Antibiotics in bone and joint infections Françoise Van Bambeke, PharmD, PhD Pharmacologie cellulaire et moléculaire Louvain Drug Research Institute & Centre de Pharmacie clinique Université catholique de Louvain, Brussels, Belgium

25/04/2013

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Antibiotics recommended in bone and joint infections microorganisms

Preferred treatment

MSSA

nafcillin-cefazolinceftriaxone

Enteroccoci; Pen-S

penicillin G-ampicillin

Alternative treatment vancomycin-daptomycinlinezolid

MRSA Enteroccoci; Pen-R

vancomycin

-hemolytic streptococci Propionibacterium

daptomycin-linezolid vancomycin

penicillin G-ceftriaxone

clindamycin-vancomycin

P. aeruginosa

cefepime-meropenem

ciprofloxacin-ceftazidime

Enterobacter spp

cefepime-ertapenem

ciprofloxacin

Enterobacteriacae

IV -lactam-ciprofloxacin IDSA Guidelines; CID (2013) 56: e1-25

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Pharmacologic criteria for antibiotic selection

PHARMACOKINETICS

PHARMACODYNAMICS

SPECIFIC FORMS OF INFECTION

SAFETY PROFILE

http://www.tintin.com/journal/journal/00757/C07%2058%20A.jpg

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Pharmacokinetics

Herge

http://quotiriens.blog.lemonde.fr/files/2011/09/milou-sceptre.jpg

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Tissue penetration

bioavailable fraction

Landersdorfer et al., Clin Pharmacokinet (2009) 48: 89-124 25/04/2013

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Tissue penetration

Landersdorfer et al., Clin Pharmacokinet (2009) 48: 89-124 25/04/2013

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Tissue penetration what about more recent molecules ?

Moenster et al., J Clin Pharm Ther. 2013; 38:89-96 25/04/2013

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Pharmacodynamics

J. Roba

www.fr.fnac.be

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PK/PD: more questions than answers Do classical PD criteria apply in bone and joint infections ? Bioavailable drug fraction ?

Cooperation with host defenses ?

Antibiotic expression of activity ? 25/04/2013

Bacterial responsiveness ? Orthopaedica Belgica - Spa

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Antibiotic combinations Foreign body osteomyelitis

combinations prevent emergence of resistance to rifampicin Vergidis et al., AAC 2011; 55: 1182–6 25/04/2013

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Combinations with rifampicin Antibiotic

In vitro (broth)

In the clinics*

cloxacillin, cefazolin

antagonism

= cloxacillin alone

vancomycin

synergy

= vancomycin alone

fluoroquinolone

antagonism

> fluoroquinolone alone

fusidic acid

indifference

= fusidic acid alone

clindamycin

synergy

90 % success

cotrimoxazole

antagonism

= cotrimoxazole alone

linezolid

indifference

90 % success

daptomycin

indifference

42 % success

cyclines

synergy

40 % failures

* different types of infection and evaluation criteria … « checkerboard » not predictive of in vivo activity of combinations … Coiffier et al., Revue du rhumatisme 2012; 79: 397–404 25/04/2013

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Specific forms of infection

Hergé

http://24.media.tumblr.com/tumblr_m8q2lpiFtM1rq3prxo1_500.jpg

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Intracellular survival Evidence of an intracellular reservoir in osteocytes (A,B), osteoblasts (C) and bone matrix of a patient with recurrent osteomyelitis

Bosse et al., J Bone Joint Surg Am. 2005; 87:1343-7 25/04/2013

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Small Colony Variants Evidence of Small Colony Variants and of intracellular S. aureus after treatment failure * in patients with prosthetic joint infections

* Fluclox, CIP+ RIF, VAN + FEP 25/04/2013

Sendi et al., Clin Infect Dis. 2006; 43:961-7 Orthopaedica Belgica - Spa

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Biofilms biofilm observed in electron microscopy on a bone sequester obtained from a patient with bone necrosis (Enterobacter sp.)

biofilm observed in electron microscopy on a steel component of an Ilizarov device obtained from a patient with clinical infection (S. aureus)

Bartoszewicz et al; Orttopediia Traumatologia Rehabilitacja 2007; 9:310-8 25/04/2013

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Three forms of persistent infections … osteoblasts

intracellular persistence Y

Y

Y

Y Y

Y

biofilm surfac e

SCVs Based on Coiffier et al., Revue du rhumatisme 2012; 79: 397–404 25/04/2013

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Extracellular vs intracellular activity at Cmax All antibiotics show reduced activity intracellularly against S. aureus

THP-1 monocytes,24 h, MSSA ATCC25923 25/04/2013

Barcia-Macay et al., AAC 2006; 50:841-51 Orthopaedica Belgica - Spa

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A pharmacodynamic model to assess antibiotic intracellular activity Opsonization

moxifloxacin

log CFU from time 0

3

Cs « rel. potency »

