Endocarditis Debate:IV to P.O. or IV to

N.O.Kirthana Beaulac, PharmD, BCPS

Tufts Medical CenterMaureen Campion, PharmD, BCIDP

UMass Memorial Medical Center

Objectives

• 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.

Pathophysiology

Tricuspid valve

Aortic Valve

Right Ventricle

Mitral Valve

Trauma, Turbulence

Bacteriocins, IgA protease, bacterial

adherence

Valvular Endothelium

Platelet-Fibrin Deposition

Nonbacterial Thrombotic Endocarditis

Adherence

Colonization

Mature Vegetation

Mucous Membranes or Other Colonized

Tissue

Trauma

Bacteremia

Bacterial division, fibrin deposition, platelet aggregation, extracellular proteases,

protection from neutrophils

Right Side vs Left Side

• 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 4/10/19Chambers HF,. Ann Intern Med. 1988;109:619–624

Interventions

Surgery

• Vegetation • Persistent after systemic

embolization • Mitral valve leaflet vegetation > 10

mm• > 1 embolic events in first 2 weeks

of ABX therapy

• Valvular dysfunction • Mild to Moderate congestive heart

failure• New heart block

• Valve perforation or rupture• IE caused by resistant organism• Presence of myocardial abscess• Early PVE (< 1 year)

Antimicrobial Therapy

• Inoculum Effect• Higher bacterial densities more

challenging to treat

• Antibiotic resistant subpopulations

• Bactericidal drugs• Beneficial for eradication of infection

• PK/PD parameters target for efficacy

• Duration of Therapy• Native vs. Prosthetic valve

• Surgery vs. Conservative management

• Right sided vs. left sided

Native Valve Endocarditis

Native Valve Endocarditis

Viridans Group Strep Penicillin G 12-18 million units/day IV either continuously or in 4-6 divided doses

OR Ceftriaxone 2 g IV/IM q 24 h

4 weeks

4 weeks

Ceftriaxone 2 g IV/IM q 24 hours PLUS

Gentamicin 3 mg/kg d IV/IM

2 weeks

2 weeks

Penicillin “Relatively” Resistant

Penicillin G 24 million units/day IV continuously or in 4-6 divided doses

PLUSGentamicin 3 mg/kg/day IV/IM

4 weeks

2 weeks

Ceftriaxone 2 g every IV/IM every 24 hoursPLUS

Gentamicin 3 mg/kg/d IV/IM

4 weeks

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 divided doses or Cefazolin 2 g IV every 8 hours

6 weeks

Vancomycin 15 mg/kg every 12 hours 6 weeks

Prosthetic Valve Endocarditis

Viridans Group Streptococci

Penicillin G 24 million units/day IV continuously or in 4-6 divided dosesOR

Ceftriaxone 2 G every IV/IM every 24 hoursWITH OR WITHOUT

Gentamicin 3 mg/kg/d IV/IM

6 weeks6 weeks2 weeks

Staphylococcus Nafcillin or oxacillin 12 g/ 24 h continuously or in 4-6 divided dosesPLUS

Rifampin 300 mg IV/PO every 8 hoursPLUS

Gentamicin 3 mg/kg every 8 hours

> 6 weeks> 6 weeks 2 weeks

Vancomycin 15 mg/kg every 12 hoursPLUSRifampin 300 mg IV/PO every 8 hoursPLUS

Gentamicin 3 mg/kg every 8 hours

> 6 weeks

> 6 weeks

2 weeks

Enterococcus Ampicillin 2 g every 4 hoursOR

Penicillin 18-30 million units/24 h IV continuously or in 6 divided dosesPLUS

Gentamicin 3 mg/kg in 2-3 divided doses

4-6 weeks4-6 weeks4-6 weeks

Ampicillin 2 g every 4 hoursPLUS

Ceftriaxone 2 g every 12 hours

6 weeks

6 weeks

Daptomycin 10-12 mg/kg every 24 hours > 6 weeks

Bactericidal vs Bacteriostatic

• “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;132:1435-1486Habib G. ESC Guidelines for the management of endocarditis. European Heart Journal, Volume 36, Issue 44, 21 November 2015, Pages 3075–3128.

