What do we have to change from the 2015 AHA & ESC IE ... · What do we have to change from the...

What do we have to change from the 2015

AHA & ESC IE Clinical Practice Guidelines?

II Jornadas de Actualización de la Endocarditis Infecciosa

Avances en Tratamiento AntibióticoHospital Clinic of San Carlos, Madrid (Spain) - May 17th 2019

Prof. Jose M. Miro Infectious Diseases ServiceHospital Clínic – IDIBAPS

University of BarcelonaBarcelona, Spain

Email address: jmmiro@ub.edu

Potential conflict of interest

Dr. José M Miró has received honoraria for speaking or

participating in Advisory Boards and/or research grants from

the following Pharmaceutical Companies:

Merck

Medtronic

Novartis

Pfizer

Theravance

ViiV Healthcare

Angelini

Abbvie

Bristol-Myers Squibb

Cubist

Gilead Sciences

Genentech

• Introduction

• What are the differences ?

• Future challenges on antimicrobial treatment

• Take home messages

What do we have to change from the 2015

AHA & ESC IE Clinical Practice Guidelines?

2015Circulation. 2015; On line.

2015Eur Heart J. 2015; On line.

www.americanheart.org

www.secardiologia.es

What are the differences between the 2015

AHA & ESC IE Clinical Practice Guidelines?

AHA ESC

Antibiotic prophylaxis No (2009) Yes

“Endocarditis Team” No Yes

18F-FDG PET/CT as diagnostic

criteria for PVE

No Yes

Antimicrobial regimens Several differences

Surgical indications Some differences

• Introduction

• What are the differences ?

• Future challenges on antimicrobial treatment

• Take home messages

What do we have to change from the 2015

AHA & ESC IE Clinical Practice Guidelines?

What are the differences in the antimicrobial regimens?

AHA ESCEmpirical antibiotic

therapy

Depend on symptom evolution and

epidemiological factors

(“case by case basis”)

Defined for NVIE &

PVE, CA-IE & N/NN HCA

IE

VGS/S. gallolyticus IE No differences

ESC also recommends Amoxicillin

E. faecalis IE No differences

ESC also recommends Amoxicillin and Gentamicin is given QD

Staphylococcal NV IE No differences for MSSA and MRSA. Vancomycin first choice

for MRSA. ESC recommends as alternative trimethoprim–

sulfamethoxazole + clindamycin. Gentamicin QD/BID

Staphylococcal PVE No differences for MSSA and MRSA. Vancomycin first choice

for MRSA. ESC recommends Gentamicin QD/BID

Alternative as first line treatment for MSSA or

MRSA native valve endocarditis (ESC Guidelines)

Habib G et al. Eur Heart J. 2015

Casalta JP et al. Intern J Antimicrob Agents 2013

Habib G et al. Eur Heart J 2015

• Rationale– High morbi-mortality for S. aureus endocarditis with current treatment guidelines

– Toxins ?

– One single center experience (‘letter’, n=31)

• Limitations– Two RCT found that TMP/SMZ is less effective than vancomycin for S. aureus BSI

– Clindamycin also inferior to vancomycin for BSI (RCT)

– Hematotoxicity associated with 6 weeks of high doses TMP/SMZ

– No evidence for any role of toxins in S. aureus endocarditis

Markowitz N et al. Annals Intern Med 1992

Paul M et al BMJ 2015

Watanakunakorn et al. Am J Med 1976

Bouchiat C et al. Infect Gen Evol 2015

Trimethoprim–sulfamethoxazole + clindamycin as

alternative for S. aureus NV IE (ESC Guidelines)

International ID Experts of IE are not following the

Antibiotic Regimens of 2015 AHA/ESC Guidelines

H. Tissot-Dupont et al. CMI. 2017; 23 (2017) 736e739

• Recommendations from more than 30 years ago

• New antibiotics not evaluated in clinical trials

• No evidence-based medicine to change clinical guidelines

Day

0- Aortic valve lesion - catheter (carotid artery)

- I.V. microorganism challenge

ANTIBIOTIC TREATMENT

- Animal sacrifice. Qualitative & quantitative culture of aortic valve vegetations

1

5

2

ANTIBIOTIC DIFUSSION INTO VEGETATIONS

ANTIBIOTIC PROPHYLAXIS

Garrison & Freedman, 1970; Durack & Benson, 1972; Sande & Irwin, 1974.