2

Culture medium + human serum

intra extra

Phagocytosis

1

Extracellular Wash (Gentamicin 100 X MIC; ~1 h)

0 -1

Emax « efficacy »

-2 -3

5 -10 x105 CFU/mg prot. Time 0

-4 -5 -1

0

1

2

3

4

5 Incubation (with antibiotics)

log10 concentration (X MIC)

For up to 24 h (control: Gentamicin 0.5 X MIC)

Lemaire et al., JAC 2011; 66:596-607 25/04/2013

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Dose-response curves of the 3 most active antibiotics against extra- and intracellular SCV (24 h of exposure)

Bimodal effect

Gray zones: clinically-relevant range of concentrations

 Extracellular activity: • all drugs show concentration-dependent bacteridal effects  Intracellular activity: • RIF and MXF show markedly reduced activity • ORI shows a bimodal effect with maximal activity  3 log Nguyen et al., AAC 2009; 53:1434-42 25/04/2013

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FME

Antibiotic combinations against intracellular SCVs

1.25

synergy

1.00

additivity indifference

0.75 0.50

synergistic !

antagonism

0.25

antagonism

antagonism

0.00 0.1

0.3

0.5

0.7

0.9

0.3

0.1

drug A 0.9

0.7

0.5

drug B

additive !

Nguyen et al., AAC 2009; 53:1443-49 25/04/2013

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A pharmacodynamic model to assess antibiotic activity against biofilms biofilm mass

moxifloxacin

crystal violet

120

C25 « rel. potency »

viability resazurin

% control value

100 80

Emax « efficacy »

60 40 20

resorufin

CV RF

0 CT

0.5 1.0 1.5 2.0 2.5 3.0 3.5

log10 concentration (X MIC) Bauer, Siala et al., AAC 2013, Epub, PMID: 23571532 25/04/2013

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Antibiotic activity against biofilms- MRSA 120

120

100

100

80 60 40 20

CT

80 60 40 20

CV RF

0

CT

log10 concentration (X MIC)

moxifloxacin

daptomycin 120

100

100

80 60 40

80 60 40 20

CV

CV RF

RF

0

0 CT

0.5 1.0 1.5 2.0 2.5 3.0 3.5

log10 concentration (X MIC)

120

20

CV RF

0

0.5 1.0 1.5 2.0 2.5 3.0 3.5

% control value

% control value

rifampin

% control value

% control value

vancomycin

0.5 1.0 1.5 2.0 2.5 3.0 3.5

CT

log10 concentration (X MIC)

0.5 1.0 1.5 2.0 2.5 3.0 3.5

log10 concentration (X MIC)

Bauer, Siala et al., AAC 2013; Epub PMID: 23571532 25/04/2013

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Antibiotic activity against biofilms

RIFAMPICIN

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DAPTOMYCIN

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Safety profile

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Main problems associated with antibiotics in bone infections

resistance ?

safety ?

efficacy ?

Thompson & Townsend, Injury, Int. J. Care Injured 42 (2011) S5, S7–S10 25/04/2013

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Perspectives for improvement in the future ?

P. Delvaux

http://ginette-villeneuve.forumactif.com/t5780-un-squelette-age-chausse-ses-lunettes

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Daptomycin • very bactericidal towards Gram (+) organisms through membrane destabilization • spare mammalian cells because they lack phosphatidylglycerol (critical for binding to Gram(+) membranes)

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Daptomycin efficacy in osteomyelitis

Seaton et al., JAC 2013 Epub PMID: 23515247 25/04/2013

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Daptomycin safety in osteomyelitis Creatinine phosphokinase levels

Seaton et al., JAC 2013 Epub PMID: 23515247 25/04/2013

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Lipoglycopeptides • very bactericidal towards Gram (+) organisms through dual mode of action • oritavancin highly active intracellularly and on biofilms

Van Bambeke et al., TIPS 2008; 29:123-34 25/04/2013

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Telavancin efficacy in osteomyelitis A few encouraging case reports ….

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Antibiotic-loaded beads

Campoccia et al., Biomaterials 2010; 31:6363-77 25/04/2013

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Antibiotic-loaded beads

Barth et al., IJAA 2011; 38:371–75 25/04/2013

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Release of antibiotics from spacers and beads

Anagnostakos et al., Acta Orthopaedica 2009; 80: 193–7 25/04/2013

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Antibiotic bone cements Interest in total joint arthroplasty

Engeseater et al., Acta Orthop 2006;77:351-8. 25/04/2013

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Bone cements

Iarikov et al., CID 2012; 55:1474-80 25/04/2013

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Unanswered questions … • Bone concentrations are lower than serum concentrations, but what about PD paramaters (AUC/MIC, T > MIC) ? • Combinations help preventing resistance, but are there really synergistic ? • Specific lifestyles may affect antibiotic efficacy (intracellular, biofilm, SCV), how to act upon these ? • Treatment should be long, any safety concern ?

CURED

This remains the question ! 25/04/2013

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