Upload
others
View
8
Download
0
Embed Size (px)
Citation preview
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
Jose M. Miro, MD, PhDInfectious Diseases ServiceHospital Clínic – IDIBAPS
University of BarcelonaBarcelona, Spain
Jose M. Miro, MD, PhDInfectious Diseases ServiceHospital Clínic – IDIBAPS
University of BarcelonaBarcelona, Spain
E-mail address: [email protected] address: [email protected]
The Challenge of MDR and XDR InfectionsBarcelona (Spain), September 14th 2018
The Challenge of MDR and XDR InfectionsBarcelona (Spain), September 14th 2018
Potential conflict of interestPotential conflict of interestDr. José M Miró has received honoraria for speaking or
participating in Advisory Boards and/or research grants from the following Pharmaceutical Companies:
Dr. José M Miró has received honoraria for speaking or participating in Advisory Boards and/or research grants from
the following Pharmaceutical Companies:
MerckMedtronicNovartisPfizerRoche TheravanceViiV Healthcare
MerckMedtronicNovartisPfizerRoche TheravanceViiV Healthcare
Abbvie Angelini-Allergan Bristol-Myers Squibb Contrafect Genentech Gilead ScienciesJansen
Abbvie Angelini-Allergan Bristol-Myers Squibb Contrafect Genentech Gilead ScienciesJansen
• Introduction• Empirical antimicrobial therapy• Targeted antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
• Introduction• Empirical antimicrobial therapy• Targeted antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
MRSA Rates Worldwide (2011‐2014)
CDDEP 2015, WHO 2014 and PAHO 2016
Staphylococcus aureus: percentage (%) of invasive isolates resistant to meticillin (MRSA), by EU/EEA countries, 2008–2011
Staphylococcus aureus: percentage (%) of invasive isolates resistant to meticillin (MRSA), by EU/EEA countries, 2008–2011
MicroorganismsMicroorganisms N-HCAN-HCA NN-HCANN-HCA CACA Total (%)Total (%)
CoNSS. aureus- MRSAEnterococcus- E. faecalis- E. faeciumS. pneumoniaeViridans groupListeriaS. pyogenesOther GPB
CoNSS. aureus- MRSAEnterococcus- E. faecalis- E. faeciumS. pneumoniaeViridans groupListeriaS. pyogenesOther GPB
8762147655213
10111
8762147655213
10111
2620699-811-3
2620699-811-3
9357
13103
51159711
9357
13103
51159711
122 (27)117 (25)27 (23)
101 (22)7424
62 (14)26 (6)11 (2)8 (2)
15 (3)
122 (27)117 (25)27 (23)
101 (22)7424
62 (14)26 (6)11 (2)8 (2)
15 (3)N, nosocomial; NN, non-nosocomial; HCA, nosocomial health care–associated; CA, community-acquired
CoNS, coagulase-negative staphylococci; GPB, Gram-positive bacteriaN, nosocomial; NN, non-nosocomial; HCA, nosocomial health care–associated; CA, community-acquired
CoNS, coagulase-negative staphylococci; GPB, Gram-positive bacteria
Gram-Positive Bacteremia - Barcelona (Spain), 2008Cervera C et al. Int J Antimicrob Agents. 2009;34 Suppl. 4:S26-30.
Gram-Positive Bacteremia - Barcelona (Spain), 2008Cervera C et al. Int J Antimicrob Agents. 2009;34 Suppl. 4:S26-30.
Staphylococcus aureus*Coag. Neg. staphylococciViridans group streptococciStreptococcus bovisOther streptococciEnterococciHACEK**Fungi/YeastPolymicrobialCulture negativeOther
Staphylococcus aureus*Coag. Neg. staphylococciViridans group streptococciStreptococcus bovisOther streptococciEnterococciHACEK**Fungi/YeastPolymicrobialCulture negativeOther
31%11%17%
6%6%
10%2%2%1%
10%4%
31%11%17%
6%6%
10%2%2%1%
10%4%
Etiology of Endocarditis - ICE, N=2,781 (2000-05)Murdoch DR et al. Arch Intern Med. 2009;169:463-473
Etiology of Endocarditis - ICE, N=2,781 (2000-05)Murdoch DR et al. Arch Intern Med. 2009;169:463-473
* 31% of isolates were MRSA; ** HACEK = Haemophilus spp., Aggregatibacter (formerly Actinobacillus)actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species
* 31% of isolates were MRSA; ** HACEK = Haemophilus spp., Aggregatibacter (formerly Actinobacillus)actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species
MRSA 31%
MRSA BSI & IE MortalityMRSA BSI & IE Mortality
MRSA Bacteremia- Gasch et al. (N=579)1
- Holmes et al (N=202) 2
MRSA IE- ICE-MD 1979-99 (N=43) 3
- ICE-PCS 2000-05 (N=141) 4
MRSA Bacteremia- Gasch et al. (N=579)1
- Holmes et al (N=202) 2
MRSA IE- ICE-MD 1979-99 (N=43) 3
- ICE-PCS 2000-05 (N=141) 4
MortalityMortality
32%22%
37%30%
32%22%
37%30%
1Gasch O et al. CMI; 2012; 2Holmes N et al. JID; 2011; 3Miro JM, et al. Clin Infect Dis. 2005; 4Fowler V, et al. JAMA, 2005.