Penicillin Trials

Verhagen DWM. Antimicrobial treatment of infective endocarditis caused by viridans streptococci highly susceptible to penicillin. Journal of Antimicrobial Chemotherapy (2006) 57, 819–824

Failure with Monotherapy and Shorter Courses

Verhagen DWM. Antimicrobial treatment of infective endocarditis caused by viridans streptococci highly susceptible to penicillin. Journal of Antimicrobial Chemotherapy (2006) 57, 819–824

Inoculum Effect

• High inoculum vegetations (108-1010 colony forming units) may be present in endocarditis limiting the concentration of antibiotics

• Minimum inhibitory concentrations (MIC) can increase with inoculum

Hunter TH. Speculations on the mechanism of cure of bacterial endocarditis. J Am Med Assoc. 1950;144:524–527Sabath LD, Effect of inoculum and of beta-lactamase Antimicrob Agents Chemother. 1975;8:344–349

MIC 4 MIC 64

106 cfu 1010 cfu

Inoculum Effect on Staph AureusRatio of MIC for non-diluted and diluted (10-4) Staphylococcus aureus

Isolates showing Indicated change is susceptibility %

Penicillins No change or two-fold

Four fold-or greater

Eight fold or greater

16 fold of greater

>32 fold

Methicillin 93 7 0 0 0

Nafcillin 84 16 3 0 0

Dicloxacillin 47 53 19 5 1

Cloxacillin 40 60 19 14 0

Oxacillin 48 52 26 11 3

Benzyl-penicillin

7 93 93 90 90

Nafcillin and Oxacillin are the most stable to the inoculum effect.

Dicloxacillin is stable against high

inoculums only 50% of the time.

Sabath LD. AAC Sept 1975; 344-329.

IV is the way to 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

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.

Barriers

Physician Driven

• Mythical properties of intravenous antibiotics

• IV anything is better than oral

• Priorities, team dynamics and the medical hierarchy

• Consumerism and ‘complaints culture’

Patient Driven

• Clinical stability• Ability to absorb

• Ability to hold down food/meds

• Perceived adequacy of care• IV is more potent

• Desire for “big guns”

• Clinical improvement of infection signs and symptoms

*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.

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.

PO Switch Exclusively IV

30d Mortality 1/188 (0.5%) 25/200 (10%)

90d Mortality 5/145 (3.4%) 45/195 (23.1%)

Oral Treatment for MRSA Bacteremia

• Single center, observational cohort study of OOAT vs OPAT for complicated or uncomplicated MRSA bacteremia

• Primary outcome: 90 day clinical failure- recurrent MRSA BSI, deep-seated MRSA infection, or mortality

• 492 patients discharged to complete therapy, 422 OPAT, 70 OOAT• OPAT patients had higher Charlson Comorbidity (3 vs.1), more diabetes and CKD, and less

IVDU (18% vs. 31%)

• Complicated bacteremia was present in 67.3% of OPAT vs 51.4% OOAT (p=0.010)

• Median duration of antibiotics: OPAT 35 (22-44 days) vs OOAT 21 (14-37) (p=0.001)

• OOAT antibiotics: linezolid (50%), smx/tmp (34%), clindamycin (16%)

• OPAT antibiotics: vancomycin (46%), daptomycin (46%), ceftaroline (12%)

• 68 patients experienced clinical failure: 5 (7.1%) in OOAT vs 63 (14.9%) OPAT

• After propensity weighting, only prior S. aureus infection was predictive of failure

Jorgensen SCJ, Lagnf AM, Bhatia S, Shamim MD, Rybak MJ. Sequential IV to oral outpatient antibiotic therapy for MRSA bacteremia: one step closer. J Antimicrob Chemother. 2019; 74: 489-498.

