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Alternatives a VancomicinaJuan M Pericàs
Servei de Malalties InfecciosesHospital Clínic de Barcelona
IDIBAPS-UB
SESSIÓ SCMIMC 21/05/15
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OBJECTIUS1. Exposar l’evidència (fonamentalment clínica) que
recolça l’ús d’antibiòtics alternatius a vancomicina en les infeccions per SASM, SARM i CoNS.
2. Posar el focus en l’eficàcia que han demostrat front a soques amb CMI de vancomicina ≥1.5 µg/mL.
3. Extrapolar conclusions a partir BSI/IE.4. Fonamentar les recomanacions sobre dosificació i
ús en combinació. 5. Fer esment dels mecanismes de resistència més
comuns i les taxes aproximades que s’han descrit.
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Quins problemes planteja l’ús de vancomicina en el tractament de les
infeccions estafilocòciques?
- Pobra activitat bactericida- Escassa difussió a les vegetacions- CMI (AUC/MIC PD target)- Soques hVISA- Tolerància→ Alta taxa de fracassos
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Antimicrobial Agents Against Staphylococcal Infections
Old drugs• TMP-SMX• Fusidic acid• Fosfomycin
† 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
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Therapy for Endocarditis Due to Methicillin-Susceptible Staphylococcus aureus (MSSA) or Coagulase Negative
Staphylococci (MS-CoNS) in the Absence of Prosthetic MaterialBaddour L et al. Circulation. 2005; Habib G et al. Eur Heart J, 2009.
Antibiotic Dosage and Route Duration
Nafcillin/Cloxacillin± Gentamicin
Cefazolin± Gentamicin
Vancomycin*Daptomycin (RS-IE)
2 g/4 h IV + 1 mg/kg/8 h IV/IM
2 g/8 h IV+ 1 mg/kg/8 h IV/IM
30 mg/kg/24 h IV (in 2 doses)6 mg/kg/24 h IV
4-6 wk3-5 days
4-6 wk3-5 days
4-6 wk4-6 wk
CNS: Coagulase-Negative Staphylococci; IV: intravenously; IM: intramuscularly. * Adjust dosage to achieve 1-h serum concentration of 40–45 µg/mL and trough concentration of 15–20 µg/mL;
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Therapy for Endocarditis Caused by Methicillin-Resistant Staphylococcus aureus (MRSA)Baddour L et al. Circulation. 2005; Habib G et al. Eur Heart J, 2009
Vancomycin± Rifampin± Gentamicin
Daptomycin
LinezolidFosfomycin+ ImipenemOther drugs
30 mg/kg/24 h. IV (in 2 doses)* + 300 mg/8 h. PO/IV+ 3 mg/kg/24h. IV/IM (in 2-3 doses)
6 mg/kg 24 h. IV
600 mg/12 h. PO/IV2 g/6h IV+ 1 g/6h IV
≥ 6≥ 62
≥ 6
≥ 6≥ 6≥ 6
-
Regimen Dosage and route Duration (weeks)*
* Adjust dosage to achieve trough concentration of 15–20 µg/mL.
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Clinical 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
Difference in success rates: –4.0%95% CI: –20.3, 12.3
Difference in success rates: 12.6%, 95% CI: –7.4, 32.6
48.644.6 44.4
31.8
Patie
nts, %
0
10
20
30
40
50
33/74 34/70 20/45 14/44
MSSA (n=144) MRSA (n=89)
DaptomycinComparator
Efficacy of daptomycin at 6 mg/kg for SAB/IEFowler VG et al. N Engl J Med 2006;355:653–665
What is the best empiric therapy againstMSSA and MRSA Bacteremia/IE?
Daptomycin (A-I)Nafcillin/Cloxacillin + Vancomycin (B-III)
Gudiol F et al. Enferm Infecc Microbiol Clin. 2015
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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
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)** 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.