1Gasch O et al. CMI; 2012; 2Holmes N et al. JID; 2011; 3Miro JM, et al. Clin Infect Dis. 2005; 4Fowler V, et al. JAMA, 2005.
• Introduction• Empirical antimicrobial therapy• Targeted antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
• Introduction• Empirical antimicrobial therapy• Targeted antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
What is the best empiric antibiotic therapy against MSSA and MRSA Bacteremia/IE?
What is the best empiric antibiotic therapy against MSSA and MRSA Bacteremia/IE?
ß-Lactam [e.g. cloxacillin] (MSSA)
Vancomycin (MSSA/MRSA)
Vancomycin plus ß-Lactams (MRSA/MSSA)
Daptomycin alone (MSSA/MRSA)
Daptomycin plus ß-Lactam/Fosfomycin (MRSA/MSSA)
ß-Lactam [e.g. cloxacillin] (MSSA)
Vancomycin (MSSA/MRSA)
Vancomycin plus ß-Lactams (MRSA/MSSA)
Daptomycin alone (MSSA/MRSA)
Daptomycin plus ß-Lactam/Fosfomycin (MRSA/MSSA)
What is the best empiric antibiotic therapy against MSSA and MRSA Endocarditis?
What is the best empiric antibiotic therapy against MSSA and MRSA Endocarditis?
ß-Lactam [e.g. cloxacillin] (MSSA)
Vancomycin (MSSA/MRSA)
Vancomycin plus ß-Lactams (MRSA/MSSA)
Daptomycin alone (MSSA/MRSA)
Daptomycin plus ß-Lactam/Fosfomycin (MRSA/MSSA)
ß-Lactam [e.g. cloxacillin] (MSSA)
Vancomycin (MSSA/MRSA)
Vancomycin plus ß-Lactams (MRSA/MSSA)
Daptomycin alone (MSSA/MRSA)
Daptomycin plus ß-Lactam/Fosfomycin (MRSA/MSSA)
What is the best empiric therapy againstMSSA and MRSA Bacteremia/IE?Daptomycin in combination (A-I)
Nafcillin/Cloxacillin + Vancomycin (C-III)Gudiol F et al. Enferm Infecc Microbiol Clin. 2015; 33:626-32.
00
2020
4040
6060
8080
100100
AllAll Left-side/bilateralLeft-side/bilateralinvolvementinvolvement
Right-sideRight-sideinvolvementinvolvement
Definite IE by DukeDefinite IE by Dukecriteriacriteria
Infe
ctio
n-re
lated
mor
talit
y (%
)In
fect
ion-
relat
ed m
orta
lity (
%)
β-lactam (n=44)β-lactam (n=44) Vancomycin (n=28)Vancomycin (n=28)
Vancomycin Increased Mortality as Empirical Treatment in MSSA IE in IVDA
Lodise T et al. Antimicrob Agents Chemother 2007;51:3731–3733
Vancomycin Increased Mortality as Empirical Treatment in MSSA IE in IVDA
Lodise T et al. Antimicrob Agents Chemother 2007;51:3731–3733
• Retrospective population-based cohort analysis of IVDU with the following:– MSSA-positive bloodstream infection fulfilling modified Duke criteria for infectious
endocarditis and documented recent IVDU.– Empirical treatment with vancomycin or a β-lactam antibiotic.
• Retrospective population-based cohort analysis of IVDU with the following:– MSSA-positive bloodstream infection fulfilling modified Duke criteria for infectious
endocarditis and documented recent IVDU.– Empirical treatment with vancomycin or a β-lactam antibiotic.
P=0.005P=0.005
P=0.08P=0.08
P=0.04P=0.04
P=0.02P=0.02
Clinical success* in S. aureus-infected patients: mITT populationClinical success* in S. aureus-infected patients: mITT population
*Clinical success at the visit 6 weeks after the end of therapy. Failure defined as clinical failure, microbiological failure, death, failure to obtain blood culture, receipt of potentially effective non-study antibiotics or premature discontinuation of the study medication
*Clinical success at the visit 6 weeks after the end of therapy. Failure defined as clinical failure, microbiological failure, death, failure to obtain blood culture, receipt of potentially effective non-study antibiotics or premature discontinuation of the study medication
Difference in success rates: –4.0%95% CI: –20.3, 12.3
Difference in success rates: –4.0%95% CI: –20.3, 12.3
Difference in success rates: 12.6%, 95% CI: –7.4, 32.6
Difference in success rates: 12.6%, 95% CI: –7.4, 32.6
48.648.644.644.6 44.444.4
31.831.8
Patie
nts,
%Pa
tient
s, %
00
1010
2020
3030
4040
5050
33/7433/74 34/7034/70 20/4520/45 14/4414/44
MSSA (n=144)MSSA (n=144) MRSA (n=89)MRSA (n=89)
Daptomycin 6 mg/kgDaptomycin 6 mg/kgComparatorComparator
Efficacy of daptomycin for MSSA/MRSA Bacteremia/IEFowler VG et al. N Engl J Med 2006;355:653–665
Efficacy of daptomycin for MSSA/MRSA Bacteremia/IEFowler VG et al. N Engl J Med 2006;355:653–665
• 19 patients (16%) had microbiological failure.- Complications of endocarditis, 7 cases- Intravascular infections, 6 cases- Osteomyelitis or septic arthritis, 4 cases- Undrained abscesses, 2 cases
Daptomycin MIC increased on therapy from 0.25 (5 isolates) or 0.5 (1) to 2.0 (5) and 4.0 (1) µg/mL.
