Vancomycin

Stato dell’arte della terapia delle infezioni da
MRSA?
Matteo Bassetti, MD, PhD
Infectious Diseases Division
Santa Maria Misericordia University
Hospital
Udine, Italy
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?
Efficacy of vancomycin in bacteraemia due to
MSSA compared with β-lactams
Gonzalez C. et al.
Clin Infect Dis 1999; 29: 1171-7
Fortun J. et al.
Clin Infect Dis 2001; 33: 120-5
Chang F et al.
Medicine (Baltimore) 2003;82:333–339
Lodise TP, et al.
ArchIntern Med 2006;166:2138–214
Stryjewski ME et al.
Clin Infect Dis 2007; 44: 190.
Sung-Han K, et al.
Antimicrob Agents Chemother 2008; 52: 192-7
Empiric
antimicrobial
therapy with
vancomycin in
bacteraemia due
to MSSA was
associated with
poor prognosis
(failure or death)
Efficacy of nafcillin versus vancomycin
in preventing persistent bacteraemia and
relapse in MSSA bacteraemia
25
Nafcillin (n=18)
Vancomycin (n=70)
21
19
20
15
11
10
6
7
5
0
0
0
0
Persistent
>3 days
Chang FY et al. Medicine 2003;82:333-339i
Persistent
>7 days
Relapse
Bacteriologic
Failure
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
Vancomycin
SSP
20
45
14
43
33
74
Success by
Pathogen-specific Therapy
Fowler VG et al. NEJM 2006;355
286
0
20
45
144
4
Success by
Comparator Agent
33
74
347
0
Number of MRSA strains with glycopeptide
MICs of ≤ 0.5, 1, and ≥ 2 mg/L in Italy
60
50
40
30
1990-99
2000-2007
20
10
0
V AN
< 0,5
Te ico
< 0,5
V AN
1
Te ico
1
V AN
2
Te ico
2
Campanile F et al. Ann Clin Microb Antimicrob 2009, 8:22
Eradication rates of MRSA related to
vancomycin MIC
Eradication rate (%)
100
80
77
71
P<0.01
60
40
21
20
0
0.5
1.0
2
MIC value (g/ml)
Moise et al. Antimicrob Agents Chemother 2007; 51: 2582-2586
Vancomycin MICs and outcome in MRSA
pneumonia
n = 158
60
P=0.016
51.7
Mortality (%)
50
40
30.2
30
23.3
20
10
0
1
1.5
2
MIC value (g/ml)
Haque N et al. Chest 2010;138:1356-1362
Teicoplanin MICs and outcome in MRSA
bacteremia
n = 101
60
P=0.022
48.9%
Mortality (%)
50
40
30
26.8 %
20
10
0
< 1.5
> 1.5
MIC value (g/ml)
Chang HJ et al. J Antimicrob Chemother 2012;67:736-41
Dosaggio e tollerabilità
Recommended trough serum concentrations
and dosage adjustments
• 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
MRSA MIC ≤ 1 g/ml
MRSA MIC ≥2 g/ml
>400 AUC/MIC
<400 AUC/MIC
Rybak et al. Clin Infect Dis 2009;49:325-7
*bacteraemia, endocarditis, osteomyelitis, meningitis
and hospital-acquired pneumonia
Typical vancomycin dosing fails to achieve target
concentrations for sepsis even after 4 days
Distribution of vancomycin trough concentrations
over the first 4 days of therapy
Predicted concentration (mg/l)
25
1 g q12h (normal renal function)
20
15
*
*
*
*
10
*
*
*
*
*
*
*
*
Sepsis
20
0
12
24
36
48
60
72
84
Time after the start of therapy (hours)
Thompson AH et al. J Antimicrob Agents 2009;63:1050–1057
96
The significance of a vancomycin
AUC > 400
Rate of nephrotoxicity (%)
P<0.05
40
33
30
21
20
10–15 g/ml
(n=44)
15–20 g/ml
(n=15)
20
10
5
0
<10 g/ml
(n=95)
Initial trough value, g/ml
Lodise et al. Clin Infect Dis 2009;49:507-14
>20 g/ml
(n=12)
Teicoplanin vs Vancomycin for Proven
or Suspected Gram-positive Infection
Cochrane Review of 24 studies (N=2610)
Clinical cure or improvement
Risk Ratio (95% CI)
1.03 (0.98, 1.08)
Microbiologic cure
0.98 (0.93, 1.03)
Mortality
1.02 (0.79, 1.30)
Nephrotoxicity*
0.66 (0.48, 0.90)
Skin rash
0.57 (0.35, 0.92)
Red-man syndrome
0.21 (0.08, 0.59)
0.0
0.5
Favors Teicoplanin
1.0
1.5
2.0
Favors Vancomycin
* 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
Treatment
success
Nephrotoxicity
Teicoplanin
15-20 mg/L
24/28 (85.7%)
Vancomycin
> 20 mg/L
31/34 (91.2%)
P
NS
2/28 (7.1%)
4/34 (11.8%)
NS
Seki M et al. Clin Pharmacol. 2012;4:71-5
Batteriocidia
Daptomycin retains potent bactericidal activity
against high-inoculum MRSA in vitro
Bactericidal activity: daptomycin > vancomycin > teicoplanin
9
Log CFU/ml
8
7
Teicoplanin = 0.38 mg/l
(400 mg/24 h)
6
5
Vancomycin = 0.25 mg/l
(1 g/12 h)
4
3
Daptomycin = 0.19 mg/l (6 mg/kg/24 h)
2
0
6
12
18
24
30
Time (hours)
