Alternatives a VancomicinaJuan M Pericàs

Servei de Malalties InfecciosesHospital Clínic de Barcelona

IDIBAPS-UB

SESSIÓ SCMIMC 21/05/15

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.

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

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

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;

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.

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

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.

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

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

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)

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

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, …

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

• 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

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.

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)

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 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.

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

Daptomycin plus Fosfomycin or Rifampin and Fosfomycin and Imipenem against MRSA in the

Experimental FBI ModelGarrigós et al, AAC 2013

• 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)

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

Daptomycin plus Cloxacillin is as effective as Cloxacillinplus Rifampin in vivo against MSSA in the FBI Model

El Haj et al, AAC 2015

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

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

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)

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.

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

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

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

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

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.

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

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

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

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%

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)

Metaanalysis of the efficacy of Linezolid vs. Glycopeptides or Betalactams for GPC infections

Falagas et al, Lancet Infect Dis 2008

Tedizolid vs. Linezolid in Acute Bacterial SSSIsShorr et al, AAC 2015

Tedizolid for MRSA IE in the Rabbit ModelChan et al, AAC 2015

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

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)

Once-Weekly Dalvabancin vs. Daily Conventional Therapy for Skin Infections

Boucher et al, NEJM 2014

Single dose Oritavancin for the Treatment of Acute Bacterial Skin Infections

Corey GR et al, NEJM 2014

Potential Role of Telavancin in Bacteremic Patients due to S. aureus

Corey et al, CID 2015

Totes les soques amb MIC <1 µg/mL

Telavancin against Dapto-NS MRSA in the Rabbit Ao IE modelXiong et al, AAC 2012

MIC VAN=2 µg/mLMIC VAN= 4 µg/mL

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!

TeixobactinLing et al, Science 2015

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?

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