• 19 patients (16%) had microbiological failure.- Complications of endocarditis, 7 cases- Intravascular infections, 6 cases- Osteomyelitis or septic arthritis, 4 cases- Undrained abscesses, 2 cases
Daptomycin MIC increased on therapy from 0.25 (5 isolates) or 0.5 (1) to 2.0 (5) and 4.0 (1) µg/mL.
Reasons for Microbiological Failure in Patients with SAB/IE Treated with Daptomycin at 6 mg/kg
Fowler VG et al. N Engl J Med 2006;355:653–665
Reasons for Microbiological Failure in Patients with SAB/IE Treated with Daptomycin at 6 mg/kg
Fowler VG et al. N Engl J Med 2006;355:653–665
Mechanism of Action (MoA) of Daptomycin
Ca++ dependent insertion of lipid tail → Rapid membrane depolarization→ Bactericidal – [DAP] dependent
Distribution of charge on the surface of the structure of daptomycin. Red region denotes negative charge, blue region as positive and white region as neutral.
CDA = Calcium-dependent antibiotic
++
+
+
- ---
+
+
+
+
Daptomycin-Resistance and Cell Surface Electrostatic Repulsion in S. aureus
Ernst et al., PLoS Pathog 2009; 5:e1000660 Tran et al. Ann. N.Y. Acad. Sci. 2015;1354:32–53 CAMPs = Cationic antimicrobial peptides
DAP &
DAP & CAMPs
Increased positive surface charge → Repulsion
Genes associated with daptomycin-resistance in S. aureus: MprF, dltABCD, yycFG, cls, pgsA
How Can we Increase Daptomycin Efficacy When Treating S. aureus/CoNS Bacteremia/IE?
How Can we Increase Daptomycin Efficacy When Treating S. aureus/CoNS Bacteremia/IE?
• Increase daptomycin dose is not enough- ↑↑ Cmax/MIC - ↑↑ AUC/MIC- 8-10 mg/kg/d- Even higher doses (12 mg/kg/d)?
→ Daptomycin must be given in combination*- To look for synergy and greater bactericidal activity- To avoid development of resistance- To decrease individual doses
• Increase daptomycin dose is not enough- ↑↑ Cmax/MIC - ↑↑ AUC/MIC- 8-10 mg/kg/d- Even higher doses (12 mg/kg/d)?
→ Daptomycin must be given in combination*- To look for synergy and greater bactericidal activity- To avoid development of resistance- To decrease individual doses
* Gentamicin, -lactams, fosfomycin, rifampin, TMX-SMX.* Gentamicin, -lactams, fosfomycin, rifampin, TMX-SMX.
• Introduction• Empirical antimicrobial therapy• Targeted antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
• Introduction• Empirical antimicrobial therapy• Targeted antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
What are the problems when we are treating MRSA BSI/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 IDSA & AHA/ESC Guidelines
- 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 IDSA & AHA/ESC Guidelines
Mortality of S. aureus Bacteremia According to the Vancomycin MIC (mg/L) and the Antibiotic Treatment and the S. aureus Susceptibility
Holmes NE et al. J Infect Dis. 2011;204:340–47.
Mortality of S. aureus Bacteremia According to the Vancomycin MIC (mg/L) and the Antibiotic Treatment and the S. aureus Susceptibility
Holmes NE et al. J Infect Dis. 2011;204:340–47.
*P<0.05; **P<0.01*P<0.05; **P<0.01
Influence of pharmacokinetics/pharmacodynamics of antibacterials in their dosing regimen selectionScaglione F et al. Expert Rev. Anti Infect. Ther. 2006; 4: 479–490.
AUC: Area under the concentration–time curve; Cmax: Maximum plasma; concentration; PD: Pharmacodynamic; PK: Pharmacokinetic.
AUC: Area under the concentration–time curve; Cmax: Maximum plasma; concentration; PD: Pharmacodynamic; PK: Pharmacokinetic.
Vancomycin AUC/MIC >350Vancomycin 15 mg/kg /12 h IV
Cmin = 10 mcg/mLAUC = 400
MIC = 0.5 AUC/MIC 800MIC = 1 AUC/MIC 400
MIC = 2 AUC/MIC 200 !
Vancomycin MIC (E-test) in 199 S. aureus isolates from consecutive patients diagnosed of SAIE at the H. Clinic of Barcelona (1995-2012)
Garcia de la Maria C et al. 2017; Unpublished data.
