IV to P.O. IV to P.O. or IV to or IV to N.O. N.O. Maureen - - PowerPoint PPT Presentation

En Endo docardit carditis is De Deba bate: te: IV to IV to P.O. P.O. or IV to

• r IV to

N.O. N.O.

Kirthana Beaulac, PharmD, BCPS Tufts Medical Center Maureen Campion, PharmD, BCIDP UMass Memorial 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

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

• r Other Colonized

Tissue

Trauma Bacteremia

Bacterial division, fibrin deposition, platelet aggregation, extracellular proteases, protection from neutrophils

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

• Vegetation
• Persistent after systemic

embolization

• Mitral valve leaflet vegetation > 10

mm

• > 1 embolic events in first 2 weeks
• f 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

Na Native ive Va Valve e En Endo docard arditis itis

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 PLUS Gentamicin 3 mg/kg/day IV/IM 4 weeks 2 weeks Ceftriaxone 2 g every IV/IM every 24 hours PLUS 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 doses OR Ceftriaxone 2 G every IV/IM every 24 hours WITH OR WITHOUT Gentamicin 3 mg/kg/d IV/IM 6 weeks 6 weeks 2 weeks Staphylococcus Nafcillin or oxacillin 12 g/ 24 h continuously or in 4-6 divided doses PLUS Rifampin 300 mg IV/PO every 8 hours PLUS Gentamicin 3 mg/kg every 8 hours > 6 weeks > 6 weeks 2 weeks Vancomycin 15 mg/kg every 12 hours PLUS Rifampin 300 mg IV/PO every 8 hours PLUS Gentamicin 3 mg/kg every 8 hours > 6 weeks > 6 weeks 2 weeks Enterococcus Ampicillin 2 g every 4 hours OR Penicillin 18-30 million units/24 h IV continuously or in 6 divided doses PLUS Gentamicin 3 mg/kg in 2-3 divided doses 4-6 weeks 4-6 weeks 4-6 weeks Ampicillin 2 g every 4 hours PLUS Ceftriaxone 2 g every 12 hours 6 weeks 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

• rter

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 (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;144:524–527 Sabath LD, Effect of inoculum and of beta-lactamase Antimicrob Agents Chemother. 1975;8:344–349

MIC 4 MIC 64 106 cfu 1010 cfu

Ino nocu culum lum Effect ect on

• n 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

• r two-fold

Four fold-or greater Eight fold or greater 16 fold of greater >32 fold

Methicillin

93 7

Nafcillin

84 16 3

Dicloxacillin

47 53 19 5 1

Cloxacillin

40 60 19 14

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%

• f the time.

Sabath LD. AAC Sept 1975; 344-329.

IV is V is the he wa way to

• 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

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.

Ba Barriers ers

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%)

Or Oral l Tr Treatment atment fo for MRSA A Bactere teremia mia

• 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

An Antibiot biotic ic Tr Trea eatme ment nt Re Regi gime mens ns

• 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/F 9% Amox +R/F 35% Moxi + R/F/clinda 2% Linezolid + R/F 11% Pen alone/+R 2% Moxi + linezolid 7% Amox + Moxi 20% Amox + linez 11% Other 3%

Pr Prima mary y Ou Outcome come

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

Ti Time me to Ou

• Outco

come me

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)

Sa Safet ety

• 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 Su n Summ mmar ary

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 2 Amoxicillin 1 g x 4 and rifampicin 0.6 g x 2 Linezolid 0.6 g x2 and fusidic acid 0.75 g x 2 Linezolid 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

• f 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 2 Linezolid 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

• f 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 2 Amoxicillin 1 g x 4 and moxifloxacin 0.4 g x 1 Linezolid 0.6 g x 2 and rifampicin 0.6 g x 2 Linezolid 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 de Effec ects ts

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

Ad Adhe herenc ence e

• 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 Faecalis IV: 24/76 (31.5%) Oral: 4/38 (10.5%) Oral: 4/38 (10.5%) Oral: 4/38 (10.5%)

Ca Cardi diac ac Su Surge gery ry - A Cu A Cut to

• Cu

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 creased Duration ration of f Antibi tibiotics

• tics wit

ith Cardiac rdiac surgery rgery

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

post-cardiac surgery Results:

• 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; 41:187–94 Munoz et al. Clin Microbiol Infect 2012; 18: 293–299

Sh Shor

• rt Co

Cour urse e IV The V Therap apy y

• Viridans Group Streptococcus

& Streptococcus gallolyticus

Penicillin MIC < 0.12 mcg/mL

• Using 2 IV agents allows for

2 week short course therapy

• Ceftriaxone/gentamicin once daily

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

POET T Trial ial

Ou Outpa tpatient tient Antimic timicrobial robial Th Therapy rapy (OP OPAT) AT)

• 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
• nce a month
• Weekly monitoring of labs is consistently done

Norris A. Clinical Infectious Diseases, ciy745,

Compl mplications ications wit ith h OP OPAT T are in infre frequent quent

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

Ap Appl plica icability bility to th

• the

e Co Comm mmon

• nwe

wealth alth

• 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, ofw157 https://www.americashealthrankings.org/explore/annual/measure/Obesity/state/MA Accessed on4.12.19, CDC Behavioral Risk Factor Surveillance System

Su Summ mmar ary

• 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.

Co Comp mplicati ications

• ns of
• f OP

OPAT AT

• 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

Lo Logi gisti stics cs of

• f Ho

Home me IV Th V Ther erap apy

• 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)

Ins nsuranc urance e Co Cover erage age

• 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?

Cl Clos

• sing

ing Ar Argu gume ment nts

En Endo docardit carditis is De Deba bate: te: IV IV to P. to P.O.

• O. or
• r IV

IV to to N. N.O. O.