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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
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
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
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
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
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
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
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
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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