MIC (E-test) MSSA (%) MRSA (%) Total(%)0.5 0 (0) 1 (3) 1 (0.5)
0.75 7 (4.3) 2 (5) 9 (4.5)
1 65 (40) 19 (53) 84 (42)1.5 85 (52) 13 (36) 99 (50)
2 6 (3.7) 1 (3) 7 (3)
Total 163 (100) 36 (100) 199 (100)
Efficacy of Vancomycin-HD (Cmin 20 mg/L) in the treatment of MRSA EE according to the vancomycin MIC
Castañeda X et al. Antimicrob Agents Chemother. 2017.
Treatmentgroups
- Van MIC 0.5/0.5*
- Van MIC 1/1.5*
- Van MIC 2/2*
Treatmentgroups
- Van MIC 0.5/0.5*
- Van MIC 1/1.5*
- Van MIC 2/2*
Median (IQR) log10 cfu/g veg
0 (0; 3.4)c
5 (3; 8.0)d
1 (0; 2.2)d
Median (IQR) log10 cfu/g veg
0 (0; 3.4)c
5 (3; 8.0)d
1 (0; 2.2)d
No. sterile vegetations/ No. total (%)
10/16 (62)a
3/17 (13)b
8/16 (50%)b
No. sterile vegetations/ No. total (%)
10/16 (62)a
3/17 (13)b
8/16 (50%)b
* Microdilution/EtestAll animals had Vancomycin AUC/MIC >350* Microdilution/EtestAll animals had Vancomycin AUC/MIC >350
“a” vs. “b” P=0.103“a” vs. “b” P=0.103“c” vs. “d” P=0.091“c” vs. “d” P=0.091
Daptomycin vs. Vancomycin in the treatment of Experimental Endocarditis due to MRSA with a vancomycin MIC of 2 µg/mL
Marco F et al. Antimicrob Agents Chemother. 2008; 52:2538-43
Treatmentgroups
- Control
- Vancomycin-RD
- Vancomycin-HD
- Daptomycin - 6 mg/kg
Treatmentgroups
- Control
- Vancomycin-RD
- Vancomycin-HD
- Daptomycin - 6 mg/kg
Median (IQR) log10 cfu/g veg
9 (8.6; 9.3)
2 (0; 5.6)&
1 (0; 2)
0 (0; 1.5)&
Median (IQR) log10 cfu/g veg
9 (8.6; 9.3)
2 (0; 5.6)&
1 (0; 2)
0 (0; 1.5)&
No. sterile vegetations/ No. total (%)
0/20(0)
7/20 (35)*
9/18 (50%)
13/18 (72)*
No. sterile vegetations/ No. total (%)
0/20(0)
7/20 (35)*
9/18 (50%)
13/18 (72)** p=0.02; &p=0.02* p=0.02; &p=0.02
Vancomycin-RD (recommended dose) simulating 1 g q 12 h i.v.; vancomycin-HD (high dose; [AUC/MIC>350]) simulating 1 g q 6 h i.v.; Daptomycin, simulating 6 mg/kg q 24 h i.v.
Vancomycin-RD (recommended dose) simulating 1 g q 12 h i.v.; vancomycin-HD (high dose; [AUC/MIC>350]) simulating 1 g q 6 h i.v.; Daptomycin, simulating 6 mg/kg q 24 h i.v.
Antibiotic penetration into vegetationsCremieux AL et al. J Infect Dis. 1989.
SepticVegetation
Aminoglycosides, Quinolones, Rifampin, Daptomycin
Aminoglycosides, Quinolones, Rifampin, Daptomycin
Homogeneous pattern
Peripheral pattern
Vancomycin, TeicoplaninVancomycin, Teicoplanin
Gradient pattern
-Lactams-Lactams
Bacterial coloniesBacterial colonies
Antibioticconcentration
Efficacy of daptomycin for SAB/IE at 6 mg/KgFowler VG et al. N Engl J Med 2006;355:653–665
Efficacy of daptomycin for SAB/IE at 6 mg/KgFowler VG et al. N Engl J Med 2006;355:653–665
Success rates at 6-week TOC by final diagnosis*: mITT populationSuccess rates at 6-week TOC by final diagnosis*: mITT population
56.356.3
43.343.3 42.142.1
11.111.1
55.255.2
37.737.743.843.8
22.222.2
Uncomplicatedbacteraemia
Uncomplicatedbacteraemia
ComplicatedbacteraemiaComplicatedbacteraemia
Right-sidedIE
Right-sidedIE
00
1010
2020
3030
4040
5050
6060
7070
Succ
ess r
ate (
%)
Succ
ess r
ate (
%)
DaptomycinComparatorDaptomycinComparator
23/6123/61 7/167/16 2/92/916/2916/29 1/91/918/3218/32 26/6026/60 8/198/19
Left-sidedIE†
Left-sidedIE†
*Final diagnoses as follows: 26% uncomplicated bacteraemia; 51% complicated bacteraemia, 15% right-sided IE, 8% left-sided IE; †Limited data in left-sided IE preclude determination of efficacy.