PATHOGENESIS

Experimental Endocarditis Model

• Introduction

• What are the differences ?

• Future challenges on antimicrobial treatment

• Take home messages

What do we have to change from the 2015

AHA & ESC IE Clinical Practice Guidelines?

• No gentamicin for MSSA NA IE … but daptomycin?

• Role of rifampin – The ARREST Trial = No role !

• Better therapies for susceptible GP cocci

• Better therapies for MDR GP cocci

• New strategies: IV – Oral De-escalation (several RCT)

• Role of new antibiotics: Dalbavancin for OPAT,

Tedizolid for sequential oral therapy.

• Optimal treatment for HACEK, ABI/GRA, Fungal,

Whipple, Q fever and Bartonella IE

Needs in IE Antimicrobial Therapy

Treatment groupAnimals with sterile

vegetations/total (%)

Median log10 CFU/g of

vegetation (IQR)

Control (No treatment) 0 / 10 (0) 9 (8.1 - 9.3)

Daptomycin (6mg/kg/24h) 0 / 11 (0) 2 (2 – 3.3)

Cloxacillin (2g/4h) 0 / 10 (0) 3 (2 – 4.5)e

Cloxacillin (2g/4h)

+ Gentamicin (1mg/kg/8h)3 / 10 (30) 2 (0.5 – 2)e

aP= .001; bP< .001; cP= .001; dP< .001; eP= .026; fP= .086; gP= .008

Cloxacillin plus Gentamicin vs. Cloxacillin plus Daptomycin

for the Treatment of MSSA EEGarcia de la Maria C et al. ECCMID, Amsterdam, NL, April 2016. Manuscript in preparation

Treatment groupAnimals with sterile

vegetations/total (%)

Median log10 CFU/g of

vegetation (IQR)

Control (No treatment) 0 / 10 (0) 9 (8.1 - 9.3)

Daptomycin (6mg/kg/24h) 0 / 11 (0)a,b 2 (2 – 3.3) c,d

Cloxacillin (2g/4h) 0 / 10 (0) 3 (2 – 4.5)e

Cloxacillin (2g/4h)

+ Gentamicin (1mg/kg/8h)3 / 10 (30)f,g 2 (0.5 – 2)e,h,i

Cloxacillin (2g/4h)

+ Daptomycin (6mg/kg/24h) 8/11 (73)a,f 0 (0 – 1)c,h

Fosfomycin (2g/6h)

+ Daptomycin (6mg/kg/24h) 10/11 (91)b,g 0 (0 – 0)d,i

aP= .001; bP< .001; cP= .001; dP< .001; eP= .026; fP= .086; gP= .008; hP= .080; iP= .005

Cloxacillin plus Gentamicin vs. Cloxacillin plus Daptomycin

for the Treatment of MSSA EEGarcia de la Maria C et al. ECCMID, Amsterdam, NL, April 2016

• Recruitment: 2 yr. Europe

• Only MSSA IE

• End points: TOC 12 weeks after finishing Rx, Toxicity, Relapses, Resistance, Surgery and Mortality.

Multicenter, Randomized (1:1) Open-label Clinical Trial

Cloxacillin 4-6 wk

Cloxacillin (1 wk)+ Daptomycin (4-6 wk)

RCT of the Efficacy and Safety of Cloxacillin vs. Cloxacillin

plus Daptomycin for the Treatment of MSSA IE

MSSA IE

(N=TBD)

What are the problems when we are

treating MSSA/MRSA IE with Vancomycin?

- Poor bactericidal activity

- Poor diffusion within the vegetations

- Vancomycin MIC issues (AUC/MIC PD target)

- hVISA strains

- Tolerance

- … Renal toxicity

→ High rate of failures

→ Still recommended by 2015 AHA/ESC Guidelines

Pilot RCT: Combination of Vancomycin and β-lactam

(BL) therapy for MRSA Bacteremia (CAMERA)

Davis JS et al. CID 2016.

Van Van+BL

• Recruitment: 2016-19; 12 weeks of F/U.

• Drugs adjusted to renal failure

• β-lactams: flucloxacillin, cloxacillin, or cefazolin

• Primary Endpoint (composite outcome at 90-d): Mortality, BC+ 5 days, Relapse, Rx failure.