• Prospective RCT across all 6 Danish regional cardiac centers

• Adults with L-sided endocarditis, in stable condition with satisfactory response to initial therapy, with positive blood culture for S. aureus, coag-neg Staphylococcus, Enterococcus, or Streptococcus

• Exclusion: BMI>40, concomitant infection requiring IV therapy, valvular abscess, inability to consent, suspicion of impaired absorption, and concerns with compliance

• Study treatment: everyone gets at least 10 days IV therapy • At least 7 days after surgery for those undergoing source control

• IV arm must stay hospitalized, PO arm allowed to be discharged with outpatient follow up 2-3 times per week

1% high penicillin MIC

1% ampicillin resistant

31% penicillin susceptible/ 69% MSSA/ 0% MRSA

30% pen susceptible/35% methicillin susceptible/35% meth resistant

Antibiotic Treatment Regimens• Penicillin-susceptible S. aureus or coag-neg Staphylococus

• Amoxicillin 1g q6h +R/F

• Linezolid 600 mg BID +R/F

• Methicillin-susceptible S. aureus or coag-neg Staphylococus• Dicloxacillin 1g q6h +R/F

• Linezolid 600 mg BID +R/F

• Methicillin-resistant coag-neg Staphylococus• Linezolid 600 mg BID +R/F

• Enterococcus faecalis• Amoxicillin 1g q6h +R/M

• Linezolid 600 mg BID +R/M

• Streptococci with penicillin MIC <1 mg/L• Amoxicillin 1g q6h + rifampin 600 mg BID

• Linezolid 600 mg BID +R/M

• Streptococci with penicillin MIC <1 mg/L• Linezolid 600 mg BID + rifampin 600 mg BID

• Moxifloxacin 400 mg daily + rifampin 600 mg BID

• Moxifloxacin 400 mg daily + clindamycin 600 mg TID

+R/F= with rifampin 600 mg BID OR fusidic acid 750 mg BID+R/M= with rifampin 600 mg BID or moxifloxacin 400 mg daily

Diclox +R/F9%

Amox +R/F35%

Moxi + R/F/clinda2%

Linezolid + R/F11%

Pen alone/+R2%

Moxi + linezolid7%

Amox + Moxi20%

Amox + linez11%

Other3%

Primary Outcome

• Composite Primary outcome occurred in 42 patients-• 24 IV vs.19 PO (OR 0.72, 95% CI 0.37-1.36)

Time to Outcome

Total: 87 patients (21.8%) died, 54 in the IV group (27.1%) and 33 in the PO treated group (16.4%)

(hazard ratio, 0.57, 95% CI, 0.37 to 0.87)

Safety• PK analysis

• 7 patients had concentrations that fell below the prespecified cutoff values for 1 of the 2 drugs

• Rifampin (n=3), moxi (n=2), linezolid, and dicloxacillin

• No dosage adjustments were made based on serum concentrations

• Primary outcome did not occur in any of these 7 patients

• Adverse effects• Only AEs necessitating antibiotic switch were recorded

IV Treatment (n=12) Oral Treatment (n=10)

GI Symptoms 0 (0) 3 (30%)

Renal Failure 0 (0) 1 (10%)

Hepatic Failure 0 (0) 1 (10%)

Bone Marrow Suppression 2 (17%) 4 (40%)

Allergy 10 (83%) 1 (10%)

In Summary

OPAT

Oral Tolerability

Cardiac Surgery

USA

Organism POET Side Effects

Methicillin susceptible Staphylococcus aureus

Amoxicillin 1 g x 4 and fusidic acid 0.75 g x 2Amoxicillin 1 g x 4 and rifampicin 0.6 g x 2

Linezolid 0.6 g x2 and fusidic acid 0.75 g x 2Linezolid 0.6 g x 2 and rifampicin 0.6 g x 2

Amoxicillin: headache, diarrhea, nausea, vomiting

Fusidic Acid: not available in the US, thrombocytopenia, GI upset, jaundice

Linezolid:thrombocytopenia, optic neuropathy, abnormal LFTs

Rifampicin: hepatic insufficiency, DDI, discoloration of secretions

Dicloxacillin: abdominal pain, diarrhea

Coagulase-negative staphylococci and Methicillin sensitive Staphylococcus aureus

Dicloxacillin 1 g x 4 and fusidic acid 0.75 g x 2 Dicloxacillin 1 g x 4 and rifampicin 0.6 g x 2

Linezolid 0.6 g x 2 and fusidic acid 0.75 g x 2 Linezolid 0.6 g x 2 and rifampicin 0.6 g x 2

Methicillin Resistant coagulase-negative staphylococci

Linezolid 0.6 g x 2 and fusidic acid 0.75 g x2

Linezolid 0.6 g x2 and rifampicin 0.6 x2

Organism POET Antibiotics Side Effects

Enterococcus faecalis Amoxicillin 1g x 4 and rifampicin 0.6 g x2 Amoxicillin 1 g x4 and moxifloxacin 0.4 g x 1