*Final diagnoses as follows: 26% uncomplicated bacteraemia; 51% complicated bacteraemia, 15% right-sided IE, 8% left-sided IE; †Limited data in left-sided IE preclude determination of efficacy.
MRSA IE0/5 0/4
Clinical responses to high doses of daptomycin therapy in 250 patients with MRSA and VRE infections.
Kullar R et al. Pharmacotherapy 2011;31(6):527–536
Clinical responses to high doses of daptomycin therapy in 250 patients with MRSA and VRE infections.
Kullar R et al. Pharmacotherapy 2011;31(6):527–536
10 vs. 13 mg/kg/d
Clinical & Microbiological Responses to High Doses of Daptomycin Therapy in 250 patients with MRSA & VRE infections
Kullar R et al. Pharmacotherapy 2011;31(6):527–536
Clinical & Microbiological Responses to High Doses of Daptomycin Therapy in 250 patients with MRSA & VRE infections
Kullar R et al. Pharmacotherapy 2011;31(6):527–536
Clinical outcome - Cure- Improvement- FailureMicrobiological outcome - Eradication- Failure
Clinical outcome - Cure- Improvement- FailureMicrobiological outcome - Eradication- Failure
119 (48%)90 (36%)18 (7%)
175 (80%)17 (8%)*
119 (48%)90 (36%)18 (7%)
175 (80%)17 (8%)*
* MRSA, 11 patients and VRE, 6 patients with complicated bacteremia in 12 (70.6%), prosthetic device in 4 (23.5%), right-sided IE in 4 (23.5%), and left-sided IE in 3 (17.6%).
* MRSA, 11 patients and VRE, 6 patients with complicated bacteremia in 12 (70.6%), prosthetic device in 4 (23.5%), right-sided IE in 4 (23.5%), and left-sided IE in 3 (17.6%).
Daptomycin and β-lactams (Nafcillin)• DAP + NAF as salvage regimen
– 7 cases with persistent MRSA bacteremia(7-22 days)
– DAP used as 2nd line agent in all– Only one case with DAP non-susceptibility– Bacteremia cleared with nafcillin (NAF)
• Why?– Increased daptomycin membrane
binding with addition of NAF.– Nafcillin led to a reduction in the
net positive surface charge.
• DAP + NAF as salvage regimen– 7 cases with persistent MRSA bacteremia
(7-22 days)– DAP used as 2nd line agent in all– Only one case with DAP non-susceptibility– Bacteremia cleared with nafcillin (NAF)
• Why?– Increased daptomycin membrane
binding with addition of NAF.– Nafcillin led to a reduction in the
net positive surface charge.
Dhand A et al. Clin Infect Dis. 2011;53:158-163.Dhand A et al. Clin Infect Dis. 2011;53:158-163.
DAP (green) binding with &without NAF (yellow)
β-Lactams Increase the Antibacterial Activity of Daptomycin againstClinical MRSA Strains and Prevent Selection of Daptomycin-Resistance
Mehta S et al. AAC. 2012, 56(12):6192.
β-Lactams Increase the Antibacterial Activity of Daptomycin againstClinical MRSA Strains and Prevent Selection of Daptomycin-Resistance
Mehta S et al. AAC. 2012, 56(12):6192.
Oxacillin Imipenem
AMC Ceftriaxone
… and ceftaroline too !!!
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
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.
Two patients with complicated MRSA NV IE and one patient with MSSA PVE were succesfully treated with the combination of daptomycin plus fosfomycin.
The Combination of Daptomycin plus Fosfomycin has Synergistic, Potent, and Rapid Bactericidal Activity against
MRSA in a Rabbit Model of EE (Van MIC=2)Garcia de la Maria C et al. Antimicrob Agents Chemother. 2018 May 25.
The Combination of Daptomycin plus Fosfomycin has Synergistic, Potent, and Rapid Bactericidal Activity against
MRSA in a Rabbit Model of EE (Van MIC=2)Garcia de la Maria C et al. Antimicrob Agents Chemother. 2018 May 25.
• Recruitment: 2014-17; 12 weeks of F/U.• Drugs adjusted to renal failure• Susceptible to study drugs• End points: BC+ 7 days, TOC 12 weeks after finishing Rx, Toxicity, Resistance and Mortality.
• Recruitment: 2014-17; 12 weeks of F/U.• Drugs adjusted to renal failure• Susceptible to study drugs• End points: BC+ 7 days, TOC 12 weeks after finishing Rx, Toxicity, 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)
MRSA BSI(N=220)
Pilot RCT: Combination of Vancomycin and β-lactam (BL) therapy for MRSA Bacteremia (CAMERA)
Davis JS et al. CID 2016.
Van Van+BL
• Recruitment: 2016-18; 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.
• Recruitment: 2016-18; 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 Daptomycin vs. Vancomycin ± β-lactams for MRSA BSI – CAMERA2
Australasian Society of Infectious Diseases Clinical Research Network
MRSA BSI(N=440)
Tong et al. Trials. 2016; 17:170
• Attenuate the virulence of resistant strains (e.g. agr in MRSA)• Enhance opsono-phagocytic killing by neutrophils (e.g.
activation of teichoic acid biosynthesis and complement deposition)
• Enhance the innate immunity (e.g. cationic antimicrobial peptides)
• Enhance membrane binding and depolarization and avoid the development of daptomycin resistance.