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Activity of Cloxacillin (CLO) plus Vancomycin (VAN) against MRSA-277 EE
Strain
Control
VAN (1 g/6h)
DAP (6mg/Kg/d)
CLO+VAN
Sterile
veg/Total (%)
0/15(0)
8/16 (50)a,b
13/18 (72)b,c
13/15 (87)a,c
Median(IQR)
Log10 CFU/g veg
9 (8.6-9.5)
1 (0-2.2)d
0 (0-1.5)
0 (0-0)d
ap=0.05, bp=0.29, cp=0.6 dp=0.09
Castañeda X et al. ICAAC 2012
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Vancomycin MICs ≥1 µg/ml: Outcomes against MRSAB improved with Daptomycin in 2 cohort studies
• Patients with MRSA BSI with higher vancomycin MICs (>1 µg/ml) and failing on vancomycin have a higher probability of survival at 60 days when treated with daptomycin: p=0.0221
1. Moore CL et al. Clin Infect Dis 2011;54:51 2. Murray KP et al. Clin Infect Dis 2013;56:1562
Factor Daptomycin(N=85)
Vancomycin(N=85)
P-value
Clinical failure, n 17 (20.0) 41 (48.2) <0.001Mortality at 30 days, n 3 (3.5) 11 (12.9) 0.047Persistent bacteraemia, n 16 (18.8) 36 (42.4) 0.001Duration of bacteraemia, days 3 (2–5) 5 (3–8) 0.003Length of stay, days 11 (8–18) 12 (8–17) 0.532Duration of treatment, days 10 (8–17) 9 (6–16) 0.324Recurrence of MRSAB within 30 days, n (%)
0 (0) 3 (4.1) 0.104
Outcomes with vancomycin MIC >1 µg/ml in patients with MRSAB2
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Daptomycin vs. Vancomycin as Initial Therapy for MSSA and MRSAInfections
Jobson et al. Clin Ther 2011
Only 23% had BSIVAN=108 (73 MRSA)DAP= 57 (46 MRSA)
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Strain
Control
CLO (2 g/4h)
VAN (1.25 g/8h)
DAP (6 mg/Kg/d)
CLO+VAN
Sterile
veg/Total (%)
0/15(0)
9/15 (60)a,b
10/14 (71)c
13/13 (100)a,c,d
10/14 (71)b,d
Median (IQR)
Log10 CFU/g veg
9 (8-9.2)
0 (0-2)
0 (1-1.5)
0 (0-0)
0 (0-1.5)ap=0.02; bp=0.7; cp=0.09; dp=0.09
Activity of Cloxacillin (CLO) plus Vancomycin (VAN) against MSSA-678 EE
Castañeda X et al. ICAAC 2012
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Com podem millorar l’activitat de daptomicina?
• Sembla que augmentant la dosi de daptomicina no n’hi ha prou a l’EI.
- ↑↑ Cmax/MIC - ↑↑ AUC/MIC- 8-10 mg/kg/d - Dosis encara més altes (12 mg/kg/d)?
• Combinar daptomicina amb altres atb*- Per tractar d’assolir una acció sinèrgica amb activitat bactericida- Per evitar el desenvolupament de resistències- Per disminuir les dosis de cada atb
* Gentamicina, rifampicina, fosfomicina, b-lactàmics, …
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Efficacy of daptomycin for SAB/IE at 6 mg/kg/dFowler VG et al. N Engl J Med 2006;355:653–665
Success rates at 6-week TOC by final diagnosis*: mITT population
56.3
43.3 42.1
11.1
55.2
37.743.8
22.2
Uncomplicatedbacteraemia
Complicatedbacteraemia
Right-sidedIE
0
10
20
30
40
50
60
70
Succ
ess r
ate (%
)
DaptomycinComparator
23/61 7/16 2/916/29 1/918/32 26/60 8/19
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.
