MRSA, a Worldwide Problem …

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 ?

Françoise Van Bambeke Unité de Pharmacologie cellulaire et moléculaire Université catholique de Louvain Bruxelles, Belgium http://www.facm.ucl.ac.be Sympo – S. aureus – 11/01/07 - 1 do we need new drugs ?

Sympo – S. aureus – 11/01/07 - 2 « old » antibiotics: still usable for CA-MRSA !

Rice, Am. J. Med. (2006) 119:S11-9 Sympo – S. aureus – 11/01/07 - 3 « old » antibiotics: still usable for CA-MRSA !

Sabol et al., Ann. Pharmacother. (2006) 40:1125-33 Sympo – S. aureus – 11/01/07 - 4 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

moxifloxacin synercid telavancin CS-023/PZ-601 linezolid daptomycin oritavancin MX-2401 tigecycline dalbavancin API-1252 ceftobiprole DK-619 iclaprim new oxazolidinones retapamulin new ketolides WCK-771 ...

What will be your choice ? Sympo – S. aureus – 11/01/07 - 5 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

Let’s try to find a way … Sympo – S. aureus – 11/01/07 - 6 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

Sympo – S. aureus – 11/01/07 - 7 moxifloxacin and CA-MRSA

killing curves - 6 CA-MRSA 0 clindamycin linezolid -1 minocycline

rifampicin

-2 log CFU/ml Δ

-3 sulfametoxazole moxifloxacin

0 6 12 18 24 time (h) rap b idly act eric idal

Kaka et al., JAC (2006) 58:680-3 Sympo – S. aureus – 11/01/07 - 8 moxifloxacin: in vitro data

Distribution of MICs for 100 MRSA collected in 2002

breakpoint 60 S R cipro 50 levo Lowest MICs moxi among currently 40 available 30 quinolones, 20 but … 10 percentage of strains 0 4 8 1 2 16 32 64 0.5 128 256 0.25 MIC (mg/L) low level high level resistance resistance Noguchi et al., Int. J. Antimicrob. Ag. (2005) 25:374-9 Sympo – S. aureus – 11/01/07 - 9 moxifloxacin: pros and cons

• rapidly bactericidal • cross resistance with • easy switch iv-po other quinolones • once-a-day even if MIC lower • no major toxicity issue Æ CA-MRSA only (already quite large • risk of Ê QTc interval clinical experience) (drug interactions !)

Sympo – S. aureus – 11/01/07 - 10 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

Sympo – S. aureus – 11/01/07 - 11 linezolid

O N N O

F O

• 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)

Bozdogan & Appelbaum, Int. J. Antimicrob. Ag. (2004) 23:113-9 Sympo – S. aureus – 11/01/07 - 12 linezolid: in vitro data

Distribution of MICs for 60 MRSA collected from diabetic foot

drug range MIC 50 MIC 90 breakpoint vancomycin 0.5-1 0.5 1 8

linezolid 2-8 4 4 4

We slowly reach the limit …

Goldstein et al., AAC (2006) 50:2875-79 Sympo – S. aureus – 11/01/07 - 13 linezolid: in vitro data

Susceptibility of MRSA by site of isolation

8 4 breakpoint again we approach the limit …

Wilson et al., JAC (2006) 58:470-3 Sympo – S. aureus – 11/01/07 - 14 linezolid: clinical experience

indication Linezolid Vancomycin 600 mg iv/po 1g iv 2x/day 2x/day cSSTI (1180) 99.2 % 88.5 % Osteomyelitis (66) 84.8 % -- MRSA bacteriaemia (53) 56 % 46 %

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

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 Sympo – S. aureus – 11/01/07 - 15 linezolid: pros and cons

• excellent biodisponibility • bacteriostatic and tissue penetration • resistance already selected • easy switch iv-po • high price • twice-a-day • serious side effects (myelosuppression) • drug interactions (IMAO)

Sympo – S. aureus – 11/01/07 - 16 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

Sympo – S. aureus – 11/01/07 - 17 synercid

SA blocks peptide bound formation

dalfopristin

SYNERGY

quinupristin

SB blocks the path of the nascent peptide

Harms et al., BMB Biol (2004) 2:4 Sympo – S. aureus – 11/01/07 - 18 synercid: in vitro data

Susceptibility of 101 MRSA

breakpoint 60 S R 50

10 percentage of strains of percentage 0 1 2 0.5 0.25 0.06 0.03 0.125 0.015 0.0625 What about these ? 0.03125 0.015625 MIC (mg/L)