Multicenter, Randomized Open-label Clinical Trial

Daptomycin (6-10 mg/kg)

± β-lactam (7 days)

Vancomycin (1.5 g BID)

± β-lactam (7 days)

RCT Efficacy and Safety of β-lactam plus Daptomycin

vs. Vancomycin for MRSA BSI – CAMERA2Australasian Society of Infectious Diseases Clinical Research Network

MRSA BSI

(N=440)

Tong et al. Trials. 2016; 17:170

Daptomycin (DAP) plus Fosfomycin (FOM) is Synergistic against Methicillin-susceptible (MSSA) and Methicillin-

resistant Staphylococcus aureus (MRSA) StrainsMiro JM et al. Antimicrob Agents Chemother. 2012; 56:4511-5

MSSA (N=6) MRSA (N=6)

Two patients with complicated MRSA NV IE and one patient with MSSA PVE were

succesfully treated with the combination of daptomycin plus fosfomycin.

Daptomycin plus Fosfomycin vs. Daptomycin plus Cloxacillin

for the Treatment of MRSA EE with a Van MIC of 2 mg/LGarcia de la María C et al. Antimicrob Agents Chemother. 2018, on line.

• Recruitment: 2014-17; 12 weeks of F/U.

• Drugs adjusted to renal failure

• Susceptible to study drugs

• End points: TOC 12 weeks after finishing Rx, Toxicity, Relapses, Resistance and Mortality.

Multicenter, Randomized (1:1) Open-label Clinical Trial

Daptomycin (DAP)

10 mg/kg/d

DAP (10 mg/kg/d)

+ Fosfomycin (2 g/6h)

Evaluation of the efficacy and safety of Daptomycin ±Fosfomycin for the treatment of MRSA BSI in Spain

PI 12/01907 - Dr. Miquel Pujol (H. Bellvitge) BACSARM RCT

MRSA BSI

(N=220)

2015Circulation. 2015; On line.

2015Eur Heart J. 2015; On line.

www.americanheart.org

www.secardiologia.es

Ampicillin-Ceftriaxone vs. Ampicillin-Gentamicin

for the Treatment of E. faecalis IE: Cohort StudyFernandez-Hidalgo N et al., Clin Infect Dis. 2013; 56:1261-8. .

Type of Treatment

A+C*N=159

A+G**N=87

P value

- AE leading Rx D/C 1% 25%*** <0.001

- Died on Rx 22% 21% 0.91

- Died after Rx (3 months) 8% 7% 0.72

- Surgery 33% 40% 0.39

- Rx failure 1% 2% 0.54

- Relapses (survivors) 3% 4% 0.67

* Ampicillin 2 g/4 h plus ceftriaxone 2 g/12 h during 6 weeks; 51 (32%) cases had HLAR strains.

** Ampicillin plus gentamicin following AHA Guidelines; *** Renal failure in most cases (23% vs. 0%, P<0.001).

Ampicillin plus Short vs. Standard Gentamicin

Course for the Treatment of E. faecalis IE*Dahl A et al., Circulation. 2013;127:1810-7.

Study Periods

2002-06N=41

2007-11N=42

P value

- Duration of Gentamicin 28 (18-42) 14 (7-15) <0.001

- Gentamicin QD dosing 80% 93% 0.049

- ∆ eGFR (discharge–baseline)** -11 -1 0.009

- Died on Rx 4% 2% 0.43

- 1-yr event free survival*** 66% 69% 0.75

- Surgery 37% 33% 0.70

- Relapses (survivors) 7% 5% 0.67

* There were no cases with HLAR. Treatment duration following AHA Guidelines; ** in ml/min.

*** 1-year event free survival = No relapse, no death.

• Recruitment: 2 yr. Europe

• Only E. faecalis IE without HLAR

• End points: TOC 24 weeks after finishing Rx, Toxicity, Relapses, Surgery and Mortality.

Multicenter, Randomized (1:1) Open-label Clinical Trial

Ampicillin (4-6 wk)

+ Gentamicin (QD, 2 wk)

Ampicillin (6 [4] wk)

+ Ceftriaxone (6 [4] wk)

Evaluation of the Efficacy and Safety of Ampicillin plus

Ceftriaxone vs. Gentamicin for the Treatment of EFIE

EFIE

(N=TBD)

Miro JM et al., Circulation. 2013; 127:1763-6

→ A paradigm shift in the antibiotic

treatment of infective endocarditis may

be coming …

→ Sequential antimicrobial treatment:

from INTRAVENOUS to ORAL

Research in Antimicrobial Therapy

• Recruitment will finished by 2017.