Linezolid 0.6 x2 and rifampicin 0.6 g x 2Linezolid 0.6 g x2 and moxifloxacin 0.5 g x 2

Amoxicillin: headache, diarrhea, nausea, vomiting

Linezolid:thrombocytopenia, optic neuropathy, abnormal LFTs

Rifampicin: hepatic insufficiency, DDI, discoloration of secretions

Moxifloxacin: Cardiac abnormalities hypoglycemia, hepatoxicity, tendon rupture, peripheral neuropathy

Clindamycin: C.diff colitis, Jaundice, metallic taste

Streptococci penicillin MIC < 1 mg/L

Amoxicillin 1 g x 4 and rifampicin 0.6 g x 2Amoxicillin 1 g x 4 and moxifloxacin 0.4 g x 1

Linezolid 0.6 g x 2 and rifampicin 0.6 g x 2Linezolid 0.6 g x 2 and moxifloxacin 0.4 g x 1

Streptococci penicillin MIC > 1 mg/L

Linezolid 0.6 g x 2 and rifampicin 0.6 g x 2

Moxifloxacin 0.4 g x 1 and rifampicin 0.6 g x 2

Moxifloxacin 0.4 g x 1 and clindamycin 0.6 x 3

Side Effects

Only reported on those who had to switch therapy, did not account for overall side effects

Adherence

• Exclusion Criteria: • Reduced compliance - not defined

• Significant burden on the healthcare system• Had to be seen 2-3 times a week outpatient

Cardiac surgery during disease course: IV: 75 patients

Oral: 77 patients

Staphylococcus aureus(MSSA)

Oral: 14/22 (63.6%)

IV: 2/15 (13%)

Streptococcus

Enterococcus FaecalisIV: 24/76 (31.5%)

Oral: 4/38 (10.5%)

Oral: 4/38 (10.5%)

Oral: 4/38 (10.5%)

Cardiac Surgery - A Cut to Cure

• 38% of patients underwent cardiac surgery during the course of treatment

• Patients who had cardiac surgery were required to stay on IV antibiotics for at least 7 days following surgery

?

Decreased Duration of Antibiotics with Cardiac surgery

Population: 419 patients • Variety of Gram positive and negative orgs.• Underwent surgery for IE Primary outcome: • Relapse rates of ≤ versus > 3 weeks of therapy

post-surgery Results: • ≤ 3 weeks 2/236 vs. >3 weeks therapy: 1/122

Conclusions: Two weeks of antibiotics after cardiac surgery are sufficient

Population: 140 patients • IE with high risk of complications• Streptococcus viridans or bovis Primary outcome: • Compare re-infection & mortality at

one year for:• 15 days of therapy vs 32 days

post-cardiac surgeryResults: • Mortality, relapse and re-infection

rates were similar between groups

Conclusions: ≤15 days of therapy can be considered for high risk patients who

undergo cardiac surgery without worsening clinical outcomes

Morris AJ. Clinical Infectious Diseases 2005; 41:187–94Munoz et al. Clin Microbiol Infect 2012; 18: 293–299

Short Course IV Therapy

• Viridans Group Streptococcus & Streptococcus gallolyticus

Penicillin MIC < 0.12 mcg/mL

• Using 2 IV agents allows for2 week short course therapy

• Ceftriaxone/gentamicin once daily

Murray BE. Antimicrob Agents Chemother. 1986;30:861–864Sexton DJ,. Clin Infect Dis. 1998;27:1470–147

POET Trial

Outpatient Antimicrobial Therapy (OPAT)

• OPAT is readily available in the United States• Home infusion

• Infusion Centers

• Nursing Homes

• Emerging Infectious Disease Network Survey 2014• 81% of 555 ID physicians surveyed said prescribe OPAT greater than

once a month

• Weekly monitoring of labs is consistently done

Norris A. Clinical Infectious Diseases, ciy745,

Complications with OPAT are infrequent

Lane MA. Infect Control Hosp Epidemiol. 2014 July ; 35(7): 839–844.