Sambatakou et al., JAC (1998) 51:349-55 Sympo – S. aureus – 11/01/07 - 19 synercid: in vitro data

In vitro models - MRSA

3 5 h 24h 2

-1

-2 log CFU from time 0 time from CFU log Δ -3

-4 -2 -1 0 1 2 MIC Cmax Log concentration (mg/L)

time- and concentration-dependent bactericidal effect

Baudoux et al., ECCMID (2007) Sympo – S. aureus – 11/01/07 - 20 synercid: in vitro data

In vitro pharmacodynamic models

• poorly active alone against MRSA; highly active on VRE • combinations synergistic towards MRSA

Allen et al., AAC (2002) 46:2606-12 Sympo – S. aureus – 11/01/07 - 21 synercid : pros and cons

• highly active on VRE • poorly bactericidal • synergistic in vitro against MRSA with many ABs • 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

Sympo – S. aureus – 11/01/07 - 22 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

Sympo – S. aureus – 11/01/07 - 23 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 Sympo – S. aureus – 11/01/07 - 24 daptomycin: in vitro data

Distribution of MICs for 60 MRSA collected from diabetic foot

drug range MIC 50 MIC 90 breakpoint vancomycin 0.5-1 0.5 1 8

daptomycin 0.25-1 0.5 0.5 1

wait and see …

Goldstein et al., AAC (2006) 50:2875-79 Sympo – S. aureus – 11/01/07 - 25 daptomycin: clinical experience

indication Daptomycin Vancomycin iv 1x/day or β-lactam cSSTI (902) 4 mg/kg 83.4 % 84.2 % MRSA (28-36) 75 % 69.4 % bloodstream (31) 6 mg/kg 77 % -- MRSA (11) 100 % VRE (11) 45 %

Arbeit et al., CID (2004) 38:1673-81; Segreti et al., Pharmacotherapy (2006) 26:347-352 Sympo – S. aureus – 11/01/07 - 26 daptomycin: pros and cons

• rapidly bactericidal • inactive in pneumonia • once-a-day • VISA tend to have Ê MICs • high price • no oral route • musculotoxic in animals avoid combination with inhibitors of HMGCoA reductase • safety / efficacy not studied in < 18 years

Sympo – S. aureus – 11/01/07 - 27 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

Sympo – S. aureus – 11/01/07 - 28 tigecycline

tigecycline

• same binding site as tetracyclines in ribosome 16S RNA; additional interaction site tetracycline • Unaffected by resistance due to minocycline - ribosomal protection - Tet efflux pumps • Approved in USA in 2005 and in Europe in 2006 • wide spectrum, indicated for: cSSTI; intra-abdominal infections

Olson et al., AAC (2006) 50:2156-66 Sympo – S. aureus – 11/01/07 - 29 tigecycline: in vitro data

Distribution of MICs for 128 MRSA from USA

breakpoint

80 S R tigecycline minocycline

active 60 on minocycline-R population, but … 40

20 percentage of strains of percentage 0 1 2 4 8 16 32 64 0.5 128 256 0.25 0.125 MIC (mg/L) a few isolates above the breakpoint …

Low et al., Int. J. Antimicrob. Ag. (2002) 20:220-2 Sympo – S. aureus – 11/01/07 - 30 tigecycline clinical experience

Phase 3 - Skin and skin structure infections

Ellis-Grosse et al., Clin. Infect. Dis. (2005) 41:S341-53 Sympo – S. aureus – 11/01/07 - 31 tigecycline : pros and cons

• XL spectrum ? • XL spectrum ? • not affected • bacteriostatic by some tet resistance • CI – pregnancy, children mechanisms • no oral route (Tet efflux, ribosomal protection) • once-a-day • large tissue distribution

Sympo – S. aureus – 11/01/07 - 32 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

Sympo – S. aureus – 11/01/07 - 33 new glycopeptides: structure-activity relationship

Van Bambeke, Cur. Opin. Pharmacol. (2004) 4:471-8 Sympo – S. aureus – 11/01/07 - 34 new glycopeptides: in vitro data