• All cases of streptococcal, staphylococcal, or enterococcal left sided NV/PV IE will be included.

• Susceptible to study drugs & PK studies

• The primary end point is a composition of all-cause mortality, unplanned cardiac surgery, embolic

events, and relapses.

Multicenter, Randomized (1:1) Open-label Clinical Trial in Denmark

Full course of IV Therapy

6 weeks

IV (10 d.) to Oral Therapy

6 weeks

NV/PVIE

(N=400)

The POET Trial: IV to Oral De-escalation TrialIversen K et al. Am Heart J 2013;165:116-22

• Approved in October 2014.

• Recruitment started on March 2016.

• Only staphylococcal left sided NV/PV IE will be included. Susceptible to study drugs (MSSA, MSSE)

• The primary end point is a composition (M3) of all-cause mortality, unplanned cardiac surgery and

relapses.

Multicenter, Randomized (1:1) Open-label Clinical Trial in France

Full course of IV Therapy

6 weeks (2015 ESC)

IV (14 d.) to Oral Therapy

LEV+RIF 4 weeks

S. aureus &

CoNS IE

(N=324)

The RODEO Trial: IV to Oral De-escalation Trial

• Dalbavancin, a new lipoglycopeptide with a

half-life of 14 days. Dosage: IV 1000 mg loading

dose (LD) followed 1 week later by a 500 mg

dose.

• Indication: uSSTI, cSSTI

• Role in IE (off-label use)?

New OPAT Regimens

Dalbavancin, IE & OPAT in 2018

Type of IE

- NVE

- PVE

- PCM/ICD

Previous therapy

- Days (median, IQR)

OPAT, days (median)

- Adverse events

- Failures

- Cure rate

Spanish Study*

N= 29

Austrian Study**

N=27

31%

45%

24%

97%

16 (6-30)

NA

6%

3%

97%

59%

22%

19%

89%

NA

42***

7%

7%

93%

*Hidalgo-Tenorio C et al. ECCMID, Madrid, 2018, P2017; ** Tobudic S et al. Clin Infect Dis. 2018; on line.

*** 1/3 received 500 mg once-weekly (LD 1000 mg) and 2/3 500 mg twice-weekly (LD 1500 mg)

• Introduction

• What are the differences ?

• Future challenges on antimicrobial treatment

• Take home messages

What do we have to change from the 2015

AHA & ESC IE Clinical Practice Guidelines?

• There are several differences between 2015 AHA and ESC Guidelines

regarding the recommend antibiotic regimens and their posology.

• In addition, the ID experts do not follow these recommendations,

especially with regard to staphylococcal endocarditis in NV and PVE

and NBC-IE.

• In the next few years, the role of daptomycin in combination and

dalbavancin (OPAT) should be defined, as well as the best

antimicrobial therapy for E. faecalis IE and whether the sequential IV -

oral de-escalation antimicrobial treatment is possible in IE.

• To change the guidelines, clinical trials and multicenter cohort studies

with a large number of patients will be necessary.

Take home messages

16 y 17 de Noviembre del 2018

Congreso SEICAV 2018

Sociedad Española de Infecciones Cardiovasculares (SEICAV)

Colegio Oficial de Médicos de Sevilla

Sevilla

2018 Members of the Hosp. Clinic Cardiovascular Infections & Experimental Endocarditis Working Group

Infectious

Diseases

J. Ambrosioni

M. Hdez-Meneses

A. Tellez

J.M. Pericas

M. Ripa

A. Moreno

Experimental

Endocarditis Lab.

C. García de la María

J. García

Cardiology

C. Falces

J.C. Paré

B. Vidal

J.M. Tolosana

J. Ortiz

M. Azqueta

M. Sitges

Barcelona- Spain

Collaborations

G.R. Corey

V. Fowler

A. Bayer

J. Entenza

P. Moreillon

C. Arias

A.W. Karchmer

C.A. Mestres

C. Cervera

Microbiology

F. Marco

M. Almela

J. Vila

Cardiac

Surgery

E. Quintana

E. Sandoval

D. Pereda

R. Cartañá

S. Ninot

M. Castellà

Pathology

J. Ramírez

Other Services

D. Soy / M. Brunet

D. Fuster / U. Granados

J. Llopis / X. Urra

P. Castro

Anaesthesiology

G. Fita

I. Rovira