En Endo docardit carditis is De Deba bate: te: IV to P.O. IV to P.O. or IV to or IV to N.O. N.O. Maureen Campion, PharmD, BCIDP Kirthana Beaulac, PharmD, BCPS UMass Memorial Medical Center Tufts Medical Center
Ob Objec ectives tives • Describe the management of endocarditis. • Discuss the literature around oral and IV treatment of endocarditis. • Evaluate the generalizability of the POET Trial in Massachusetts patient population.
Pa Patho hophysio physiology logy Aortic Valve Mitral Valve Tricuspid valve Right Ventricle
Bacteriocins, IgA Mucous Membranes Valvular Trauma, protease, bacterial or Other Colonized Endothelium Turbulence adherence Tissue Platelet-Fibrin Trauma Deposition Nonbacterial Bacteremia Thrombotic Endocarditis Adherence Colonization Bacterial division, fibrin deposition, platelet aggregation, extracellular proteases, protection from neutrophils Mature Vegetation
Ri Righ ght t Side de vs Le Left t Side de • Right sided endocarditis • Tricuspid valve • Less bacterial density • Left sided endocarditis • Includes Mitral and Aortic valves • More commonly associated with embolic events or congestive heart failure Photo: http://blogs.egusd.net/eettalfonso/2012/01/20/how-does-blood-flow-through-the-heart/ Accessed on 4/10/19 Chambers HF,. Ann Intern Med. 1988;109:619 – 624
Int ntervent erventions ions Surgery Antimicrobial Therapy • Vegetation • Inoculum Effect • Persistent after systemic • Higher bacterial densities more embolization challenging to treat • Mitral valve leaflet vegetation > 10 • Antibiotic resistant subpopulations mm • > 1 embolic events in first 2 weeks • Bactericidal drugs of ABX therapy • Beneficial for eradication of infection • Valvular dysfunction • PK/PD parameters target for efficacy • Mild to Moderate congestive heart failure • • Duration of Therapy New heart block • Valve perforation or rupture • Native vs. Prosthetic valve • IE caused by resistant organism • Surgery vs. Conservative management • Presence of myocardial abscess • Right sided vs. left sided • Early PVE (< 1 year)
Native Valve Endocarditis Viridans Group Strep Penicillin G 12-18 million units/day IV either 4 weeks continuously or in 4-6 divided doses Native Na ive Va Valve e En Endo docard arditis itis OR Ceftriaxone 2 g IV/IM q 24 h 4 weeks Ceftriaxone 2 g IV/IM q 24 hours 2 weeks PLUS Gentamicin 3 mg/kg d IV/IM 2 weeks Penicillin “Relatively” Penicillin G 24 million units/day IV continuously or in 4-6 4 weeks Resistant divided doses PLUS Gentamicin 3 mg/kg/day IV/IM 2 weeks Ceftriaxone 2 g every IV/IM every 24 hours 4 weeks PLUS Gentamicin 3 mg/kg/d IV/IM 2 weeks Vancomycin 15 mg/kg IV every 12 hours 4 weeks Staphylococcus Nafcillin or oxacillin 12 g/ 24 h continuously or in 4-6 6 weeks divided doses or Cefazolin 2 g IV every 8 hours Vancomycin 15 mg/kg every 12 hours 6 weeks
Prosthetic Valve Endocarditis Viridans Group Penicillin G 24 million units/day IV continuously or in 4-6 divided doses 6 weeks Streptococci OR 6 weeks Ceftriaxone 2 G every IV/IM every 24 hours 2 weeks WITH OR WITHOUT Gentamicin 3 mg/kg/d IV/IM Staphylococcus Nafcillin or oxacillin 12 g/ 24 h continuously or in 4-6 divided doses > 6 weeks PLUS > 6 weeks Rifampin 300 mg IV/PO every 8 hours 2 weeks PLUS Gentamicin 3 mg/kg every 8 hours Vancomycin 15 mg/kg every 12 hours > 6 weeks PLUS Rifampin 300 mg IV/PO every 8 hours > 6 weeks PLUS Gentamicin 3 mg/kg every 8 hours 2 weeks Enterococcus Ampicillin 2 g every 4 hours 4-6 weeks OR 4-6 weeks Penicillin 18-30 million units/24 h IV continuously or in 6 divided doses 4-6 weeks PLUS Gentamicin 3 mg/kg in 2-3 divided doses Ampicillin 2 g every 4 hours 6 weeks PLUS Ceftriaxone 2 g every 12 hours 6 weeks Daptomycin 10-12 mg/kg every 24 hours > 6 weeks
Ba Bacteri ericidal cidal vs Ba Bacte teriostat riostatic ic • “Prolonged, parenteral, bactericidal therapy is required for attempted infection cure.” • Require prolonged therapy (6 weeks) for full sterilization • Bactericidal regimens are more effective than bacteriostatic therapy • Concern for tolerant microbes present in vegetations and biofilms • Optimal doses with bioavailable agents are needed to act on high inoculum infections due to high bacterial densities Baddour, LM. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications Circulation. 2015;132:1435-1486 Habib G. ESC Guidelines for the management of endocarditis. European Heart Journal , Volume 36, Issue 44, 21 November 2015, Pages 3075 – 3128.
