Matteo Bassetti, MD, PhD

Infectious Diseases Division

Santa Maria Misericordia University

Hospital

Udine, Italy

Stato dell’arte della terapia delle infezioni da

MRSA?

Disclosures

Research grants

- Astellas, Pfizer, MSD, Gilead

Advisor/consultant

- Astellas, Bayer, Basilea, Cubist, Pfizer,

MSD, Gilead, Angelini, Vifor, Shionogi,

Novartis

Speaker/chairman

- Astellas, Pfizer, MSD, Gilead, Angelini,

Vifor, Shionogi, Novartis, Bayer

Il «farmaco appropriato» per le

infezioni da Gram-positivi

Attività microbiologica su ceppi MS, MR, VH, streptococchi

Dosaggio e modalità di somministrazione semplici

Buon profilo di tollerabilità

Battericida

Attività su biofilm

Ottima penetrazione tissutale (polmone, osso, cute,

endocardio)

Dati di efficacia in batteriemie, endocarditi, polmoniti,

infezioni ossee, cute e tessuti molli

Disponibile in formulazione endovenosa/orale

Supportato dalla linee guida

Poco costoso

Vancomicina e teicoplanina

sono i farmaci più

appropriati?

Attività microbiologica

Vancomicina e teicoplanina

funzionano su ceppi MS?

Lodise TP, et al.

ArchIntern Med 2006;166:2138–214

Stryjewski ME et al.

Clin Infect Dis 2007; 44: 190.

Chang F et al.

Medicine (Baltimore) 2003;82:333–339

Gonzalez C. et al.

Clin Infect Dis 1999; 29: 1171-7

Sung-Han K, et al.

Antimicrob Agents Chemother 2008; 52: 192-7

Fortun J. et al.

Clin Infect Dis 2001; 33: 120-5

Empiric

antimicrobial

therapy with

vancomycin in

bacteraemia due

to MSSA was

associated with

poor prognosis

(failure or death)

Efficacy of vancomycin in bacteraemia due to

MSSA compared with β-lactams

Efficacy of nafcillin versus vancomycin

in preventing persistent bacteraemia and

relapse in MSSA bacteraemia

0

5

10

15

20

25

Persistent >3 days

Persistent >7 days

Relapse Bacteriologic Failure

Nafcillin (n=18)

Vancomycin (n=70)

6

21

0

11

0

7

0

19

Chang FY et al. Medicine 2003;82:333-339i

What to do?

“The empirical combination of vancomycin

and a beta-lactam (either nafcillin, oxacillin or

cefazolin) for Staphylococcal bacteremia may

improve infection-related clinical outcomes”

McConeghy KW et al, Clin Infect Dis 2013 Aug 28. [Epub ahead of print]

Success by Pathogen-specific Therapy vs

Comparator Agent in Staph. aureus

endocarditis

Success by

Pathogen-specific Therapy

Success by

Comparator Agent

20

45

14

43 33

74

347

0

33

74

286

0

20

45

144

4

Vancomycin

SSP

Fowler VG et al. NEJM 2006;355

Number of MRSA strains with glycopeptide

MICs of ≤ 0.5, 1, and ≥ 2 mg/L in Italy

0

10

20

30

40

50

60

VAN

< 0,5

Teico

< 0,5

VAN

1

Teico

1

VAN

2

Teico

2

1990-99

2000-2007

Campanile F et al. Ann Clin Microb Antimicrob 2009, 8:22

P<0.01

Moise et al. Antimicrob Agents Chemother 2007; 51: 2582-2586

Eradication rates of MRSA related to

vancomycin MIC

MIC value (g/ml)

Era

dic

ati

on

ra

te (

%) 77

71

21

0

20

40

60

80

100

0.5 1.0 2

Haque N et al. Chest 2010;138:1356-1362

Vancomycin MICs and outcome in MRSA

pneumonia

MIC value (g/ml)

Mo

rta

lity

(%

)

n = 158

23.3

30.2

51.7 P=0.016

0

10

20

30

40

50

60

1 1.5 2

Chang HJ et al. J Antimicrob Chemother 2012;67:736-41

Teicoplanin MICs and outcome in MRSA

bacteremia

MIC value (g/ml)

Mo

rta

lity

(%

)

n = 101

26.8 %

48.9% P=0.022

0

10

20

30

40

50

60

< 1.5 > 1.5

Dosaggio e tollerabilità

Rybak et al. Clin Infect Dis 2009;49:325-7

• To improve penetration

• To increase the probability of optimal PD target

• To improve clinical outcomes of complicated infections*

15–20 g/ml

(>400 AUC/MIC)

