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Where Do We Stand On

Periprosthetic Joint Infection

• Professor of Orthopaedic Surgery

• Vice chairman for Research

• The Rothman Institute at Thomas

Jefferson University• Interest:

• Regenerative Medicine

•Tissue engineering

•Outcome Research

•Design: Self Protective Smart Implants

• Enjoys Biking, Hiking, Travel, Reading

and Opera

• Contact: www.neareastspine.orgJavad Parvizi , MD, FRCS

http://www.neareastspine.org/

http://www.neareastspine.org/



Where Do We Stand On Periprosthetic

Joint Infection

Javad Parvizi MD

Professor

Rothman Institute at Thomas JeffersonUniversity, Philadelphia

SPINE Meeting, Beirut June 24-26, 2010



Research support:•

NIH• OREF

• DOD

• Aircast

• MTF

• Stryker Orthopaedics• Pfizer

• The Knee Society

• Kimberly Clark

• Ortho McNeill

• Adolor• Cubist

• 3M

• KCI

• Zimmer

• Biomet

Consultant for:

• Stryker Orthopaedics

Intellectual Property:• Smartech

• Smith and Nephew

• Stryker Orthopeadics

• CyruMed

Conflict of Interest




Prevention

Diagnosis

Treatment



Recent Literature

There has been rise in the

incidence of PJI caused byresistant organisms

Parvizi J, et al Instr Course Lecture 2008



Periprosthetic Infection

Major reason for

failure of TKABerry et al CORR 2006




Second most

common reason

for failure of THABozic et al AAHKS 2008



Infection

Incidence 1-4% of primary

lower limb arthroplasties•May occur in up to 30%

after revision arthroplasty



THA Infection: Medicare Data



TKA Infection: Medicare Data



Infected Revisions: 1990-2003

0

1,000

2,000

3,000

4,000

5,000

6,000

1990 1992 1994 1996 1998 2000 2002 2004

N o . o f I n f e c t e d R

e v i s i o n s

Infected THA

Infected TKA

Kurtz, S, Parvizi J JOA 2008



Two Stage Exchange

Success variable

On decline

• Elderly

• Sick

• Immunocompromised

• Surgeon volume

(rule of 80/20)



Deep Infection Rate

1 %



Cost

$100,000 per

infected joint



Annual Cost

$800 Million



But

Incidence of MRSA andother resistantorganisms on

the rise

0

5

10

15

20

25

30

35

40

45

50

1999 2000 2001 2002 2003 2004 2005 2006

P e r c e n t a g e

Sensitive Resistant

Parvizi J, et al Instr Course Lect 2008

MRSA MRSE1999 15% 8%

2006 29% 32%



Media Rubbish



The precise value of minimal inhibitory concentration

(MIC) impacts on the efficacy of vancomycin

0.25 0.5 1 2

MIC

> 50% of theMRSA

strains



C. Salgado

Higher Risk of Failure of Methicillin-resistant Staphylococcus aureus

Prosthetic Joint Infections.

Clinical Orthopaedics and Related Research 2007; 461: 48 – 53

MRSA infections 9.2

times (Odds ratio)more likely to fail



Fehring T, Parvizi J, Barrack R, Hanssen AD

Fate of methicillin resistant infections

Clinical Orthopaedics and Related Research 2009

MRSA infections –

higher failure

70% failure for I&D



New

Antibiotics



• New Glucopeptides: dalbavancin,

telavancin, oritavancin

• New betalactam: ceftobiprole

• New rifamycin: AB-0043

• New inhibitor of DHFR: iclaprim



DAPTOMYCIN

Cyclic lipopeptide

3D structure and Mechanism of actoion is unknown

Gm (+)• MRSA

• VRSA

• VRE• Synergy with Rifampicin and b-lactams

Rand Antim. Agent. Chem. 2004



TIGECYCLINE

1st Glycylcycline

•Minocycline derivative

Structural modificationsBroad-spectrum



TIGECYCLINE

Labthavikul Antim. Agent. Chem. 2003

• 4x better than Vanc against S. epi biofilm

Yin J. Antim. Chemotherap. 2005• Rabbit MRSA Osteomyelitis

• Tigecycline + Rifampicin = 100%

• Tigecyline alone = 90%

•Untreated control = 26%

Minimum data in implant associated infections

Sarah Gander



Sarah Gander

Telavancin: in vitro activity against staphylococci in a

biofilm model

J Antimicrobial Chemother 2005; 56: 337 –343

strain Log reduction strain Log reduction

R O D i h t l



R.O. Darouiche, et al

Dalbavancin compared with vancomycin for prevention of

Staphylococcus aureus colonization of devices in vivo

Journal of Infection 2005; 50:206 –209

No. animals

control

vancomycin

dalbavancin

15

17

9

No. colonized

46.9

53.1

28.1

%

32

32

32

P

0.07

(1)dalbavancin: single pre-operative dose of 10 mg/ Kg

(2)vancomycin: 1 pre-operative dose and 1 dose a day

after surgery of 20 mg/Kg/dose

(3)control group: sterile normal saline.



Dorr MB et al.