Pe Peni nicil cillin lin Tr Trials als Verhagen DWM. Antimicrobial treatment of infective endocarditis caused by viridans streptococci highly susceptible to penicillin. Journal of Antimicrobial Chemotherapy (2006) 57, 819 – 824
Fa Fail ilure ure wit ith h Monotherapy notherapy and d Shorter orter Courses urses Verhagen DWM. Antimicrobial treatment of infective endocarditis caused by viridans streptococci highly susceptible to penicillin. Journal of Antimicrobial Chemotherapy (2006) 57, 819 – 824
Ino nocu culum lum Ef Effect ect • High inoculum vegetations (10 8 -10 10 colony forming units) may be present in endocarditis limiting the concentration of antibiotics • Minimum inhibitory concentrations (MIC) can increase with inoculum 10 6 cfu 10 10 cfu MIC 4 MIC 64 Hunter TH. Speculations on the mechanism of cure of bacterial endocarditis. J Am Med Assoc. 1950;144:524 – 527 Sabath LD, Effect of inoculum and of beta-lactamase Antimicrob Agents Chemother. 1975;8:344 – 349
Ino nocu culum lum Effect ect on on St Stap aph h Aur ureu eus Ratio of MIC for non-diluted and diluted (10 -4 ) Staphylococcus aureus Isolates showing Indicated change is susceptibility % Penicillins No change Four fold-or Eight fold or 16 fold of >32 fold or two-fold greater greater greater Methicillin 93 7 0 0 0 Nafcillin and Oxacillin are the most stable to Nafcillin 84 16 3 0 0 the inoculum effect. Dicloxacillin Dicloxacillin is stable 47 53 19 5 1 against high inoculums only 50% Cloxacillin 40 60 19 14 0 of the time. Oxacillin 48 52 26 11 3 Benzyl- 7 93 93 90 90 penicillin Sabath LD. AAC Sept 1975; 344-329.
IV is V is the he wa way to o Be Be • Endocarditis is a severe infection that can have fatal complications improperly treated • Long term parenteral therapy is the standard of care recommended by the American and European guidelines • In historical trials, short courses have lead to treatment failures • Endocarditis is a high inoculum infection, requiring high concentrations of bactericidal antibiotics, sometimes in combination, to achieve efficacy
Ba Barriers ers Physician Driven Patient Driven • Mythical properties of • Clinical stability intravenous antibiotics • Ability to absorb • IV anything is better than oral • Ability to hold down food/meds • Priorities, team dynamics and • Perceived adequacy of care the medical hierarchy • IV is more potent • Desire for “big guns” • Consumerism and ‘complaints culture’ • Clinical improvement of infection signs and symptoms Broom J, Broom A, Adams K, Plage S. What prevents the IV to oral antibiotic switch: A qualitative study of hospital doctors’ accounts of what influences their clinical practice. J Antimicrob Chemother . 2016; 71(8):2295-9. Engel MF, Postma DF, Hulscher ME, et al. Barriers to an early switch from IV to oral antibiotic therapy in hospitalized patients with CAP. Eur Respir J . 2013; 41: 123-130.
*3 months after therapy, new febrile illness w/ negative cultures
MEANWHILE…
Lee B, Tam I, Weigel B, et al. Comparative outcomes of b-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches. J Antimicrob Chemother . 2015; 70: 2389-2396. Underwood J, Marks M, Collins S, et al. Intravenous catheter-related adverse events exceed drug-related adverse events in outpatient parenteral antimicrobial therapy. J Antimicrob Chemother . 2019; 74(3):787-790.
PO Switch Exclusively IV 30d Mortality 1/188 (0.5%) 25/200 (10%) 90d Mortality 5/145 (3.4%) 45/195 (23.1%) Mzabi A, Kerneis S, Richaud C, et al. Switch to oral antibiotics in the treatment of infective endocarditis is not associated with increased risk of mortality in non- severely ill patients. Clin Micro Infect . 2016; 22: 607-612.
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