Bowker KE et al. J Antimicrob Chemother 2009;64:1044–1051
36
42
48
Ceftaroline fosamil is bactericidal against
Gram-positive organisms in vitro
Staphylococcus aureus (MRSA)
Strain 1-170A (ceftaroline MIC 0.5 mg/L)
Streptococcus pneumoniae
Strain 90-71B (ceftaroline MIC 0.12 mg/L)
7
7
2 x MIC
6
4 x MIC
8 x MIC
5
Log10 CFU/mL
Log10 CFU/mL
6
2 x MIC
4
3
2
4 x MIC
8 x MIC
5
4
3
2
1
1
0
0
0
4
8
12
16
Time, h
20
24
CFU, colony forming unit; MIC, minimum inhibitory concentration;
MRSA, methicillin-resistant S. aureus
0
4
8
12
16
Time, h
20
24
Adapted from
Jones RN et al. J Antimicrob Chemother 2005;56:1047–1052
In vitro survival of methicillin-resistant
S. aureus biofilms to antibiotics
Biofilm-associated cell survival (%)
Biofilm-associated cell survival of 12 MRSA isolates
100
90
80
70
60
50
40
P<0.005
30
P<0.0001
20
10
0
Clindamycin
Daptomycin Linezolid
Tigecycline 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
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;
patients requiring surgical intervention, 1 hr post infusion (peak);
dHealthy volunteers, after 5.5 days repeated oral administration (1g/d)
ccSSTI
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;
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
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)
Linezolid
Vancomycin
95% CI: 4.9, 22.0
100
Patients (%) With
Clinical Response
80
60
P=.042
95% CI: .5, 21.6
57.6%
83.3%
95% CI: .1, 19.8
95% CI: 4.0, 20.7
80.1%
69.9%
67.8%
54.8%
46.6%
44.9%
40
20
0
95/165
81/174
Per-Protocol at EOS
Primary End Point
102/186
92/205
mITT at EOS
150/180
130/186
Per-Protocol at EOT
161/201
145/214
mITT at EOT
Secondary End Points
Wunderink RG et al. [published online ahead of print January 12, 2012] Clin Infect Dis. doi:10.1093/cid/cir895.
ZEPHyR Secondary End Point:
Microbiologic Response Rates at EOS and
EOT
Patients With Respiratory
Secretions for Culture
Per-Protocol Population
Documented eradication*
Presumed eradication†
95% CI: 12.3, 30.2
100
82.6%
(76/92)
81.9%
(149/182)
Patients (%) With
Microbiologic Response
80
60
40
95% CI: .4, 21.5
58.1%
(97/167)
47.1%
(82/174)
63.9%
(62/97)
60.6%
(114/188)
49.0%
73/149
54.1%
(59/109)
50.0%
(26/52)
48.2%
55/114
68.3%
56/82
51.0%
(76/149)
20
36.1%
(35/97)
51.8%
(59/114)
31.7%
(26/82)
0
Linezolid
61.4%
(35/57)
Vancomycin
EOS
Linezolid
Vancomycin
EOT
Linezolid
Vancomycin
EOS
* No microbiologic data, but confirmed clinical cure.
31
† 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.
Linezolid
Vancomycin
EOT
Reduced time to symptom resolution with daptomycin versus
vancomycin in CRBSIs in cancer patients
Time to symptom resolution in cancer patients with Gram-positive CRBSIs
Daptomycin (n=38)
Proportion of patients, %
100
40
60
40
Vancomycin (n=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
20
0
0
2
4
6
8
Time to symptom resolution (days)
CRBSI, catheter-related bloodstream infection
Chaftari A et al. Int J Antimicrob Agents 2010;36:182–186
10
12
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 (BIII)
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
Domani
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
?
8 mg/Kg
10 mg/kg
Daptomicina
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/
++
++
++
++
Daptomycin
+++
-
+++
+++
Linezolid
+++
+++
+
+
Tigecycline
+++
+
+
+
Ceftaroline
+++
++
++
++
Teicoplanin
CR- BSI: catheter-related bloodstream infections; BSI: bloodstream infections
-: 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.
Terapia ragionata delle
infezioni stafilococciche
Interessamento
polmonare
No
SI
Eseguire espettorato, BAS o BAL
Iniziare Linezolid
MRSA
Continua Linezolid
MSSA
Beta o Fluoro
Emocolture da VP e CVC
Iniziare Daptomicina 8 mg/kg
MSSA
Oxa o cefazolina
MRSA < 1
Dapto o Vanco
MRSA> 1
Dapto
Therapy of empiric MRSA
infections
Suspect MRSA infection
Bacteremia
Sepsis
Endocarditis
Vancomycin
DAPTOMYCIN
Ceftaroline
Pneumonia
CNS infections
LINEZOLID
Ceftaroline
cSSSI
Vancomycin
DAPTOMYCIN
LINEZOLID
CEFTAROLINE
Register at:
www.htide.net

Download Report