MRSA IE0/5 0/4
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• 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
Þ 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
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Daptomycin-Resistance and Cell Surface Electrostatic Repulsion in DNS S. aureus
Ernst et al., PLoS Pathog 2009; 5:e1000660 Cationic antimicrobial peptides (CAMPs)
DAP/
DAP/CAMPs
Mutations in MprF identified in daptomycin-NS
S. aureus
Resposta a estrés de l’envolta celular: yycFG i vraSRMetabolisme de fosfolípids: cls, pgsA, mprF Síntesi d’àcids teicoics: dltABCDSíntesi d’ARN: rpoB, rpoC
1. Augment de la càrrega positiva de la membrana
cel·lular2. Canvis en la
fluïdesa de membrana
3. Engruiximent de la paret cel·lular.
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Daptomycin and β-lactams (Nafcillin)Dhand A et al. Clin Infect Dis. 2011;53:158-163.
• 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 (green) binding with &without NAF (yellow)
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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 !!!
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Daptomycin plus Fosfomycin is Synergistic against Methicillin-susceptible (MSSA) and Methicillin-resistant
Staphylococcus aureus (MRSA) StrainsMiró 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.
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The Combination of Daptomycin plus Fosfomycin has Synergistic, Potent, and Rapid Bactericidal Activity
against MRSA in a Rabbit Model of EEMiró JM et al. 53rd ECCMID, Barcelona 2014
MIC MRSA STRAIN=2 µg/mL
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Daptomycin plus Fosfomycin or Rifampin and Fosfomycin and Imipenem against MRSA in the
Experimental FBI ModelGarrigós et al, AAC 2013
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• Recruitment: 2014-15; 12 weeks of F/U.• Drugs adjusted to renal failure• Susceptible to study drugs• End points: 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 SpainPI 12/01907 - Dr. Miquel Pujol (H. Bellvitge)
MRSA BSI
(N=240)
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Daptomycin plus Cloxacillin against MRSA in theExperimental FBI Model
Garrigós et al, AAC 2012
The combination modestly enhanced the activity of DAP and prevented the emergence of resistance
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Daptomycin plus Cloxacillin is as effective as Cloxacillinplus Rifampin in vivo against MSSA in the FBI Model
El Haj et al, AAC 2015
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Addition of Gentamicin or Rifampin Does Not Enhance the Effectiveness of Daptomycin in Treatment of MRSA
Experimental Endocarditis with a Vancomycin MIC of 2 µg/mL Miró JM et al. Antimicrob Agents Chemother. 2009; 53:4172–4177
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80 patients (70% MRSA)Prior vancomycin failure= 27.5%
66 received concomitant atb 30 BL17 RIF12 FQ9 VAN8 GEN3 CLIN2 LIN2 S/T1 TYG
NO DIFFERENCES WERE FOUND REGARDING OUTCOMES BETWEEN MSSA AND MRSA
Outcomes of Daptomycin alone or with Concomitant Beta-Lactams for SAB in Patients with mild or Moderate Renal Impairment
Moise et al, AAC 2012
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The combination of Daptomycin plus TMP/SMX is Synergistic and Rapidly Bactericidal against Daptomycin-Nonsusceptible
(DNS) MRSA in an In Vitro Model of EndocarditisSteed ME et al, AAC 2010
Time
SA-684 strain
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)
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What would be the antibiotic combinations to treat Daptomycin-Non Susceptible (DNS) SAB/IE?
§ Daptomycin + Beta-lactams*
§ Daptomycin + Trimethoprim-Sulfamethoxazole**§ Daptomycin + Fosfomycin§ Fosfomycin + Imipenem§ Other antibiotic combinations***
* Ceftaroline, cloxacillin/nafcillin.*** Trimethoprim-Sulfamethoxazole + Clindamycin;Linezolid + Carbapenems.