Distribution of MICs for MRSA

drug range (a) n = 23 (b) n=30 breakpoint MICs telavancin 0.125-1 of the same oritavancin 0.125-4 range vancomycin 0.5-4 1-2 4 as for vanco, but … dalbavancin 0.06-1

teicoplanin 0.125-8 0.5-16 4

no breakpoint yet for new GP

(a) Candiani et al., JAC (1999) 44:179-92; (b) King et al., JAC (2004) 53:797-803 Sympo – S. aureus – 11/01/07 - 35 new glycopeptides: mode of action

… rapid bactericidal effect, related to multiple modes of action

www.theravance.com Sympo – S. aureus – 11/01/07 - 36 new glycopeptides: mode of action

… rapid bactericidal effect, related to multiple modes of action

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

3 MRSA 3 VISA VRSA 2 MSSA 2 1 1 0 0 MSSA - vanco -1 -1 -2 -2 -3 -3 log CFU from time 0 time from CFU log log CFU from time 0 time from CFU log Δ Δ -4 -4 -5 -5 -2 -1 0 1 2 3 -2 -1 0 1 2 3 log concentration (X MIC) log concentration (X MIC)

Bimodal effect : Unimodal effect : • inhibition of PG synthesis • inhibition of PG synthesis • membrane permeabilization • membrane permeabilization

Barcia-Macay et al., JAC (2006) 58:1177-84 Sympo – S. aureus – 11/01/07 - 37 new glycopeptides: clinical experience

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

Van Bambeke, Curr. Opin. Investig. Drugs (2006) 7:740-9 Sympo – S. aureus – 11/01/07 - 38 new glycopeptides: clinical experience

Phase 3 - Skin and skin structure infections

Kanafani, Exp. Rev. Anti-inf. Ther. (2006) 4:743-9; www.theravance.com Sympo – S. aureus – 11/01/07 - 39 new glycopeptides : pros and cons

• rapidly bactericidal • no oral route • once-a-day / a-week • once-a-week ? • active on VISA • prolonged retention and VRSA (not DAL) in the organism (DAL) ?

Sympo – S. aureus – 11/01/07 - 40 recent and novel agents for S. aureus

recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development

Sympo – S. aureus – 11/01/07 - 41 ceftobiprole

NH2 β-lactamases S NN prodrug H H PBP2a N S N O O OH O N N O O NONH O O HO O BAL9141 BAL5788

• Capable of binding to PBP2a of MRSA

• Fast track designation from FDA for cSSTI and nosocomial pneumonia

Hebeisen et al., AAC (2001) 45:825-31 Sympo – S. aureus – 11/01/07 - 42 ceftobiprole in vitro data

Susceptibility of 1275 MRSA

drug range MIC 50 MIC 90 breakpoint

vancomycin 0.5-2 1 1 8

ceftobiprole 0.12-4 1 1 4 *

so far, so good, but for how long ? …

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

Sahm et al., ICAAC (2006) E0113 Sympo – S. aureus – 11/01/07 - 43 Ceftobiprole clinical experience

cSSSI – 784 patients

Noel et al., ICAAC (2006) L1212 Sympo – S. aureus – 11/01/07 - 44 ceftobiprole: pros and cons

• broad spectrum ? • broad spectrum ? (polymicrobial infections) • trend to MIC increase • bactericidal •iv only • synergistic with AG • twice-a-day • tissue penetration

Sympo – S. aureus – 11/01/07 - 45 a few additional criteria of choice …

Sympo – S. aureus – 11/01/07 - 46 what about Belgian isolates ?

Susceptibility of 511 MRSA from 112 hospitals

All isolates still below the breakpoint

MIC = breakpoint

100

80 breakpoint 60 vancomycin 8 40 of strains ceftobiprole 4 20 daptomycin 1 synercid 2 cumulative percentage 0 tigecycline 0.5 2 1/32 1/16 1/8 1/4 1/2 1/11 2/1 0.5 linezolid 4 0.25 0.125 0.0625

0.03125 MIC ratio but do we agree breakpoint with all breakpoints ?

Denis et al., AAC (2006) 50:2680-5 Sympo – S. aureus – 11/01/07 - 47 conclusion a lot of molecules in the pipeline Æ synercid: usefulness in Europe ? Æ daptomycin: bactericidal, but surfactant effect … Æ tigecycline: polymicrobial infections, but static … really new still to come Æ new glycopeptides: bactericidal, resistance probably difficult to select ÆFabI inhibitors: totally new target, MICs very low question for the future:

Sympo – S. aureus – 11/01/07 - 48 Thank you for your attention

and happy birthday to Hergé…

Sympo – S. aureus – 11/01/07 - 49