• Attenuate the virulence of resistant strains (e.g. agr in MRSA)• Enhance opsono-phagocytic killing by neutrophils (e.g.
activation of teichoic acid biosynthesis and complement deposition)
• Enhance the innate immunity (e.g. cationic antimicrobial peptides)
• Enhance membrane binding and depolarization and avoid the development of daptomycin resistance.
Why β-lactams are synergistic with vancomycin and daptomycin even though they are not active against MRSA
Why β-lactams are synergistic with vancomycin and daptomycin even though they are not active against MRSA
Dhand A et al. Clin Infect Dis. 2011;53:158-163; Sakoulas G et al. AAC. 2012; 56:838-44; Waters EM et al. J Infect Dis. 2017;215:80–7
• Introduction• Empirical antimicrobial therapy• Targeted Antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
• Introduction• Empirical antimicrobial therapy• Targeted Antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
Antimicrobial Agents Against Methicillin-ResistantStaphylococcus aureus (MRSA) Infections
Antimicrobial Agents Against Methicillin-ResistantStaphylococcus aureus (MRSA) Infections
Old drugs• TMP-SMX• Fusidic acid• Fosfomycin
† Teixobactim, Iclaprim, Ivernimicin, lysostaphin, new quinolones and other antibiotics.† Teixobactim, Iclaprim, Ivernimicin, lysostaphin, new quinolones and other antibiotics.
Recently approved drugs• Telavancin• Dalbavancin• Oritavancin• Ceftaroline• Ceftobiprole• TedizolidInvestigational drugs†
Marketed drugs• Quinupristin/dalfopristin• Linezolid• Tigecycline• Daptomycin
The combination of Daptomycin plus TMP/SMX is Synergistic and Rapidly Bactericidal against Daptomycin-Nonsusceptible
(DNS) MRSA in an In Vitro Model of Endocarditis1
The combination of Daptomycin plus TMP/SMX is Synergistic and Rapidly Bactericidal against Daptomycin-Nonsusceptible
(DNS) MRSA in an In Vitro Model of Endocarditis1
1.‐ Steed ME et al. Antimicrob Agents Chemother. 2010; 54:5187–5192.2.‐ Friedman L et al. Antimicrob. Agents Chemother. 2006; 50:2137–2145.1.‐ Steed ME et al. Antimicrob Agents Chemother. 2010; 54:5187–5192.2.‐ Friedman L et al. Antimicrob. Agents Chemother. 2006; 50:2137–2145.
TimeTime
SA-684 strainFour main genetic changes havebeen associated with increasedMICs and DNS S. aureus2‐mprF protein (lysylphosphatidylglycerol synthase).‐ YycG, a histidine kinase (cell membrane metabolism).‐ RpoB and RpoC proteins (RNA polymerase).
Four main genetic changes havebeen associated with increasedMICs and DNS S. aureus2‐mprF protein (lysylphosphatidylglycerol synthase).‐ YycG, a histidine kinase (cell membrane metabolism).‐ RpoB and RpoC proteins (RNA polymerase).
DAP+TMP/SMX
Klaevs KC et al. AAC. 2015. N=28 casesAddition of TMP/SMX to DAP for clinical failureMicrobiological eradication in 24 cases (86%)
Bacteremia cleared in 2.5 days (median)
Treatmentgroups
Control
Fosfomycin (FOS)Imipenem
VancomycinFOS + Imipenem
Treatmentgroups
Control
Fosfomycin (FOS)Imipenem
VancomycinFOS + Imipenem
Mean ± SDlog10 cfu/g veg
9 ± 0.5
8.5 ± 0.7b
5.6 ± 2
4.4 ± 2.6*2.1 ± 0.2c*
Mean ± SDlog10 cfu/g veg
9 ± 0.5
8.5 ± 0.7b
5.6 ± 2
4.4 ± 2.6*2.1 ± 0.2c*
Sterile vegetations
0/15 (0)
0/12 (0)1/14 (7)
5/16 (31)*11/15 (73)*
Sterile vegetations
0/15 (0)
0/12 (0)1/14 (7)
5/16 (31)*11/15 (73)*
Survivalrate (%)
15/15 (100)a
12/16 (75)14/16 (88)
16/16 (100)15/16 (94)
Survivalrate (%)
15/15 (100)a
12/16 (75)14/16 (88)
16/16 (100)15/16 (94)
a Control animals were sacrificed 18 h. after the i.v. MRSA challenge.b Five out of the 12 isolated strains (42%) developed resistance to fosfomycin. c None of the 10 isolated strains had resistance to fosfomycin.
a Control animals were sacrificed 18 h. after the i.v. MRSA challenge.b Five out of the 12 isolated strains (42%) developed resistance to fosfomycin. c None of the 10 isolated strains had resistance to fosfomycin.