2g/day in 70kg pts

*bacteraemia, endocarditis, osteomyelitis, meningitis

and hospital-acquired pneumonia

MRSA MIC ≤ 1 g/ml MRSA MIC ≥2 g/ml

>400 AUC/MIC <400 AUC/MIC

Recommended trough serum concentrations

and dosage adjustments

Thompson AH et al. J Antimicrob Agents 2009;63:1050–1057

1 g q12h (normal renal function)

* * * *

*

* * * *

*

* *

Time after the start of therapy (hours)

Pre

dic

ted

co

nc

en

tra

tio

n (

mg

/l)

12 36 48 60 72 84 96 24

0

10

25

20

15

20

Distribution of vancomycin trough concentrations

over the first 4 days of therapy

Sepsis

Typical vancomycin dosing fails to achieve target

concentrations for sepsis even after 4 days

Lodise et al. Clin Infect Dis 2009;49:507-14

The significance of a vancomycin

AUC > 400

5

<10 g/ml

(n=95)

21

10–15 g/ml

(n=44)

20

15–20 g/ml

(n=15)

33

>20 g/ml

(n=12)

30

40

20

10

0

P<0.05

Rate

of

nep

hro

toxic

ity (

%)

Initial trough value, g/ml

Teicoplanin vs Vancomycin for Proven

or Suspected Gram-positive Infection

Favors Teicoplanin Favors Vancomycin

Risk Ratio (95% CI)

1.03 (0.98, 1.08)

0.98 (0.93, 1.03)

1.02 (0.79, 1.30)

0.66 (0.48, 0.90)

0.0 0.5 1.0 1.5 2.0

0.57 (0.35, 0.92)

0.21 (0.08, 0.59)

Clinical cure or improvement

Microbiologic cure

Mortality

Nephrotoxicity*

Skin rash

Red-man syndrome

Cochrane Review of 24 studies (N=2610)

* Nephrotoxicity difference was a consistent finding: Present when vancomycin monitoring was used to guide dosing; present with or

without aminoglycosides

Cavalcanti AB et al. Cochrane Database Syst Rev. 2010;(6):CD007022.

Vancomycin vs teicoplanin with

equal through concentrations

Teicoplanin

15-20 mg/L

Vancomycin

> 20 mg/L

P

Treatment

success

24/28 (85.7%) 31/34 (91.2%) NS

Nephrotoxicity 2/28 (7.1%) 4/34 (11.8%) NS

Seki M et al. Clin Pharmacol. 2012;4:71-5

Batteriocidia

Bowker KE et al. J Antimicrob Chemother 2009;64:1044–1051

Bactericidal activity: daptomycin > vancomycin > teicoplanin

Daptomycin = 0.19 mg/l (6 mg/kg/24 h)

Vancomycin = 0.25 mg/l

(1 g/12 h)

Teicoplanin = 0.38 mg/l

(400 mg/24 h)

Time (hours)

Lo

g C

FU

/ml

0 6 12 18 24 30 36 42 48

2

3

4

5

6

7

8

9

Daptomycin retains potent bactericidal activity

against high-inoculum MRSA in vitro

Ceftaroline fosamil is bactericidal against

Gram-positive organisms in vitro

CFU, colony forming unit; MIC, minimum inhibitory concentration;

MRSA, methicillin-resistant S. aureus

Staphylococcus aureus (MRSA)

Strain 1-170A (ceftaroline MIC 0.5 mg/L)

0

1

2

3

4

5

6

7

0 4 8 12 16 20 24

Lo

g1

0C

FU

/mL

Time, h

2 x MIC

4 x MIC

8 x MIC

Streptococcus pneumoniae

Strain 90-71B (ceftaroline MIC 0.12 mg/L)

0

1

2

3

4

5

6

7

0 4 8 12 16 20 24

Lo

g1

0C

FU

/mL

Time, h

2 x MIC

4 x MIC

8 x MIC

Adapted from

Jones RN et al. J Antimicrob Chemother 2005;56:1047–1052

In vitro survival of methicillin-resistant

S. aureus biofilms to antibiotics B

iofi

lm-a

sso

cia

ted

cell s

urv

iva

l (%

)

