How to treat MRSA Bacteremia and Infective Endocarditis in ... · How to treat MRSA Bacteremia and...

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




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.

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)






What is the best empiric antibiotic therapy against MSSA and MRSA Endocarditis?

What is the best empiric antibiotic therapy against MSSA and MRSA Endocarditis?











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.

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


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


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


9 (8.6; 9.3)

2 (0; 5.6)&

1 (0; 2)

0 (0; 1.5)&


9 (8.6; 9.3)

2 (0; 5.6)&

1 (0; 2)

0 (0; 1.5)&


0/20(0)

7/20 (35)*

9/18 (50%)

13/18 (72)*


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.


10 vs. 13 mg/kg/d

Clinical & Microbiological Responses to High Doses of Daptomycin Therapy in 250 patients with MRSA & VRE infections


Clinical & Microbiological Responses to High Doses of Daptomycin Therapy in 250 patients with MRSA & VRE infections


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




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)

• 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

• 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

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