The new antistaphylococcal drugs (tigecycline, daptomycin, - - PowerPoint PPT Presentation

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The new antistaphylococcal drugs (tigecycline, daptomycin, - - PowerPoint PPT Presentation

May 22, 2023 148 likes •657 views

S. aureus : what do we need to know (and to do) in 2007 ? The new antistaphylococcal drugs (tigecycline, daptomycin, telavancin, ): is the future (really) shining ? Franoise Van Bambeke Unit de Pharmacologie cellulaire et molculaire

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1 Sympo – S. aureus – 11/01/07 -

The new antistaphylococcal drugs (tigecycline, daptomycin, telavancin, …): is the future (really) shining ?

Françoise Van Bambeke

Unité de Pharmacologie cellulaire et moléculaire Université catholique de Louvain Bruxelles, Belgium

http://www.facm.ucl.ac.be

  • S. aureus: what do we need to know (and to do) in 2007 ?
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SLIDE 2

2 Sympo – S. aureus – 11/01/07 -

do we need new drugs ?

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SLIDE 3

3 Sympo – S. aureus – 11/01/07 -

Rice, Am. J. Med. (2006) 119:S11-9

« old » antibiotics: still usable for CA-MRSA !

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SLIDE 4

4 Sympo – S. aureus – 11/01/07 -

Sabol et al., Ann. Pharmacother. (2006) 40:1125-33

« old » antibiotics: still usable for CA-MRSA !

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SLIDE 5

5 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 What will be your choice ? new oxazolidinones new ketolides ...

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SLIDE 6

6 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 new oxazolidinones new ketolides ...

Let’s try to find a way …

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SLIDE 7

7 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 new oxazolidinones new ketolides ...

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SLIDE 8

8 Sympo – S. aureus – 11/01/07 -

moxifloxacin and CA-MRSA

Kaka et al., JAC (2006) 58:680-3

killing curves - 6 CA-MRSA

6 12 18 24

  • 3
  • 2
  • 1

sulfametoxazole linezolid rifampicin minocycline clindamycin moxifloxacin

time (h) Δ log CFU/ml

rapidly bactericidal

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SLIDE 9

9 Sympo – S. aureus – 11/01/07 -

moxifloxacin: in vitro data

0.25 0.5 1 2 4 8 16 32 64 128 256 10 20 30 40 50 60 S R

cipro levo moxi

MIC (mg/L) percentage of strains

breakpoint

low level resistance high level resistance

Lowest MICs among currently available quinolones, but … Distribution of MICs for 100 MRSA collected in 2002

Noguchi et al., Int. J. Antimicrob. Ag. (2005) 25:374-9

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SLIDE 10

10 Sympo – S. aureus – 11/01/07 -

moxifloxacin: pros and cons

  • rapidly bactericidal
  • easy switch iv-po
  • once-a-day
  • no major toxicity issue

(already quite large clinical experience)

  • cross resistance with
  • ther quinolones

even if MIC lower CA-MRSA only

  • risk of QTc interval

(drug interactions !)

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SLIDE 11

11 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 new oxazolidinones new ketolides ...

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12 Sympo – S. aureus – 11/01/07 -

linezolid

  • inhibits the formation of the initiation complex
  • no cross resistance with other drugs

acting on protein synthesis (MLS)

  • resistance considered for long as improbable …

but now well described (due to mutations in 23S rRNA)

O N O HN F N O O

Bozdogan & Appelbaum, Int. J. Antimicrob. Ag. (2004) 23:113-9

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SLIDE 13

13 Sympo – S. aureus – 11/01/07 -

linezolid: in vitro data

breakpoint

We slowly reach the limit …

Distribution of MICs for 60 MRSA collected from diabetic foot

Goldstein et al., AAC (2006) 50:2875-79

drug range MIC 50 MIC 90 vancomycin 0.5-1 0.5 1 8 4 linezolid 2-8 4 4

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SLIDE 14

14 Sympo – S. aureus – 11/01/07 -

linezolid: in vitro data

Wilson et al., JAC (2006) 58:470-3

Susceptibility of MRSA by site of isolation

breakpoint

8 4

again we approach the limit …

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SLIDE 15

15 Sympo – S. aureus – 11/01/07 -

linezolid: clinical experience

Weigelt et al., AAC (2005) 49:2260-66; Senneville et al., Clin Ther. (2006) 28:1155-63; Shorr et al., JAC (2005) 56:923-929; Wunderink et al., Chest (2003)124:1789-97

indication Linezolid 600 mg iv/po 2x/day Vancomycin 1g iv 2x/day cSSTI (1180) 99.2 % 88.5 % Osteomyelitis (66) 84.8 %