*p<0.05*p<0.05
Fosfomycin plus Imipenem in the Treatment of MRSA Experimental Endocarditis (Van MIC =2)Del Rio A et al. Antimicrob Agents Chemother. 2016; 60:478-86.
PBP profiles of MRSA and GISA strains incubated with Fosfomycin (FOM) and Imipenem (IPM) alone or in
combination determined by SDS-PAGE
PBP profiles of MRSA and GISA strains incubated with Fosfomycin (FOM) and Imipenem (IPM) alone or in
combination determined by SDS-PAGE
Del Rio A et al. Antimicrob Agents Chemother. 2016; 60:478-86
Del Rio A et al. Clin Infect Dis. 2014; 59:1105-12.
70%
N = 16 cases (12 with IE)Patients with VAN or DAP microbiological failureMicrobiological eradication in all cases (100%)
Bacteremia cleared in ≤3 days
Ceftaroline for MRSA Bacteremia/IE?• In vitro PK/PD model: activity against 4 dapto non-susceptible
strains• Rabbit IE model
– Ceftaroline highly bactericidal• Reductions > 5 log10 cfu/g of vegetation• All vegetations sterilized
• In vitro PK/PD model: activity against 4 dapto non-susceptible strains
• Rabbit IE model– Ceftaroline highly bactericidal
• Reductions > 5 log10 cfu/g of vegetation• All vegetations sterilized
Treatment arm MSSA MRSA GISAControls 0/8 0/10 0/8Ceftaroline 8/8 8/8 8/8Daptomycin 5/8 4/7 8/8Tigecycline 0/6 0/5 0/6
Steed M et al. Antimicrob Agents Chemother. 2011;55:3522-6.Jacqueline C et al. J Antimicrob Chemother. 2011;66:863-6.Steed M et al. Antimicrob Agents Chemother. 2011;55:3522-6.Jacqueline C et al. J Antimicrob Chemother. 2011;66:863-6.
Large Retrospective Evaluation of the Effectiveness and Safety of Ceftaroline Fosamil Therapy
Casapao AM et al. Antimicrobial Agents Chemotherapy. 2014; 58: 2541–2546
Most cases MRSA infections and >80% previously treated with another antibiotic. 600 mg/12 h (86%). The median duration of ceftaroline therapy during hospitalization was 6 days (IQR, 4 to 9 days).
Most cases MRSA infections and >80% previously treated with another antibiotic. 600 mg/12 h (86%). The median duration of ceftaroline therapy during hospitalization was 6 days (IQR, 4 to 9 days).
21% failures
Salvage Treatment of Staphylococcal Bacteremia (N=12) or IE (N=14) with Ceftaroline plus Daptomycin: A Retrospective Study
Sakoulas G et al Clin Ther. 2014; 36:1317–1333
• Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia/IE (20 MRSA, 2 VISA, 2 MSSA, 2 MRSE) from 10 sites.
• Bacteremia persisted for a median of 10 days (range,3–23 days) on previous antimicrobial therapy.
• After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days).
• In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin, LL-37 and neutrophils.
• Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin.
• Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia/IE (20 MRSA, 2 VISA, 2 MSSA, 2 MRSE) from 10 sites.
• Bacteremia persisted for a median of 10 days (range,3–23 days) on previous antimicrobial therapy.
• After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days).
• In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin, LL-37 and neutrophils.
• Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin.
Ceftaroline plus TMP-SMX as Rescue Rx(Fabre V et al. OFID. 2014; 1: ofu046)
N=23 cases with MRSAB (8, 35%) or IE (15, 65%)MRSA microbiological eradication in 90%
Bacteremia cleared in 3 days (median) Survival 31% (25% lost F/U)
Efficacy of Telavancin in the Treatment of Experimental Endocarditis Due to Glycopeptide-Intermediate
Staphylococcus aureus (GISA)Miro JM et al. Antimicrob Agents Chemother. 2007; 51:2373–2377
Efficacy of Telavancin in the Treatment of Experimental Endocarditis Due to Glycopeptide-Intermediate
Staphylococcus aureus (GISA)Miro JM et al. Antimicrob Agents Chemother. 2007; 51:2373–2377
Ruggero MA et al. Infect Dis. 2015. N=14 cases, 11 (79%) with MRSA endocarditis
Rescue Rx (patients failing to VAN [14] and DAP [6])Microbiological eradication in 10/10 cases (100%)
Bacteremia cleared in ≤3 days in al casesSurvival in 57% (8/14)
• Introduction• Empirical antimicrobial therapy• Targeted Antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
• Introduction• Empirical antimicrobial therapy• Targeted Antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
• New antimicrobial strategies: Antibody–Antibiotic Conjugates (AAC) against rifampin-susceptible MSSA or MRSA
• New antimicrobial strategies: Antibody–Antibiotic Conjugates (AAC) against rifampin-susceptible MSSA or MRSA
Immunotherapy for Treating MRSAImmunotherapy for Treating MRSA
Lehar Sm et al. Nature. 2015 Nov 19;527(7578):323-8
Antibody–Antibiotic Conjugate (AAC)Antibody–Antibiotic Conjugate (AAC)
Lehar Sm et al. Nature. 2015 Nov 19;527(7578):323-8
Antibody–Antibiotic Conjugate DesignAntibody–Antibiotic Conjugate Design
Bacteria in kidneys were determined 4 days after IV
MRSA infection
Lysins: Bacteriophage-derived, recombinantly-produced therapeutic proteins (cell wall hydrolase enzymes)
Lysins: Bacteriophage-derived, recombinantly-produced therapeutic proteins (cell wall hydrolase enzymes)
Lysins therapy for Treating MRSALysins therapy for Treating MRSA
→ A paradigm shift in the antibiotic treatment of bacteremia/infective endocarditis may be coming …
→ Sequential antimicrobial treatment: from INTRAVENOUS to ORAL (e.g. SABATO and POET trials)
→ A paradigm shift in the antibiotic treatment of bacteremia/infective endocarditis may be coming …
→ Sequential antimicrobial treatment: from INTRAVENOUS to ORAL (e.g. SABATO and POET trials)
New strategies of treating MRSA bacteremia/endocarditis
New strategies of treating MRSA bacteremia/endocarditis
• 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 Bacteremia & IE?
