II Jornadas de Actualización de la Endocarditis Infecciosa Avances en Tratamiento Antibiótico Hospital Clinic of San Carlos, Madrid (Spain) - May 17 th 2019 What do we have to change from the 2015 AHA & ESC IE Clinical Practice Guidelines? Prof. Jose M. Miro Infectious Diseases Service Hospital Clínic IDIBAPS University of Barcelona Barcelona, 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: Angelini Abbvie Bristol-Myers Squibb Cubist Gilead Sciences Genentech Merck Medtronic Novartis Pfizer Theravance ViiV Healthcare
What do we have to change from the 2015 AHA & ESC IE Clinical Practice Guidelines? Introduction What are the differences? Future challenges on antimicrobial treatment Take home messages
2015 Circulation. 2015; On line. www.americanheart.org 2015 Eur Heart J. 2015; On line. 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 Surgical indications Several differences Some differences
What do we have to change from the 2015 AHA & ESC IE Clinical Practice Guidelines? Introduction What are the differences? Future challenges on antimicrobial treatment Take home messages
What are the differences in the antimicrobial regimens? AHA ESC Empirical antibiotic therapy VGS/S. gallolyticus IE Depend on symptom evolution and epidemiological factors ( case by case basis ) No differences ESC also recommends Amoxicillin Defined for NVIE & PVE, CA-IE & N/NN HCA IE E. faecalis IE No differences ESC also recommends Amoxicillin and Gentamicin is given QD Staphylococcal NV IE Staphylococcal PVE No differences for MSSA and MRSA. Vancomycin first choice for MRSA. ESC recommends as alternative trimethoprim sulfamethoxazole + clindamycin. Gentamicin QD/BID 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
Trimethoprim sulfamethoxazole + clindamycin as alternative for S. aureus NV IE (ESC Guidelines) Rationale High morbi-mortality for S. aureus endocarditis with current treatment guidelines Toxins? One single center experience ( letter, n=31) Limitations Casalta JP et al. Intern J Antimicrob Agents 2013 Habib G et al. Eur Heart J 2015 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
International ID Experts of IE are not following the Antibiotic Regimens of 2015 AHA/ESC Guidelines Recommendations from more than 30 years ago New antibiotics not evaluated in clinical trials No evidence-based medicine to change clinical guidelines H. Tissot-Dupont et al. CMI. 2017; 23 (2017) 736e739
Experimental Endocarditis Model Day 0 1 2 5 - Aortic valve lesion - catheter (carotid artery) ANTIBIOTIC PROPHYLAXIS - I.V. microorganism challenge PATHOGENESIS ANTIBIOTIC TREATMENT ANTIBIOTIC DIFUSSION INTO VEGETATIONS - Animal sacrifice. Qualitative & quantitative culture of aortic valve vegetations Garrison & Freedman, 1970; Durack & Benson, 1972; Sande & Irwin, 1974.
What do we have to change from the 2015 AHA & ESC IE Clinical Practice Guidelines? Introduction What are the differences? Future challenges on antimicrobial treatment Take home messages
Needs in IE Antimicrobial Therapy 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
Cloxacillin plus Gentamicin vs. Cloxacillin plus Daptomycin for the Treatment of MSSA EE Garcia de la Maria C et al. ECCMID, Amsterdam, NL, April 2016. Manuscript in preparation Treatment group Animals with sterile vegetations/total (%) Median log 10 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 a P=.001; b P<.001; c P=.001; d P<.001; e P=.026; f P=.086; g P=.008
Cloxacillin plus Gentamicin vs. Cloxacillin plus Daptomycin for the Treatment of MSSA EE Garcia de la Maria C et al. ECCMID, Amsterdam, NL, April 2016 Treatment group Animals with sterile vegetations/total (%) Median log 10 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) Cloxacillin (2g/4h) + Daptomycin (6mg/kg/24h) Fosfomycin (2g/6h) + Daptomycin (6mg/kg/24h) 3 / 10 (30) f,g 2 (0.5 2) e,h,i 8/11 (73) a,f 0 (0 1) c,h 10/11 (91) b,g 0 (0 0) d,i a P=.001; b P<.001; c P=.001; d P<.001; e P=.026; f P=.086; g P=.008; h P=.080; i P=.005
RCT of the Efficacy and Safety of Cloxacillin vs. Cloxacillin plus Daptomycin for the Treatment of MSSA IE Multicenter, Randomized (1:1) Open-label Clinical Trial MSSA IE (N=TBD) Cloxacillin 4-6 wk Cloxacillin (1 wk) + Daptomycin (4-6 wk) Recruitment: 2 yr. Europe Only MSSA IE End points: TOC 12 weeks after finishing Rx, Toxicity, Relapses, Resistance, Surgery and Mortality.