Biofilm-associated cell survival of 12 MRSA isolates

100

80

90

70

60

50

40

30

20

10

0

Clindamycin Daptomycin Linezolid Tigecycline

P<0.0001

P<0.005

Vancomycin

MRSA exposed to antibiotics at concentrations of 64 µg/mL. Each box plot represents the spread of cell survival

across the different clinical isolates; error bars are the standard deviation

Smith K et al. Int J Antimicrob Agents 2009;33:374–378

Penetrazione tissutale

Tissue penetration

(% tissue/serum)

Tissue Vancomycin Teicoplanin Linezolid

Bone 7–13% 50–60% 60%

CNS 0–18% 10% 70%

ELF 11–17% 30% 450%

Muscle 30% 40% 94%

Perit. dial fluid 20% 40% 61%

Antibiotics for MRSA cSSTIs have

different tissue penetration

8. http://www.chemnet.com/cas/en/6990-06-3/fusidic-acid.html;

9. Gee et al. Antimicrob Agents Chemother 2001;45:1843-6;

10. Skhirtladze et al. Antimicrob Agents Chemother 2006;50:1372-5;

11. Wise et al. J Hosp Infect 1986;7 Suppl A:47-55;

12. de Lalla et al. Antimicrob Agents Chemother 1993;37:2693-8;

13. Wise et al. Antimicrob Agents Chemother 2002;46:31-3;

14. Stoehr et al. Clin Pharm 1988;7:820-4;

15. Stein et al. Surg Infect (Larchmt) 2011;12:465-7;

16. Vaillant et al. Ann Dermatol Venereol 2000;127:33-9

1. ZYVOX® [package insert]. New York, NY: Pfizer Inc., 2012;

2. Vancomycin Hydrochloride [package insert]. Lake Forest, IL: Hospira, Inc., 2010;

3. Teicoplanin Complex [product data sheet]. Bioaustralis.com;

4. Cubicin [package insert]. Lexington, MA:

Cubist Pharmaceuticals, Inc., 2010;

5. http://www.drugbank.ca/drugs/DB01190;

6. http://www.drugbank.ca/drugs/DB00560;

7. Saravolatz et al. Clin Infect Dis

2011;52:1156-63;

Molecular weight Ratio of skin and soft tissue: plasma penetration

Linezolid 337.351 104%9,a

Vancomycin 1485.742 10-30%10,b

Teicoplanin 1879.73 24-77%11,12,a

Daptomycin 1620.674 68%13,a

Clindamycin 424.985 24-82%14

Tigecycline 585.656 380%15,c

Ceftaroline 762.757 Not available

Fusidic acid 516.718 49%16,d

aHealthy volunteers/patients; bDiabetic vs non-diabetic post-cardiac surgery patients; ccSSTI patients requiring surgical intervention, 1 hr post infusion (peak); dHealthy volunteers, after 5.5 days repeated oral administration (1g/d)

Ceftaroline penetration

CSF penetration: 14% +/- 5%

Lung penetration: 42.0 +/- 11.2%

Cottanoud et al. 50th ICAAC Boston 2010- Abstract B702

Jacqueline C et al. 46th ICAAC San Francisco 2006 Abstract A-1938

Garrison et al. Expt Rev Anti Infect Ther 2012

Dati di efficacia

ZEPHyR Clinical Response at EOS and EOT

(Per-Protocol and mITT Populations)

57.6% 54.8%

83.3% 80.1%

46.6% 44.9%

69.9% 67.8%

0

20

40

60

80

100

Per-Protocol at EOS mITT at EOS Per-Protocol at EOT mITT at EOT

Linezolid Vancomycin

95/165 102/186 150/180 161/201 81/174 92/205 130/186 145/214

P=.042

95% CI: .5, 21.6 95% CI: .1, 19.8

95% CI: 4.9, 22.0 95% CI: 4.0, 20.7

Wunderink RG et al. [published online ahead of print January 12, 2012] Clin Infect Dis. doi:10.1093/cid/cir895.

Primary End Point Secondary End Points

Pa

tien

ts (

%)

Wit

h

Cli

nic

al

Res

po

nse

31

ZEPHyR Secondary End Point:

Microbiologic Response Rates at EOS and

EOT

Pa

tien

ts (

%)

Wit

h

Mic

rob

iolo

gic

Res

po

nse

EOS EOT EOS EOT

58.1%

(97/167)

47.1%

(82/174)

81.9%

(149/182)

60.6%

(114/188)

95% CI: .4, 21.5

95% CI: 12.3, 30.2

†

* No microbiologic data, but confirmed clinical cure.

