 weeks Vancomycin is often included with nafcillin for initial treatment until MSSA/MRSA can be determined Baddour LM et al. Circulation 2015

PVE: Staphylococci MSSA MRSA Baddour LM et al. Circulation 2015 Rifampin seems to be the addition that allows for sterilization in patients with MRSA PVE MRSA Baddour LM et al. Circulation 2015

Abscess with Staphylococcal IE Brain abscess with MSSA Nafcillin is preferred over cefazolin due to increased penetration at the blood brain barrier If allergy prohibits nafcillin use, vancomycin should be substituted Septic pulmonary emboli Daptoymcin can be used for MRSA Baddour LM et al. Circulation 2015

Oral Therapy for MSSA IE in IDU Two studies Right-sided MSSA IE in IDU Ciprofloxacin + rifampin 4 weeks treatment Many patients HIV+ Cure rate >90% Increasing rates of resistance of MSSA to fluoroquinolones Effective absorption – must be taken correctly IV therapy in IDU is problematic. Usually keep at hospital or an extended care facility Baddour LM et al. Circulation 2015

Enterococcus Treatment

NVE and PVE: Enterococcus Double beta-lactam: saturation of penicillin binding proteins, enhanced activity of ampicillin Meningitis dosing of ceftriaxone Double beta-lactam therapy recommended in patients with CrCl <50 mL/min or those whose CrCl drops below 50 during treatment with gent-containning therapy. Baddour LM et al. Circulation 2015

NVE and PVE: Enterococcus Cut off the part of table with streptomycin recommendation Baddour LM et al. Circulation 2015

NVE and PVE: Resistant Enterococcus Or quinupristin-dalfopristin (Synercid) – needs central line and only active against E. faecium Baddour LM et al. Circulation 2015

Linezolid Not FDA approved for treatment of IE (off-label use) Not often used Dosing 600 mg IV every 12 hours Bacteriostatic Problematic for patients with immunosuppression Side effects with long-term use Myelosuppression including thrombocytopenia Baddour LM et al. Circulation 2015

Daptomycin Approved for treatment of right-sided IE Often used off label for left-sided endocarditis Dosing (with CrCl >30 mL/min) Package insert: 6 mg/kg daily Some experts: 8-10 mg/kg daily Other experts: 10-12 mg/kg daily Monitor weekly CPK May need to monitor more frequently with higher doses or concomitant statin therapy Generic projected for Summer 2016 (hopefully by early 2017) Waiting for generic to become available. May see more use as easier transition to outpatient Issues with renal dysfunction as well as obesity Smith JR, et al. Journal of Antimicrobial Chemo. 2015 Baddour LM et al. Circulation 2015

Daptoymcin/Beta-lactam Synergy Enterococcus species with daptomycin resistance are increasing nationally The rate of daptomycin resistance for E. faecalis and E. faecium have been measured around 0.5% and 4.7%, respectively Addition of ceftaroline, ertapenem, cefepime, ceftraixone, and ampicillin have shown to provide synergy to daptomycin and decrease time to blood clearance compared to monotherapy Ceftaroline has been shown to restore daptomycin susceptibility in non- susceptible strains MIC of 4 or greater for enterococcus Even strains with MIC 2 to 4 have shown to develop mutations and can be resistant Cefazolin and cefotaxime did not show synergy with daptomycin Smith JR, et al. Journal of Antimicrobial Chemo. 2015

Patient Case #2 MP is a 64 year old male who has been experiencing fever and chills for the past 3.5 months. The patient has positive blood cultures for Gram-positive cocci in pairs. The patient has a history of hypertension, hyperlipidemia, chronic kidney disease (CrCl ~40 mL/min), and mitral valve replacement. What is the likely causative organism in this patient based on the Gram-stain? What treatment should be recommended and how long should this patient receive antibiotic therapy? GPC in pairs: Enterococcus CKD : amp + ceftriaxone for 6 weeks 6 weeks for both previous valve replacement as well as duration of symptoms.

HACEK Organisms Haemophilius species Aggregatibacter species Cardiobacterium hominis Eikenella corrodens Kingella species Historically, all strains were susceptible to ampicillin Increased β-lactamase production Most all susceptible to ceftriaxone 4-6 weeks of treatment Account for 5-10% of community-acquired NVE in patients who are not IDUs These organisms grow SLOWLY and may require prolonged incubation Bacteremia with these organisms even without a focus of infection is highly suggestive of IE Resistance to ampicillin can also occur in strains without beta-lactamase production If susceptibility results are unknown- assume amp resistance and do not use amp or penicillin Baddour LM et al. Circulation 2015

NVE or PVE: HACEK Organisms Ceftriaxone dosing is daily, not BID as with synergy dosing Baddour LM et al. Circulation 2015

Culture-negative IE Failure to isolate an organism in IE patients can lead to problematic treatment regimens Risk of not covering organism Risk of treating with extra agents Most studies estimate around 5-10% of IE is culture negative Study of 820 patients with confirmed IE showed around 20% of patients were culture negative Fastidious organisms Fungi Low bacterial concentration in blood Antibiotics prior to blood cultures Account for 5-10% of community-acquired NVE in patients who are not IDUs These organisms grow SLOWLY and may require prolonged incubation Bacteremia with these organisms even without a focus of infection is highly suggestive of IE Resistance to ampicillin can also occur in strains without beta-lactamase production If susceptibility results are unknown- assume amp resistance and do not use amp or penicillin Baddour LM et al. Circulation 2015

Patient Case #3 MR is a 30 year old intravenous drug user with a history of hypertension. She presents to the emergency department 1 day ago with fatigue over the past 3 days, a fever of 102oF, and chills. The patient was empirically started on vancomycin and piperacillin/tazobactam. Blood cultures were positive for Gram-positive cocci in clusters still awaiting sensitivities. How would you adjust antimicrobial therapy in this patient? Either wait until sensitivities to narrow What test are we waiting for? Could change to nafcillin + vanc until we know MRSA vs MSSA

Pharmacist’s Role in Management of Endocarditis Follow culture and sensitivity results – communication with microbiology lab Recommend appropriate antimicrobial therapy Provide pharmacokinetic services Vancomycin, aminoglycosides Optimize dosing of antibiotics Analyze overall medication regimen and screen for drug-drug interactions Patient education of antibiotics List is not all-enclusive

Self-assessment Question A patient with suspected endocarditis reveals blood cultures positive for Streptococcus gallolyticus (S. bovis). Which additional testing is recommended for this patient? CT of the chest with contrast MRI of the head Colonoscopy Endoscopy

Self-assessment Question A patient with suspected endocarditis reveals blood cultures positive for Streptococcus gallolyticus (S. bovis). Which additional testing is recommended for this patient? CT of the chest with contrast MRI of the head Colonoscopy Endoscopy

9/28/2016 Megan Patch MS, PharmD, BCPS Antimicrobial Stewardship Pharmacist Don’t Go Veggin’ my Heart: Updates to the Infective Endocarditis Diagnosis and Treatment Guidelines