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) Van Van+BL Davis JS et al. CID 2016.
RCT Efficacy and Safety of β-lactam plus Daptomycin vs. Vancomycin for MRSA BSI CAMERA2 Australasian Society of Infectious Diseases Clinical Research Network Multicenter, Randomized Open-label Clinical Trial MRSA BSI Daptomycin (6-10 mg/kg) ± β-lactam (7 days) (N=440) Vancomycin (1.5 g BID) ± β-lactam (7 days) 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. Tong et al. Trials. 2016; 17:170
Daptomycin (DAP) plus Fosfomycin (FOM) is Synergistic against Methicillin-susceptible (MSSA) and Methicillinresistant Staphylococcus aureus (MRSA) Strains Miro JM et al. Antimicrob Agents Chemother. 2012; 56:4511-5 Two patients with complicated MRSA NV IE and one patient with MSSA PVE were succesfully treated with the combination of daptomycin plus fosfomycin. MSSA (N=6) MRSA (N=6)
Daptomycin plus Fosfomycin vs. Daptomycin plus Cloxacillin for the Treatment of MRSA EE with a Van MIC of 2 mg/l Garcia de la María C et al. Antimicrob Agents Chemother. 2018, on line.
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 Multicenter, Randomized (1:1) Open-label Clinical Trial MRSA BSI Daptomycin (DAP) 10 mg/kg/d (N=220) DAP (10 mg/kg/d) + Fosfomycin (2 g/6h) 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.
2015 Circulation. 2015; On line. www.americanheart.org 2015 Eur Heart J. 2015; On line. www.secardiologia.es
Ampicillin-Ceftriaxone vs. Ampicillin-Gentamicin for the Treatment of E. faecalis IE: Cohort Study Fernandez-Hidalgo N et al., Clin Infect Dis. 2013; 56:1261-8.. A+C* N=159 Type of Treatment 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. 2002-06 N=41 Study Periods 2007-11 N=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.
Evaluation of the Efficacy and Safety of Ampicillin plus Ceftriaxone vs. Gentamicin for the Treatment of EFIE Multicenter, Randomized (1:1) Open-label Clinical Trial EFIE (N=TBD) Ampicillin (4-6 wk) + Gentamicin (QD, 2 wk) Ampicillin (6 [4] wk) + Ceftriaxone (6 [4] wk) Recruitment: 2 yr. Europe Only E. faecalis IE without HLAR End points: TOC 24 weeks after finishing Rx, Toxicity, Relapses, Surgery and Mortality. Miro JM et al., Circulation. 2013; 127:1763-6
Research in Antimicrobial Therapy A paradigm shift in the antibiotic treatment of infective endocarditis may be coming Sequential antimicrobial treatment: from INTRAVENOUS to ORAL
The POET Trial: IV to Oral De-escalation Trial Iversen K et al. Am Heart J 2013;165:116-22 Multicenter, Randomized (1:1) Open-label Clinical Trial in Denmark NV/PVIE (N=400) Full course of IV Therapy 6 weeks IV (10 d.) to Oral Therapy 6 weeks 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.
The RODEO Trial: IV to Oral De-escalation Trial Multicenter, Randomized (1:1) Open-label Clinical Trial in France S. aureus & CoNS IE (N=324) Full course of IV Therapy 6 weeks (2015 ESC) IV (14 d.) to Oral Therapy LEV+RIF 4 weeks 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.
New OPAT Regimens 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)?
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 31% 45% 24% 97% 16 (6-30) NA 6% 3% 97% *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) Austrian Study** N=27 59% 22% 19% 89% NA 42*** 7% 7% 93%
What do we have to change from the 2015 AHA & ESC IE Clinical Practice Guidelines? Introduction What are the differences? Future challenges on antimicrobial treatment Take home messages
Take home messages 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.
Sociedad Española de Infecciones Cardiovasculares (SEICAV) Congreso SEICAV 2018 Colegio Oficial de Médicos de Sevilla Sevilla 16 y 17 de Noviembre del 2018
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 Microbiology F. Marco M. Almela J. Vila Cardiology C. Falces J.C. Paré B. Vidal J.M. Tolosana J. Ortiz M. Azqueta M. Sitges Other Services D. Soy / M. Brunet D. Fuster / U. Granados J. Llopis / X. Urra P. Castro Cardiac Surgery E. Quintana E. Sandoval D. Pereda R. Cartañá S. Ninot M. Castellà Pathology J. Ramírez Anaesthesiology G. Fita I. Rovira Experimental Endocarditis Lab. C. García de la María J. García Collaborations G.R. Corey V. Fowler A. Bayer J. Entenza P. Moreillon C. Arias A.W. Karchmer C.A. Mestres C. Cervera Barcelona- Spain