Megan Patch MS Pharm D BCPS Antimicrobial Stewardship

Megan Patch MS, Pharm. D, BCPS Antimicrobial Stewardship Pharmacist 9/28/2016 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 • 4 th most common life-threatening infectious process • High morbidity and mortality • Staphylococcus aureus is the most common causative organism 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 Baddour LM et al. Circulation 2015

2015 Update American Heart Association - IDSA 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 Baddour LM et al. Circulation 2015

Duke Criteria Baddour LM et al. Circulation 2015

Diagnosis • Early identification is key • 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 • 1 st 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) http: //www. bd. com/ds/product. Center/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 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 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 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 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 Baddour LM et al. Circulation 2015

Treatment Viridans Group Streptococcus gallolyticus Abiotrophia defectiva Granulicatella species

NVE: Highly PCN-susceptible S. gallolyticus Baddour LM et al. Circulation 2015

NVE: Relatively PCN-resistant S. gallolyticus and VGS Baddour LM et al. Circulation 2015

NVE: Highly PCN-resistant S. gallolyticus and VGS • Ampicillin 12 g/day (2 g 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 Baddour LM et al. Circulation 2015

PVE: Penicillin-resistant S. gallolyticus and VGS Baddour LM et al. Circulation 2015

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

Highly PCN-susceptible Streptococcus pneumoniae • Penicillin MIC < 0. 1 µg/m. L • NVE • 4 weeks of antibiotic therapy • Penicillin, cefazolin, or ceftriaxone • Vancomycin therapy recommended with β-lactam allergy • PVE • 6 weeks of antibiotic therapy • Penicillin, cefazolin, or ceftriaxone • Vancomycin therapy recommended with β-lactam allergy Baddour LM et al. Circulation 2015

PCN-resistant Streptococcus pneumoniae • Penicillin MIC > 0. 1 µg/m. L • If no meningitis present • High-dose penicillin or 3 rd generation cephalosporin • If meningitis present • High-dose cefotaxime or ceftriaxone 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 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?

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

Treatment Staphylococci

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 (Co. NS) was associated with PVE • S. aureus becoming a larger cause of PVE • Prevalence of Co. NS NVE is increasing • Increase in the incidence of S. aureus IE due to healthcare contact • Treatment is complicated with increasing resistance Baddour LM et al. Circulation 2015

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

Coagulase-Negative Staphylococci (Co. NS) • 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 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 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

PVE: Staphylococci MSSA 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 Baddour LM et al. Circulation 2015

Treatment Enterococcus

NVE and PVE: Enterococcus Baddour LM et al. Circulation 2015

NVE and PVE: Resistant Enterococcus 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 Cr. Cl >30 m. L/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) 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 nonsusceptible strains 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 (Cr. Cl ~40 m. L/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?

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 Baddour LM et al. Circulation 2015

NVE or PVE: HACEK Organisms 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 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 102 o. F, 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?

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

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? A. B. C. D. CT of the chest with contrast MRI of the head Colonoscopy Endoscopy

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