† Microbiologic data available, confirmed microbiologic eradication.

Wunderink RG et al. [published online ahead of print January 12, 2012] Clin Infect Dis. doi:10.1093/cid/cir895.

Per-Protocol Population Patients With Respiratory

Secretions for Culture

36.1%(35/97)

31.7%(26/82)

51.0%(76/149) 51.8%

(59/114)

61.4%(35/57)

50.0%(26/52)

82.6%(76/92)

54.1%(59/109)

63.9%(62/97)

68.3%56/82

49.0%73/149

48.2%55/114

0

20

40

60

80

100

Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin

Documented eradication* Presumed eradication

Chaftari A et al. Int J Antimicrob Agents 2010;36:182–186

Time to symptom resolution (days)

Pro

port

ion o

f patients

, %

Daptomycin (n=38) Vancomycin (n=40)

0 2 4 6 8 10 12 0

20

100

40

60

40

The authors compares the outcome of

38 oncologic patients with CRBSIs treated

with daptomycin (6 mg/kg/24 h) and a

historical cohort of 40 patients treated with

vancomycin matched by co-morbidity,

neutropenia and type of microorganism

Time to symptom resolution in cancer patients with Gram-positive CRBSIs

CRBSI, catheter-related bloodstream infection

Reduced time to symptom resolution with daptomycin versus

vancomycin in CRBSIs in cancer patients

Linee guida

IDSA Guidelines 2011:

What is the management of MRSA

bacteraemia and infective endocarditis?

For adults with uncomplicated (at least 2

weeks) and complicated bacteraemia (4–6

weeks):

- Vancomycin (A-II) or

- Daptomycin 6 mg/kg/dose IV once daily (A-I)

Some experts recommend higher dosages of

daptomycin at 8–10mg/kg/dose IV once daily (B-

III)

Liu C et al. Clin Infect Dis 2011;52:285–292

IDSA Guidelines 2011:

What is the management of empirical MRSA

treatment for hospitalised patients with cSSTI?

Options include the following:

- IV vancomycin (A-I)

- PO or IV linezolid 600 mg twice daily (A-I)

- Daptomycin 4 mg/kg/dose IV once daily (A-I)

- Telavancin 10 mg/kg/dose IV once daily (A-I)

- Clindamycin 600 mg IV or PO 3 times a day (A-III)

Liu C et al. Clin Infect Dis 2011;52:285–292

Quale dosaggio?

Dosaggi nelle Sepsi

Anni ’80

(mg)

Anni ’90

(mg)

Oggi

Vancomicina 1000 x 2 500 x 4 Dose di carico

poi 30 mg/Kg

Infusione

continua

Teicoplanina 200 – 400 600 – 800 10-12 mg/Kg

+ dose di

carico

Daptomicina 8 mg/Kg

Domani

?

?

10 mg/kg

Costo

Costo di 10 giorni di terapia

per un uomo di 70 kg

Costi ex factory marzo 2012

Empirical and targeted

therapy for MRSA infections

Antibiotic cSSTI Pneumonia CR- BSI Primary BSI

Vancomycin/

Teicoplanin

++ ++ ++ ++

Daptomycin +++ - +++ +++

Linezolid +++ +++ + +

Tigecycline +++ + + +

Ceftaroline +++ ++ ++ ++

-: Do not use; + use only as alternative; ++: good drug in this indication; +++: very good

drug in this indication Bassetti M et al. Minerva Anestesiol 2011; 77:821-7 mod.

CR- BSI: catheter-related bloodstream infections; BSI: bloodstream infections

Terapia ragionata delle

infezioni stafilococciche

Interessamento

polmonare

SI

Eseguire espettorato, BAS o BAL

Iniziare Linezolid

MRSA MSSA

Continua Linezolid Beta o Fluoro

No

Emocolture da VP e CVC

Iniziare Daptomicina 8 mg/kg

MSSA

Oxa o cefazolina

MRSA < 1 MRSA> 1

Dapto o Vanco Dapto

Therapy of empiric MRSA

infections

Bacteremia

Sepsis

Endocarditis

Pneumonia

CNS infections cSSSI

Vancomycin

DAPTOMYCIN

Ceftaroline

LINEZOLID

Ceftaroline

Vancomycin

DAPTOMYCIN

LINEZOLID

CEFTAROLINE

Suspect MRSA infection

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