** Steed ME et al. AAC. 2010; 54:5187–5192;Claeys KC et al. AAC. 2015 59: 1969-1976.
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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*
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)
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
Fosfomycin Combined with Imipenem in the Treatment of Experimental Endocarditis due to MRSA
García de la Màría C et al. 43rd ICAAC. Chicago. 2003. Abs. B-1091
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Clin Infect Dis. 2014 Oct 15;59(8):1105-12. doi: 10.1093/cid/ciu580. Epub 2014 Jul 21
70%
N = 16 cases (12 with IE)Patients with VAN or DAP microbiological
failureMicrobiological eradication in all cases
(100%)Bacteremia cleared in <3 days
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Vancomycin+ Rifampin (PVE)+ Gentamicin (PVE)
30 mg/kg/24 h. IV (in 2 doses)*+ 300 mg/8 h. PO/IV+ 3 mg/kg/24h. IV/IM (in 2-3 doses)
≥ 6≥ 62
* Adjust vancomycin to achieve trough concentration of 15–20 µg/mL
Therapy for Prosthetic Valve Endocarditis Caused by Methicillin-Resistant CoNSBaddour L et al. Circulation. 2005; Habib G et al. Eur Heart J. 2009.
Regimen Dosage and route Duration (weeks)*
Alternatives- Daptomycin- Linezolid- Other
≥ 6 mg/kg 24 h. IV600 mg/12 h. PO/IV
≥6≥6
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Influence of Methicillin Susceptibility and Vancomycin MIC on the Outcome of 85 Episodes of Coagulase-
Negative Staphylococci (CoNS) IEGarcia de la Maria C et al. PLoS One. 2015
S. epidermidis strainsPV/MCP IESurgeryMortality*
CloxacillinN=38
Van MIC≤1.5 mg/L
N=27
66%71%74%21%
74%63%59%44%
85%65%60%55%
*P = 0.022
Van MIC≥2.0 mg/L
N=20
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Daptomycin in the Treatment of Experimental Endocarditis due to Methicillin-Resistant Staphylococcus epidermidis (MRSE)
Garcia-de-la-Maria C et al. Antimicrob Agents Chemother. 2010, 54:2781–2786
Treatmentgroups
ControlVancomycin-SD (1 g q12h iv)Vancomycin-HD (1 g q6h iv)Daptomycin-SD (6 mg/kg q24h iv)Daptomycin-HD (10 mg/kg q24h iv)
Median (IQR) log10 cfu/g veg
7.4 (6; 8.3)2 (2; 2)2 (0; 3) 0 (0; 4)0 (0; 1)
# Sterile veg./ # total (%)
0/15 (0)3/16 (19)&
5/15 (33)* 9/15 (60)&
11/15 (73%)*
&P=0.02 *P=0.03. Vancomycin and Daptomycin MIC/MBCs were 2/4 and 0.5/1 mg/L, respectively.
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Clinical success was defined as the sum of cured and improved patients
84
7 9
88
93
72
1117
75
25
0
20
40
60
80
100
S. epidermidis (n=44) Other CoNS (n=32) E. faecalis (n=18) E. faecium (n=4)
Prop
ortio
nof p
atien
ts, %
Success
Non -evaluableFailure
Daptomycin for CoNS Endocarditis – EU-COREDohmen P et al. 20th ECCMID, Vienna (Austria), 2010 Poster O 511
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PVEDaptomycin*+ Rifampin (PVE)+ Gentamicin (PVE)
10 mg/kg/24 h. IV + 300 mg/8 h. PO/IV+ 3 mg/kg/24h. IV/IM (in 2-3 doses)
≥ 6≥ 62
* Fosfomycin plus Imipenem; Telavancin, Dalbavancin; Oritavancin, Tedizolid and other active antibiotics against MRSE
New Therapies for NVE & PVE Caused by Methicillin-Resistant CoNS
Regimen Dosage and route Duration (weeks)*
Alternatives- Ceftaroline- Linezolid- Other antibiotics*
600 mg/kg/8h IV600 mg/12 h. PO/IV
≥6≥6
NVEDaptomycin*+ Beta-Lactams or
Fosfomycin
10 mg/kg/24 h. IV + 2 g/4 h. IV+ 2 g/6 h. IV (in 2-3 doses)
4-64-64-6
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Antimicrobial Agents Against Staphylococcal Infections
Old drugs• TMP-SMX• Fusidic acid• Fosfomycin
† 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