Human pharmacokinetics and rationale for once-weekly dosing

of dalbavancin, a semi-synthetic glycopeptide

J Antimicrob Chemother 2005;55 (Suppl2):25-30

0

50

100

150

200

250

300

0 8 14 days

mg/L

Total

free

1000 mg

500 mg

• No adjustment in mild renal dysfunction

• Less-nephrotoxic

• Well-tolerated



Ceftobiprole: the first betalactam with activity against MRSA



Ceftobiprole is a broad-spectrum antibiotic

MIC90 (mg/L)Gram positive microorganisms

staphylococci

methicillin-susceptible

methicillin-resistant

group A streptococci

B-hemolytic streptococci

0.25 - 0.5

2

0.06

≤0.015

Gram negative microorganismsEnterobacteriaceae spp

P. aeruginosa

0.06 – 0.12

8



PBP 41 2 3

JM



Staphylococcus aureus (MSSA)

PBP 1 2 3 4

peptidoglucan

B-lactactam

JM



PBP 1 2 3 4

peptidoglucan

B-lactam

Staphylococcus aureus (MSSA)

JM



PBP 1 2 3 42a

peptidoglucan

B-lactam

Staphylococcus aureus (MRSA)

JM

ceftobiprole



PBP 1 2 3 42a

B-lactam

Staphylococcus aureus (MRSA)

JM

ceftobiprole



Pierre Vaudaux, et al

Intensive Therapy with Ceftobiprole of Experimental

Foreign-Body Infection by MRSA

Antimicrob Agents and Chemother 2005; 49: 3789 –

3793



ABI-0043: a new rifamycin

• Similar efficacy to rifampin in

an animal model of foreign-

body infection due to S. aureus

• No or minimal induction of

liver microsomal enzymes

(cytochrome P-450 system)




Prevention

Diagnosis

Treatment



Diagnosis of Periprosthetic Infection

1994 NIH Consensus

Diagnosis of periprostheticinfection — challenging

Still true



Experimental InvestigationsPolymerase Chain Reaction

Target:

• Segment of the 16S

ribosomal RNA gene unique

to eubacteria

Report:

• Sensitivity 100%

• Specificity 49%

(Mariani & Tuan 1985

Tuan et al JBJS 2008)



Experimental InvestigationsMicroarray

Gene signature

Promising for future Numerous genes----

• Individual

• Time

• Disease

• Type of infection



Ibis 5000: Step 1Sample Prep and Broad Range PCR



Primer Set Mass Base CountBlue 18234.970 A12G17C17T13

Blue 17948.926 A14G14C12T18

Blue 18610.017 A11G19C15T15

Blue 17936.912 A11G17C16T14

Blue 18877.118 A18G15C15T13


Blue 17948.926 A14G14C12T18

Blue 18610.017 A11G19C15T15

Blue 17936.912 A11G17C16T14

Blue 18877.118 A18G15C15T13


Blue 17948.926 A14G14C12T18

Blue 18610.017 A11G19C15T15

Blue 17936.912 A11G17C16T14

Blue 18877.118 A18G15C15T13


Blue 17948.926 A14G14C12T18

Blue 18610.017 A11G19C15T15

Blue 17936.912 A11G17C16T14

Blue 18877.118 A18G15C15T13

Primer #1 Mass Base Count

Blue 18234.970 A12G17C17T13

Blue 17948.926 A14G14C12T18

Blue 18610.017 A11G19C15T15

Blue 17936.912 A11G17C16T14

Blue 18877.118 A18G15C15T13

Ibis Process Part 3: Triangulation UsingMultiple Primer Pairs



Pill S, Parvizi J, Zhuang H, Alavi A. Clin Orthop 2006

Non-specific

Infection



Pregnancy Test for PJI

•Neutrophil enzymes

•Detected in joint aspirate

•1 minute for response

Protected by patent (METHODS AND DEVICES FOR DETECTING PERIPROSTHETIC JOINT INFECTION. Patent Number 29880)

l i l SA



Multiplex ELISA

Macroglobulin a-2

Leucocyte esterase

Leucocyte elastase

IL-8

CRP

Parvizi J, et al AAOS 2010

P i h i J i I f i




Prevention

Diagnosis

Treatment



Two Stage Exchange

COST

•Social

•Psychological

•Economic

R l



Results

“True” success rate (noinfection, no mechanical

failure, no reoperation)----

65%Parvizi et al CORR 2009

RESISTANCE DEVELOPMENT



RESISTANCE DEVELOPMENT

Parham Sendi, et al.



Staphylococcus aureus Small Colony Variants

in Prosthetic Joint Infection

Clin Infect Dis 2006; 43:961-7

Intracellular S. aureus in periprosthetic tissue

Bi fil



Biofilm

Natural barriers (opsonins)

Immunization

• fragments of RNA to elicit cellularimmunity)

• Staph aureus vaccine (University of

Rochester)

P i th ti I f ti




Systemic antibiotics

Local Delivery

Coating

• Sol-gel (Duchane 2006)

• Hydrogel

• Chitosan (Hoggard)

• Silver coating

• Calcium sulfate (Jackson)

• PMMA

Permanent Binding

• ATPS (Parvizi 2004)

• Dansol (Jannsen 2006)

• Poly-ethyle glycol (Anset

CORR 2006)



Passivation

– OH

–

OH – OH

Silanization

O

OO

Si NH2

APTS

OO

HO O

HN

Fmoc

AEEA

2x

Linker

Deprotection – APTS – AEEA – AEEA

OUR SOLUTION

GRAFT ANTIBIOTICS TO TI ALLOY

OO

O

Si NH2

Ti-APTS

Vancomycin

Implant: Ti90Al6V4

Linking: APTS + AEEA

Antibiotic: Vancomycin



B t i id l S f P t



Bactericidal Surface-Permanent

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

AntibioticAntibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic



Vancomycin-Modified Ti6Al4V Inhibits

Biofilm Formation

Investigations



Investigations

Does It Work

in-vivo?

Animal Experiments



Animal Experiments

SURGICAL X-RAYS



Animal Model: micro CT



Animal Model: micro-CT



Animal Experiments: Micro CT

7L 7R

10D, 107 CFU INJECTED IN 150 MCL

Animal Model: Microbiology



Animal Model: Microbiology

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