• 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 Bacteremia & IE?
New Approaches for Treating SAB & IE in OPAT Regimens
New Approaches for Treating SAB & IE in OPAT Regimens
• Introduction• Empirical antimicrobial therapy• Targeted antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
• Introduction• Empirical antimicrobial therapy• Targeted antimicrobial therapy• New antimicrobials / combinations• New challenges • Conclusions
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
How to treat MRSA Bacteremia and Infective Endocarditis in 2018
• The treatment of MRSA BSI and IE is challenging since mortality is very high (20-40%).
• The combination of daptomycin plus β-lactams or fosfomycin is thebest empirical antimicrobial therapy for treating SAB/IE in settingswith a high MRSA prevalence.
• For MRSAB/IE, daptomycin is currently the drug of choice and mustbe given at high dose (≥10 mg/kg) and combined with β-lactams orfosfomycin. The combination of cloxacillin plus vancomycin is a goodalternative. The CAMERA2 RCT will tell us what is the best antibiotic combination.
• New treatments are coming and their good preliminary results should be confirmed in clinical trials.
• The treatment of MRSA BSI and IE is challenging since mortality is very high (20-40%).
• The combination of daptomycin plus β-lactams or fosfomycin is thebest empirical antimicrobial therapy for treating SAB/IE in settingswith a high MRSA prevalence.
• For MRSAB/IE, daptomycin is currently the drug of choice and mustbe given at high dose (≥10 mg/kg) and combined with β-lactams orfosfomycin. The combination of cloxacillin plus vancomycin is a goodalternative. The CAMERA2 RCT will tell us what is the best antibiotic combination.
• New treatments are coming and their good preliminary results should be confirmed in clinical trials.
Take Home MessagesTake Home Messages
2018 Members of the Hosp. Clinic Cardiovascular Infections & Experimental Endocarditis Working Group
2018 Members of the Hosp. Clinic Cardiovascular Infections & Experimental Endocarditis Working Group
Infectious Diseases
J. AmbrosioniM. Hdez-Meneses
A. TellezJ.M. Pericas
M. RipaA. MorenoJ.M. Miro
Infectious Diseases
J. AmbrosioniM. Hdez-Meneses
A. TellezJ.M. Pericas
M. RipaA. MorenoJ.M. Miro
Experimental Endocarditis Lab.
C. García de la MaríaJ. García
Experimental Endocarditis Lab.
C. García de la MaríaJ. García
CardiologyC. FalcesJ.C. ParéB. Vidal
J.M. TolosanaJ. Ortiz
M. AzquetaM. Sitges
CardiologyC. FalcesJ.C. ParéB. Vidal
J.M. TolosanaJ. Ortiz
M. AzquetaM. Sitges
Barcelona- Spain
CollaborationsG.R. CoreyV. FowlerA. Bayer
J. EntenzaP. Moreillon
C. AriasA.W. KarchmerC.A. MestresC. Cervera
CollaborationsG.R. CoreyV. FowlerA. Bayer
J. EntenzaP. Moreillon
C. AriasA.W. KarchmerC.A. MestresC. Cervera
MicrobiologyF. Marco
M. AlmelaJ. Vila
MicrobiologyF. Marco
M. AlmelaJ. Vila
Cardiac Surgery
E. QuintanaE. SandovalD. PeredaR. Cartañá
S. NinotM. Castellà
Cardiac Surgery
E. QuintanaE. SandovalD. PeredaR. Cartañá
S. NinotM. Castellà
PathologyJ. RamírezPathologyJ. Ramírez
Other ServicesD. Soy / M. Brunet
D. Fuster / U. GranadosJ. Llopis / X. Urra
P. Castro
Other ServicesD. Soy / M. Brunet
D. Fuster / U. GranadosJ. Llopis / X. Urra
P. CastroAnaesthesiology
G. FitaI. Rovira
AnaesthesiologyG. Fita
I. Rovira