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Ceftaroline for Salvage Treatment of SABAuthor, year N, types of strains Rates of
success (%)Comments
Vázquez JA, 2015 48, 67% MRSA 58 27 with ABSSSI, 21 with CABPPaladino JA, 2014 16, 100% MRSA MIC
VANCO >281 16 controls treated with VAN
(SR: 44%, P=0,06)File TM Jr, 2010 38, SAB? MIC? 82,6 FOCUS; Comparator: CROCorey GR, 2010 47, SAB? 85 CANVAS; Comparator
VAN+AZTrPolenakovik, 2013 21, 100% MRSA 66Ho, 2012 3, 100% MRSA 66Liu, 2013 5, MRSA 80 1 failure due to delayed
removal of knee prosthesisArshad, 2013 24, MRSA, CMI >1 83 8% relapsesRybak, 2013 4, MRSA differ. CMI 75 -Casapao, 2014 148, 86% MRSA 88 -
354 cases with an ≈ cure rate of 79%
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Ceftaroline for Staph. IEAround 60 cases published as rescue Rx
- 51 MRSA, 4 MSSA & 5 MRSE- 26 cases combined with DAP- 1 case combined with TMX/SFX- > 50% strains MIC over 1.5 µg/mL
Blood cultures cleared before 3 days in the majority of cases.Cure rates at EOT ≈ 80% (No data ToC)
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Metaanalysis of the efficacy of Linezolid vs. Glycopeptides or Betalactams for GPC infections
Falagas et al, Lancet Infect Dis 2008
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Tedizolid vs. Linezolid in Acute Bacterial SSSIsShorr et al, AAC 2015
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Tedizolid for MRSA IE in the Rabbit ModelChan et al, AAC 2015
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Tygecicline alone or plus Rifampin in the FBI Exp. ModelGarrigós et al, J Infect 2011
MIC vanco 2 µg/mL
The only favourable property is that tyg prevented the development of RIF resistance
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Once-Week Dalvabancin vs. Linezolid bid for the Treatment of Complicated SSSIs
Jauregui et al, CID 2005
N=572 N=283 90% S. aureus (51% MRSA)
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Once-Weekly Dalvabancin vs. Daily Conventional Therapy for Skin Infections
Boucher et al, NEJM 2014
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Single dose Oritavancin for the Treatment of Acute Bacterial Skin Infections
Corey GR et al, NEJM 2014
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Potential Role of Telavancin in Bacteremic Patients due to S. aureus
Corey et al, CID 2015
Totes les soques amb MIC <1 µg/mL
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Telavancin against Dapto-NS MRSA in the Rabbit Ao IE modelXiong et al, AAC 2012
MIC VAN=2 µg/mLMIC VAN= 4 µg/mL
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CONCLUSIONS• Daptomicina s’ha de fer servir en dosis altes (10 mg/kg) i en
combinació. • Evitar l’ús combinat de daptomicina i rifampicina durant les
fases inicials de la bacterièmia.• Hi ha diverses opcions en combinació per a evitar el
desenvolupament de R a daptomicina.• Tedizolid no aporta gran cosa quant a eficàcia i no evita
sempre els mecanismes de resistència que afecten a linezolid.
• Ceftarolina és el fàrmac recentment comercial·litzat ambmajor potencial en SAB i EI
• No ens oblidem de fosfomicina i cotrimoxazol!
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TeixobactinLing et al, Science 2015
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Combinations of Betalactams and Aminoglycosides with Plectasin are Synergistic against MRSA and MSSA
Hu et al, PLoSone 2015
Decrease vanco MIC with combined txMIC vanco in vivo strains?
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Efficacy of NZ2114, a Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in EE due to
MRSAXiong et al, AAC 2011
MIC vanco 0.5 µg/mL