Applicability to the Commonwealth

• PWID – only 5 patients included in POET • IE increased from 7% to 12.1% from 2000 to 2013

• Especially in 15-34 year olds

• Obesity in Massachusetts is on rise

Wurcel AG. Open Forum Infectious Diseases, Volume 3, Issue 3, Summer 2016, ofw157https://www.americashealthrankings.org/explore/annual/measure/Obesity/state/MA Accessed on4.12.19,

CDC Behavioral Risk Factor Surveillance System

Summary

• IV therapy is the standard of care• Is necessary in high inoculum infections

• Short course IV therapy is available for high susceptible infections or those undergoing CT Surgery

• POET “holes”• Oral antibiotics have multiple side effects that limit tolerability

• Compliance was re-enforced with frequent outpatient visits, which can be a burden on the healthcare system

• OPAT is readily available in the USA and can be safely administered

• Obesity • ¼ of Massachusetts population is defined as obese and the number is rising

• Gastric absorption issues were not defined and drug levels are readily available to make adjustments in the USA for these agents.

Complications of OPAT• Complications reported in 24% of patients receiving OPAT

• Most common• Allergic reactions• Hematologic complications• Diarrhea• Readmission• Line related complications

• CLABSI estimated as 0.79-4.9 infections per 1000 line days

• Switches and readmissions common• In Boston, 400 OPAT courses with a beta-lactam, 12.5% required a switch• In GAMES prospective cohort study, 10.6% of patients had a readmission solely related to the

catheter or antibiotic 10.6% of 429 patients w/ IE• Illinois cohort: identified 20% of 216 OPAT patients had 30D readmissions; 24% were due to adverse

reactions to the antibiotics 16% were catheter related complications

• Minimal Physician Oversight• 92% of ID Physicians review labs at least weekly• 29% of ID Physicians see OPAT patients at least weekly• 14% have no coverage nights/ weekends for complications

Muldoon EG, Snydman DR, Penland EC, et al. Clin Inf Dis. 2013; 57(3):419-424. // Means LM, Blesdale S, Sikka M, et al. Pharmacotherapy. 2016;36(8):934-939.Norris AH, Shrestha NK, Allison GM, et al. Clin Inf Dis. 2019; 68(1):e1-e35. // Percias JM, Llopis J, Gonzalez-Ramallo V, et al. Clin Inf Dis. 2019; doi: 10.1093/cid/ciz030

Complications warranting switch in POET: IV arm- 43 patients (22%)PO arm- 24 patients (12%) p<0.01

Logistics of Home IV Therapy

• Nurses will come to the home not more frequently than q24h• Often less than that

• Infusions often require 15-30 mins of prep time, and 15-30 mins at the end of infusion for clean up

• Not licensed to dispense meds for IV Push• Unrealistic to give antibiotic more than q12h

• Patients (or family members)• Maintain the PICC, including flushes• Manage dressing changes• Monitor for access complications

• Medications are delivered to the house• May require activation/reconstitution (Add-Vantage, MiniBag Plus, etc)• Storage under refrigeration (in the patient’s home food refrigerator)

Insurance Coverage• Characteristics of patients at risk for endocarditis generally associated

with patients on Medicare or Medicaid• Advanced age• IV Drug Use• Hemodialysis

• CMS does not cover Home Infusion Therapy for antibiotics• The majority of Medicare beneficiaries (FFS) do not have coverage for home

infusion therapy• Medicare Part D covers drug, but no one covers nursing, supplies, and home visits• Exception only for those considered to be homebound

• Masshealth does not cover home infusion therapy for antibiotics• Will cover cost of drug, but will not cover nursing, supplies, or visits

• In spite of lack of payment, must be an accredited with CMS to provide services

• Commercial insurance and Medicare Part C (Medicare Advantage Plans) generally cover home infusion therapy

• There is mounting evidence that endocarditis does not uniformly require 4-6 weeks of IV therapy

• There are still gaps and several patients who wouldn’t qualify for the available studies based on their clinical status

• In spite of being the current “standard of care,” long courses of IV antibiotics bear a heavy toll with many risks and notable cost

• External factors will likely impact care paradigms in the future• For example: opioid crisis, pressure from payers, political climate• Currently moving towards lower cost, higher efficiency treatments

which aligns with the outpatient oral treatment of endocarditis

• Where do you think the pendulum should land?

Closing Arguments

Endocarditis Debate:IV to P.O. or IV to

N.O.