  • MRSA bacteriaemia (53)

56 % 46 % nosocomial pneumonia (1019) MRSA (160) 53 % 59 % 52.2 % 35.5 %

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16 Sympo – S. aureus – 11/01/07 -

linezolid: pros and cons

  • excellent biodisponibility

and tissue penetration

  • easy switch iv-po
  • bacteriostatic
  • resistance already selected
  • high price
  • twice-a-day
  • serious side effects

(myelosuppression)

  • drug interactions (IMAO)
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SLIDE 17

17 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 new oxazolidinones new ketolides ...

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18 Sympo – S. aureus – 11/01/07 -

synercid

Harms et al., BMB Biol (2004) 2:4

SA blocks peptide bound formation SB blocks the path of the nascent peptide

dalfopristin quinupristin

SYNERGY

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19 Sympo – S. aureus – 11/01/07 -

synercid: in vitro data

Susceptibility of 101 MRSA

What about these ?

Sambatakou et al., JAC (1998) 51:349-55

breakpoint

0.015625 0.03125 0.0625 0.125 0.25 0.5 1 2 10 20 30 40 50 60 S R 0.015 0.03 0.06

MIC (mg/L) percentage of strains

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SLIDE 20

20 Sympo – S. aureus – 11/01/07 -

synercid: in vitro data

In vitro models - MRSA

Baudoux et al., ECCMID (2007)

time- and concentration-dependent bactericidal effect

  • 2
  • 1

1 2

  • 4
  • 3
  • 2
  • 1

1 2 3 5 h 24h

Log concentration (mg/L) Δlog CFU from time 0

Cmax MIC

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21 Sympo – S. aureus – 11/01/07 -

synercid: in vitro data

In vitro pharmacodynamic models

Allen et al., AAC (2002) 46:2606-12

  • poorly active alone against MRSA; highly active on VRE
  • combinations synergistic towards MRSA
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22 Sympo – S. aureus – 11/01/07 -

synercid : pros and cons

  • highly active on VRE
  • synergistic in vitro

with many ABs

  • poorly bactericidal

against MRSA

  • bid or tid administration
  • no oral route
  • cross-resistance with ML
  • drug interactions (CYP450 3A4)

caution with drugs prolonging QTc

  • myalgia/arthralgia frequent
  • high price
  • not studied in children
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SLIDE 23

23 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 new oxazolidinones new ketolides ...

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24 Sympo – S. aureus – 11/01/07 -

daptomycin

  • very bactericidal towards Gram (+) organisms through membrane destabilization
  • spare mammalian cells because they lack phosphatidylglycerol

(critical for binding to Gram(+) membranes)

  • fast track registration in the US because of activity against vancomycin-resistant

enterococci (VRE)

  • indications: cSSTI; Phase III trial on bacteriemia completed
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25 Sympo – S. aureus – 11/01/07 -

daptomycin: in vitro data

breakpoint

wait and see …

Distribution of MICs for 60 MRSA collected from diabetic foot

Goldstein et al., AAC (2006) 50:2875-79

drug range MIC 50 MIC 90 vancomycin 0.5-1 0.5 1 8 1 daptomycin 0.25-1 0.5 0.5

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26 Sympo – S. aureus – 11/01/07 -

daptomycin: clinical experience

Arbeit et al., CID (2004) 38:1673-81; Segreti et al., Pharmacotherapy (2006) 26:347-352

indication Daptomycin iv 1x/day Vancomycin

  • r

β-lactam cSSTI (902) MRSA (28-36) 4 mg/kg 83.4 % 75 % 84.2 % 69.4 % bloodstream (31) MRSA (11) VRE (11) 6 mg/kg 77 % 100 % 45 %

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27 Sympo – S. aureus – 11/01/07 -

daptomycin: pros and cons

  • rapidly bactericidal
  • once-a-day
  • inactive in pneumonia
  • VISA tend to have MICs
  • high price
  • no oral route
  • musculotoxic in animals

avoid combination with inhibitors

  • f HMGCoA reductase
  • safety / efficacy not studied

in < 18 years

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SLIDE 28

28 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 new oxazolidinones new ketolides ...

