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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: [email protected]
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