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SLIDE 29

29 Sympo – S. aureus – 11/01/07 -

tigecycline

Olson et al., AAC (2006) 50:2156-66

tigecycline tetracycline minocycline

  • same binding site as tetracyclines in

ribosome 16S RNA; additional interaction site

  • Unaffected by resistance due to
  • ribosomal protection
  • Tet efflux pumps
  • Approved in USA in 2005 and in

Europe in 2006

  • wide spectrum, indicated for:

cSSTI; intra-abdominal infections

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30 Sympo – S. aureus – 11/01/07 -

tigecycline: in vitro data

a few isolates above the breakpoint …

0.125 0.25 0.5 1 2 4 8 16 32 64 128 256 20 40 60 80 S R

tigecycline minocycline

MIC (mg/L) percentage of strains

breakpoint

active

  • n minocycline-R

population, but …

Low et al., Int. J. Antimicrob. Ag. (2002) 20:220-2

Distribution of MICs for 128 MRSA from USA

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31 Sympo – S. aureus – 11/01/07 -

tigecycline clinical experience

Ellis-Grosse et al., Clin. Infect. Dis. (2005) 41:S341-53

Phase 3 - Skin and skin structure infections

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SLIDE 32

32 Sympo – S. aureus – 11/01/07 -

tigecycline : pros and cons

  • XL spectrum ?
  • not affected

by some tet resistance mechanisms

(Tet efflux, ribosomal protection)

  • once-a-day
  • large tissue distribution
  • XL spectrum ?
  • bacteriostatic
  • CI – pregnancy, children
  • no oral route
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SLIDE 33

33 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 new oxazolidinones new ketolides ...

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34 Sympo – S. aureus – 11/01/07 -

new glycopeptides: structure-activity relationship

Van Bambeke, Cur. Opin. Pharmacol. (2004) 4:471-8

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35 Sympo – S. aureus – 11/01/07 -

new glycopeptides: in vitro data

no breakpoint yet for new GP

MICs

  • f the same

range as for vanco, but … Distribution of MICs for MRSA

breakpoint

range drug (a) n = 23 (b) n=30 telavancin 0.125-1

  • ritavancin

0.125-4 1-2 0.5-16 vancomycin 0.5-4 4 4 dalbavancin 0.06-1 teicoplanin 0.125-8

(a) Candiani et al., JAC (1999) 44:179-92; (b) King et al., JAC (2004) 53:797-803

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36 Sympo – S. aureus – 11/01/07 -

new glycopeptides: mode of action

… rapid bactericidal effect, related to multiple modes of action

www.theravance.com

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37 Sympo – S. aureus – 11/01/07 -

new glycopeptides: mode of action

… rapid bactericidal effect, related to multiple modes of action

Barcia-Macay et al., JAC (2006) 58:1177-84

  • 2
  • 1

1 2 3

  • 5
  • 4
  • 3
  • 2
  • 1

1 2 3

MRSA MSSA

log concentration (X MIC) Δ log CFU from time 0

  • 2
  • 1

1 2 3

  • 5
  • 4
  • 3
  • 2
  • 1

1 2 3

VISA VRSA

log concentration (X MIC) Δ log CFU from time 0

Activity of telavancin after 3 h towards S. aureus with different resistance phenotypes Bimodal effect :

  • inhibition of PG synthesis
  • membrane permeabilization

Unimodal effect :

  • inhibition of PG synthesis
  • membrane permeabilization

MSSA - vanco

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SLIDE 38

38 Sympo – S. aureus – 11/01/07 -

new glycopeptides: clinical experience

Van Bambeke, Curr. Opin. Investig. Drugs (2006) 7:740-9

  • ritavancin (5-10 mg/kg 1x day ~ 10 days)
  • skin and soft tissue infection (Phase III)
  • bloodstream infection (Phase II)

telavancin (10 mg/kg 1x day ~ 10 days)

  • skin and soft tissue infection (Phase III)

fast track designation by the FDA for the treatment of hospitally-acquired pneumonia (MRSA or multiresistant S. pneumoniae) MRSA-associated complicated skin and skin structure infection

dalbavancin (1 g followed by 500 mg 1 week later)

  • skin and skin structure infections (Phases II and III)
  • catheter-related bloodstream infections (Phase II)

priority review status by the FDA for the treatment of MRSA complicated skin and soft tissue infections.

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SLIDE 39

39 Sympo – S. aureus – 11/01/07 -

new glycopeptides: clinical experience

Kanafani, Exp. Rev. Anti-inf. Ther. (2006) 4:743-9; www.theravance.com

Phase 3 - Skin and skin structure infections

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SLIDE 40

40 Sympo – S. aureus – 11/01/07 -

new glycopeptides : pros and cons

  • rapidly bactericidal
  • once-a-day / a-week
  • active on VISA

and VRSA (not DAL)

  • no oral route
  • once-a-week ?
  • prolonged retention

in the organism (DAL) ?

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SLIDE 41

41 Sympo – S. aureus – 11/01/07 -

recent and novel agents for S. aureus

recently brought on the Belgian market

  • n the market;

not yet in Belgium (late) stage of clinical development investigational moxifloxacin linezolid synercid daptomycin tigecycline telavancin

  • ritavancin

dalbavancin ceftobiprole CS-023/PZ-601 MX-2401 API-1252 WCK-771 iclaprim retapamulin DK-619 new oxazolidinones new ketolides ...

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SLIDE 42

42 Sympo – S. aureus – 11/01/07 -

ceftobiprole

Hebeisen et al., AAC (2001) 45:825-31

O HO N S O H N O N O N OH N N NH S NH2 H

BAL9141 BAL5788

prodrug

N O O O O O

  • Capable of binding to PBP2a of

MRSA

  • Fast track designation from FDA

for cSSTI and nosocomial pneumonia β-lactamases PBP2a

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SLIDE 43

43 Sympo – S. aureus – 11/01/07 -

ceftobiprole in vitro data

Susceptibility of 1275 MRSA

drug range MIC 50 MIC 90 vancomycin 0.5-2 1 1 8 4 ceftobiprole 0.12-4 1 1

Sahm et al., ICAAC (2006) E0113

breakpoint

so far, so good, but for how long ? …

*

* provisional breakpoint

Mouton et al, AAC (2004) 48:1713-8.

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SLIDE 44

44 Sympo – S. aureus – 11/01/07 -

Ceftobiprole clinical experience

Noel et al., ICAAC (2006) L1212

cSSSI – 784 patients

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SLIDE 45

45 Sympo – S. aureus – 11/01/07 -

ceftobiprole: pros and cons

  • broad spectrum ?

(polymicrobial infections)

  • bactericidal
  • synergistic with AG
  • tissue penetration
  • broad spectrum ?
  • trend to MIC increase
  • iv only
  • twice-a-day
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SLIDE 46

46 Sympo – S. aureus – 11/01/07 -

a few additional criteria of choice …

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SLIDE 47

47 Sympo – S. aureus – 11/01/07 -

what about Belgian isolates ?

Susceptibility of 511 MRSA from 112 hospitals

Denis et al., AAC (2006) 50:2680-5

breakpoint

All isolates still below the breakpoint

vancomycin daptomycin synercid linezolid tigecycline ceftobiprole 8 4 1 2 0.5 4

but do we agree with all breakpoints ?

0.03125 0.0625 0.125 0.25 0.5 1 2 20 40 60 80 100 MIC = breakpoint 1/1 1/2 1/4 1/8 1/16 1/32 2/1

ratio MIC breakpoint cumulative percentage

  • f strains
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SLIDE 48

48 Sympo – S. aureus – 11/01/07 -

a lot of molecules in the pipeline

synercid: usefulness in Europe ? daptomycin: bactericidal, but surfactant effect … tigecycline: polymicrobial infections, but static …

really new still to come

new glycopeptides: bactericidal, resistance probably difficult to select FabI inhibitors: totally new target, MICs very low

question for the future:

conclusion

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SLIDE 49

49 Sympo – S. aureus – 11/01/07 -

Thank you for your attention

and happy birthday to Hergé…